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Zheng Y, Bai B, Wei Z, Zhang M, Zhang Q, Li X. Plasma Exosomal-Derived SERPINA1 and GNAI2 Downregulation as Potential Diagnostic Biomarkers of Kawasaki Disease with Coronary Artery Aneurysms. Int J Mol Sci 2025; 26:2668. [PMID: 40141310 PMCID: PMC11942354 DOI: 10.3390/ijms26062668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 03/28/2025] Open
Abstract
Kawasaki disease (KD) with coronary artery aneurysms (CAAs) is currently the primary cause of childhood acquired heart disease with an unclear pathogenesis. We established five groups for the discovery of differentially expressed proteins (DEPs): healthy control, febrile control, KD without CAAs, KD with small and medium CAAs, and KD with giant CAAs (n = 8 in each group). The validation of selected DEPs was conducted in another five groups (n = 4 in each group). We conducted comprehensive bioinformatics analyses to elucidate the functional roles of the DEPs in the groups of KD with CAAs and KD without CAAs. A total of 104 DEPs were identified in KD patients, which were primarily associated with complement-related pathways. A trend analysis of these 104 DEPs revealed 54 significantly changed DEPs associated with increased disease severity, which were primarily associated with G-protein-related functions. The alterations in α-1-antitrypsin short peptide (SERPINA1) and guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2), which were selected from complement-related and G-protein-related pathways, respectively, were validated by Western blotting, and they were significantly decreased in KD patients with vs. without CAAs. In addition, we conducted an analysis of the DEPs in the groups of KD with CAAs and KD without CAAs, separately. There were 91 DEPs specifically expressed in KD patients with CAAs, associated with the neutrophil extracellular trap and complement pathways, while 16 DEPs were specific to those without CAAs, associated with viral infection and immunity pathways. Additionally, for DEPs among different severities of CAAs, there were 102 DEPs in KD patients with small and medium CAAs, associated with complement pathways and platelet activation pathways, whereas 34 DEPs were specific to giant CAAs, associated with the Rap1 signaling pathway and cell functions. In conclusion, this study provides plasmatic exosomal protein profiles in KD patients with CAAs, suggesting that SERPINA1 and GNIA2 might serve as novel potential diagnostic biomarkers for KD with CAAs.
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Affiliation(s)
- Yang Zheng
- Department of Cardiovascular Medicine, Children’s Hospital Capital Institute of Pediatrics, Peking Union Medical College Graduate School, Beijing 100020, China;
| | - Baoling Bai
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China;
| | - Zhimiao Wei
- Department of Cardiovascular Medicine, Children’s Hospital Capital Institute of Pediatrics, Beijing 100020, China; (Z.W.); (M.Z.)
| | - Mingming Zhang
- Department of Cardiovascular Medicine, Children’s Hospital Capital Institute of Pediatrics, Beijing 100020, China; (Z.W.); (M.Z.)
| | - Qin Zhang
- Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China;
| | - Xiaohui Li
- Department of Cardiovascular Medicine, Children’s Hospital Capital Institute of Pediatrics, Peking Union Medical College Graduate School, Beijing 100020, China;
- Department of Cardiovascular Medicine, Children’s Hospital Capital Institute of Pediatrics, Beijing 100020, China; (Z.W.); (M.Z.)
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Dong XQ, Zhang YH, Luo J, Li MJ, Ma LQ, Qi YT, Miao YL. Keratin 1 modulates intestinal barrier and immune response via kallikrein kinin system in ulcerative colitis. World J Gastroenterol 2025; 31:102070. [PMID: 39958441 PMCID: PMC11752705 DOI: 10.3748/wjg.v31.i6.102070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 12/06/2024] [Accepted: 12/19/2024] [Indexed: 01/10/2025] Open
Abstract
BACKGROUND External factors in ulcerative colitis (UC) exacerbate colonic epithelial permeability and inflammatory responses. Keratin 1 (KRT1) is crucial in regulating these alterations, but its specific role in the progression of UC remains to be fully elucidated. AIM To explore the role and mechanisms of KRT1 in the regulation of colonic epithelial permeability and inflammation in UC. METHODS A KRT1 antibody concentration gradient test, along with a dextran sulfate sodium (DSS)-induced animal model, was implemented to investigate the role of KRT1 in modulating the activation of the kallikrein kinin system (KKS) and the cleavage of bradykinin (BK)/high molecular weight kininogen (HK) in UC. RESULTS Treatment with KRT1 antibody in Caco-2 cells suppressed cell proliferation, induced apoptosis, reduced HK expression, and increased BK expression. It further downregulated intestinal barrier proteins, including occludin, zonula occludens-1, and claudin, and negatively impacted the coagulation factor XII. These changes led to enhanced activation of BK and HK cleavage, thereby intensifying KKS-mediated inflammation in UC. In the DSS-induced mouse model, administration of KRT1 antibody mitigated colonic injury, increased colon length, alleviated weight loss, and suppressed inflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-α. It also facilitated repair of the intestinal barrier, reducing DSS-induced injury. CONCLUSION KRT1 inhibits BK expression, suppresses inflammatory cytokines, and enhances markers of intestinal barrier function, thus ameliorating colonic damage and maintaining barrier integrity. KRT1 is a viable therapeutic target for UC.
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Affiliation(s)
- Xiang-Qian Dong
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Ying-Hui Zhang
- Department of Gastroenterology, Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan Province, China
| | - Juan Luo
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Mao-Juan Li
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Lan-Qing Ma
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Ya-Ting Qi
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
| | - Ying-Lei Miao
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Province Clinical Research Center for Digestive Diseases, Kunming 650032, Yunnan Province, China
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Gong F, Zheng X, Zhao S, Liu H, Chen E, Xie R, Li R, Chen Y. Disseminated intravascular coagulation: cause, molecular mechanism, diagnosis, and therapy. MedComm (Beijing) 2025; 6:e70058. [PMID: 39822757 PMCID: PMC11733103 DOI: 10.1002/mco2.70058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 12/12/2024] [Accepted: 12/13/2024] [Indexed: 01/19/2025] Open
Abstract
Disseminated intravascular coagulation (DIC) is a complex and serious condition characterized by widespread activation of the coagulation cascade, resulting in both thrombosis and bleeding. This review aims to provide a comprehensive overview of DIC, emphasizing its clinical significance and the need for improved management strategies. We explore the primary causes of DIC, including sepsis, trauma, malignancies, and obstetric complications, which trigger an overactive coagulation response. At the molecular level, DIC is marked by excessive thrombin generation, leading to platelet and fibrinogen activation while simultaneously depleting clotting factors, creating a paradoxical bleeding tendency. Diagnosing DIC is challenging and relies on a combination of existing diagnostic criteria and laboratory tests. Treatment strategies focus on addressing the underlying causes and may involve supportive care, anticoagulation therapy, and other supportive measures. Recent advances in understanding the pathophysiology of DIC are paving the way for more targeted therapeutic approaches. This review highlights the critical need for ongoing research to enhance diagnostic accuracy and treatment efficacy, ultimately improving patient outcomes in those affected by DIC.
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Affiliation(s)
- Fangchen Gong
- Department of EmergencyRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xiangtao Zheng
- Department of EmergencyRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Shanzhi Zhao
- Department of EmergencyRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Huan Liu
- Department of EmergencyRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Erzhen Chen
- Department of EmergencyRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Institute of Aviation Medicine, Shanghai Jiao Tong University Medical School Affiliated Ruijin HospitalShanghaiChina
| | - Rongli Xie
- Department of General SurgeryRuijin Hospital Lu Wan Branch, Shanghai Jiaotong University School of MedicineShanghaiChina
| | - Ranran Li
- Department of Critical Care MedicineRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Ying Chen
- Department of EmergencyRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
- Department of Emergency and Critical Care MedicineRuijin Hospital Wuxi Branch, Shanghai Jiao Tong University School of MedicineWuxiChina
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Ricklin D. Complement-targeted therapeutics: Are we there yet, or just getting started? Eur J Immunol 2024; 54:e2350816. [PMID: 39263829 PMCID: PMC11628912 DOI: 10.1002/eji.202350816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 08/31/2024] [Accepted: 09/02/2024] [Indexed: 09/13/2024]
Abstract
Therapeutic interventions in the complement system, a key immune-inflammatory mediator and contributor to a broad range of clinical conditions, have long been considered important yet challenging or even unfeasible to achieve. Almost 20 years ago, a spark was lit demonstrating the clinical and commercial viability of complement-targeted therapies. Since then, the field has experienced an impressive expansion of targeted indications and available treatment modalities. Currently, a dozen distinct complement-specific therapeutics covering several intervention points are available in the clinic, benefiting patients suffering from eight disorders, not counting numerous clinical trials and off-label uses. Observing this rapid rise of complement-targeted therapy from obscurity to mainstream with amazement, one might ask whether the peak of this development has now been reached or whether the field will continue marching on to new heights. This review looks at the milestones of complement drug discovery and development achieved so far, surveys the currently approved drug entities and indications, and ventures a glimpse into the future advancements yet to come.
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Affiliation(s)
- Daniel Ricklin
- Molecular Pharmacy Group, Department of Pharmaceutical SciencesUniversity of BaselBaselSwitzerland
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5
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Witzdam L, White T, Rodriguez-Emmenegger C. Steps Toward Recapitulating Endothelium: A Perspective on the Next Generation of Hemocompatible Coatings. Macromol Biosci 2024; 24:e2400152. [PMID: 39072925 DOI: 10.1002/mabi.202400152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 06/26/2024] [Indexed: 07/30/2024]
Abstract
Endothelium, the lining in this blood vessel, orchestrates three main critical functions such as protecting blood components, modulating of hemostasis by secreting various inhibitors, and directing clot digestion (fibrinolysis) by activating tissue plasminogen activator. No other surface can perform these tasks; thus, the contact of blood and blood-contacting medical devices inevitably leads to the activation of coagulation, often causing device failure, and thromboembolic complications. This perspective, first, discusses the biological mechanisms of activation of coagulation and highlights the efforts of advanced coatings to recapitulate one characteristic of endothelium, hereafter single functions of endothelium and noting necessity of the synergistic integration of its three main functions. Subsequently, it is emphasized that to overcome the challenges of blood compatibility an endothelium-mimicking system is needed, proposing a synergy of bottom-up synthetic biology, particularly synthetic cells, with passive- and bioactive surface coatings. Such integration holds promise for developing advanced biomaterials capable of recapitulating endothelial functions, thereby enhancing the hemocompatibility and performance of blood-contacting medical devices.
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Affiliation(s)
- Lena Witzdam
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Carrer de Baldiri Reixac, 10, 12, Barcelona, 08028, Spain
- DWI - Leibniz Institute for Interactive Materials, Forckenbeckstraße 50, 52074, Aachen, Germany
- Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, Worringerweg 2, 52074, Aachen, Germany
| | - Tom White
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Carrer de Baldiri Reixac, 10, 12, Barcelona, 08028, Spain
| | - Cesar Rodriguez-Emmenegger
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Carrer de Baldiri Reixac, 10, 12, Barcelona, 08028, Spain
- DWI - Leibniz Institute for Interactive Materials, Forckenbeckstraße 50, 52074, Aachen, Germany
- Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, Barcelona, 08010, Spain
- Biomedical Research Networking, Center in Bioengineering, Biomaterials and Nanomedicine, The Institute of Health Carlos III, Madrid, 28029, Spain
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He Q, Wei Y, Qian Y, Zhong M. Pathophysiological dynamics in the contact, coagulation, and complement systems during sepsis: Potential targets for nafamostat mesilate. JOURNAL OF INTENSIVE MEDICINE 2024; 4:453-467. [PMID: 39310056 PMCID: PMC11411436 DOI: 10.1016/j.jointm.2024.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 01/17/2024] [Accepted: 02/07/2024] [Indexed: 09/25/2024]
Abstract
Sepsis is a life-threatening syndrome resulting from a dysregulated host response to infection. It is the primary cause of death in the intensive care unit, posing a substantial challenge to human health and medical resource allocation. The pathogenesis and pathophysiology of sepsis are complex. During its onset, pro-inflammatory and anti-inflammatory mechanisms engage in intricate interactions, possibly leading to hyperinflammation, immunosuppression, and long-term immune disease. Of all critical outcomes, hyperinflammation is the main cause of early death among patients with sepsis. Therefore, early suppression of hyperinflammation may improve the prognosis of these patients. Nafamostat mesilate is a serine protease inhibitor, which can inhibit the activation of the complement system, coagulation system, and contact system. In this review, we discuss the pathophysiological changes occurring in these systems during sepsis, and describe the possible targets of the serine protease inhibitor nafamostat mesilate in the treatment of this condition.
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Affiliation(s)
- Qiaolan He
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yilin Wei
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yiqi Qian
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ming Zhong
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Lung Inflammation and Injury, Shanghai, China
- Shanghai Institute of Infectious Disease and Biosecurity, School of Public Health, Fudan University, Shanghai, China
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7
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Hou M, Wu J, Li J, Zhang M, Yin H, Chen J, Jin Z, Dong R. Immunothrombosis: A bibliometric analysis from 2003 to 2023. Medicine (Baltimore) 2024; 103:e39566. [PMID: 39287275 PMCID: PMC11404911 DOI: 10.1097/md.0000000000039566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 08/10/2024] [Accepted: 08/14/2024] [Indexed: 09/19/2024] Open
Abstract
BACKGROUND Immunothrombosis is a physiological process that constitutes an intravascular innate immune response. Abnormal immunothrombosis can lead to thrombotic disorders. With the outbreak of COVID-19, there is increasing attention to the mechanisms of immunothrombosis and its critical role in thrombotic events, and a growing number of relevant research papers are emerging. This article employs bibliometrics to discuss the current status, hotspots, and trends in research of this field. METHODS Research papers relevant to immunothrombosis published from January 1, 2003, to May 29, 2023, were collected from the Web of Science Core Collection database. VOSviewer and the R package "Bibliometrix" were employed to analyze publication metrics, including the number of publications, authors, countries, institutions, journals, and keywords. The analysis generated visual results, and trends in research topics and hotspots were examined. RESULTS A total of 495 target papers were identified, originating from 58 countries and involving 3287 authors from 1011 research institutions. Eighty high-frequency keywords were classified into 5 clusters. The current key research topics in the field of immunothrombosis include platelets, inflammation, neutrophil extracellular traps, Von Willebrand factor, and the complement system. Research hotspots focus on the mechanisms and manifestations of immunothrombosis in COVID-19, as well as the discovery of novel treatment strategies targeting immunothrombosis in cardiovascular and cerebrovascular diseases. CONCLUSION Bibliometric analysis summarizes the main achievements and development trends in research on immunothrombosis, offering readers a comprehensive understanding of the field and guiding future research directions.
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Affiliation(s)
- Mengyu Hou
- Department of Research Ward, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jingxuan Wu
- Department of Research Ward, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jiangshuo Li
- Department of Research Ward, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Meijuan Zhang
- Department of Research Ward, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hang Yin
- Department of Research Ward, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jingcheng Chen
- Department of Research Ward, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhili Jin
- Department of Research Ward, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ruihua Dong
- Department of Research Ward, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Heeger PS, Haro MC, Jordan S. Translating B cell immunology to the treatment of antibody-mediated allograft rejection. Nat Rev Nephrol 2024; 20:218-232. [PMID: 38168662 DOI: 10.1038/s41581-023-00791-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/10/2023] [Indexed: 01/05/2024]
Abstract
Antibody-mediated rejection (AMR), including chronic AMR (cAMR), causes ~50% of kidney allograft losses each year. Despite attempts to develop well-tolerated and effective therapeutics for the management of AMR, to date, none has obtained FDA approval, thereby highlighting an urgent unmet medical need. Discoveries over the past decade from basic, translational and clinical studies of transplant recipients have provided a foundation for developing novel therapeutic approaches to preventing and treating AMR and cAMR. These interventions are aimed at reducing donor-specific antibody levels, decreasing graft injury and fibrosis, and preserving kidney function. Innovative approaches emerging from basic science findings include targeting interactions between alloreactive T cells and B cells, and depleting alloreactive memory B cells, as well as donor-specific antibody-producing plasmablasts and plasma cells. Therapies aimed at reducing the cytotoxic antibody effector functions mediated by natural killer cells and the complement system, and their associated pro-inflammatory cytokines, are also undergoing evaluation. The complexity of the pathogenesis of AMR and cAMR suggest that multiple approaches will probably be required to treat these disease processes effectively. Definitive answers await results from large, double-blind, multicentre, randomized controlled clinical trials.
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Affiliation(s)
- Peter S Heeger
- Comprehensive Transplant Center, Department of Medicine, Division of Nephrology Cedars-Sinai Medical Center Los Angeles, Los Angeles, CA, USA
| | - Maria Carrera Haro
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, Mount Sinai, NY, USA
| | - Stanley Jordan
- Comprehensive Transplant Center, Department of Medicine, Division of Nephrology Cedars-Sinai Medical Center Los Angeles, Los Angeles, CA, USA.
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Kirschfink M, Frazer-Abel A, Balogh E, Goseberg S, Weiss N, Prohászka Z. External quality assurance program for diagnostic complement laboratories: evaluation of the results of the past seven years. Front Immunol 2024; 15:1368399. [PMID: 38596685 PMCID: PMC11002221 DOI: 10.3389/fimmu.2024.1368399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 03/07/2024] [Indexed: 04/11/2024] Open
Abstract
Introduction The complement external quality assurance (EQA) program was first organized in 2010 by a group of researchers working in diagnostic complement laboratories. Starting in 2016, INSTAND e.V., a German, non-profit interdisciplinary scientific medical society dedicated to providing expert EQA programs for medical laboratories, started organizing the EQAs for complement diagnostic laboratories together with the same group of experienced scientists and doctors who also work as EQA experts. The aim of the current work is to provide descriptive analysis of the past seven years' complement EQA results and evaluate timeline changes in proficiency testing. Methods Each year, in March and October, blinded samples (normal, pathological) were sent to the participating diagnostic laboratories, where complement parameters were evaluated exactly as in daily routine samples. Since no reference method/target values exist for these parameters, and participants used different units for measurement, the reported results were compared to the stable mean (Algorithm A) of the participants using the same method/measurement units. A reported result was qualified as "passed" if it fell into the 30-50% evaluation/target range around the mean of reported results (depending on the given parameter). Results While the number of participating laboratories has increased in the past years (from around 120 to 347), the number of complement laboratories providing multiple determinations remained mostly unchanged (around 30 worldwide). C3, C4, C1-inhibitor antigen and activity determinations provided the best proficiency results, with >90% passing quotas in the past years, independent of the applied method. Determination of the functional activity of the three activation pathways was good in general, but results showed large variance, especially with the pathological samples. Complement factor C1q and regulators FH and FI are determined by only a few laboratories, with variable outcomes (in general in the 85-90% pass range). Activation products sC5b-9 and Bb were determined in 30 and 10 laboratories, respectively, with typical passing quotas in the 70-90% range, without a clear tendency over the past years. Conclusion With these accumulated data from the past seven years, it is now possible to assess sample-, method-, and evaluation related aspects to further improve proficiency testing and protocolize diagnostic complement determinations.
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Affiliation(s)
- Michael Kirschfink
- Institute of Immunology, University of Heidelberg, Heidelberg, Germany
- Instand eV, Düsseldorf, Germany
| | | | - Emese Balogh
- Department of Pharmaceutics, Semmelweis University, Budapest, Hungary
| | | | | | - Zoltán Prohászka
- Instand eV, Düsseldorf, Germany
- Department of Internal Medicine and Hematology, Füst György Complement Diagnostic Laboratory, Semmelweis University, Budapest, Hungary
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Poblete RA, Zhong C, Patel A, Kuo G, Sun PY, Xiao J, Fan Z, Sanossian N, Towfighi A, Lyden PD. Post-Traumatic Cerebral Infarction: A Narrative Review of Pathophysiology, Diagnosis, and Treatment. Neurol Int 2024; 16:95-112. [PMID: 38251054 PMCID: PMC10801491 DOI: 10.3390/neurolint16010006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 12/22/2023] [Accepted: 01/03/2024] [Indexed: 01/23/2024] Open
Abstract
Traumatic brain injury (TBI) is a common diagnosis requiring acute hospitalization. Long-term, TBI is a significant source of health and socioeconomic impact in the United States and globally. The goal of clinicians who manage TBI is to prevent secondary brain injury. In this population, post-traumatic cerebral infarction (PTCI) acutely after TBI is an important but under-recognized complication that is associated with negative functional outcomes. In this comprehensive review, we describe the incidence and pathophysiology of PTCI. We then discuss the diagnostic and treatment approaches for the most common etiologies of isolated PTCI, including brain herniation syndromes, cervical artery dissection, venous thrombosis, and post-traumatic vasospasm. In addition to these mechanisms, hypercoagulability and microcirculatory failure can also exacerbate ischemia. We aim to highlight the importance of this condition and future clinical research needs with the goal of improving patient outcomes after TBI.
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Affiliation(s)
- Roy A. Poblete
- Keck School of Medicine, The University of Southern California, Los Angeles, CA 90033, USA; (C.Z.); (A.P.); (G.K.); (J.X.); (Z.F.); (N.S.); (A.T.); (P.D.L.)
| | - Charlotte Zhong
- Keck School of Medicine, The University of Southern California, Los Angeles, CA 90033, USA; (C.Z.); (A.P.); (G.K.); (J.X.); (Z.F.); (N.S.); (A.T.); (P.D.L.)
| | - Anish Patel
- Keck School of Medicine, The University of Southern California, Los Angeles, CA 90033, USA; (C.Z.); (A.P.); (G.K.); (J.X.); (Z.F.); (N.S.); (A.T.); (P.D.L.)
| | - Grace Kuo
- Keck School of Medicine, The University of Southern California, Los Angeles, CA 90033, USA; (C.Z.); (A.P.); (G.K.); (J.X.); (Z.F.); (N.S.); (A.T.); (P.D.L.)
| | - Philip Y. Sun
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA;
| | - Jiayu Xiao
- Keck School of Medicine, The University of Southern California, Los Angeles, CA 90033, USA; (C.Z.); (A.P.); (G.K.); (J.X.); (Z.F.); (N.S.); (A.T.); (P.D.L.)
| | - Zhaoyang Fan
- Keck School of Medicine, The University of Southern California, Los Angeles, CA 90033, USA; (C.Z.); (A.P.); (G.K.); (J.X.); (Z.F.); (N.S.); (A.T.); (P.D.L.)
| | - Nerses Sanossian
- Keck School of Medicine, The University of Southern California, Los Angeles, CA 90033, USA; (C.Z.); (A.P.); (G.K.); (J.X.); (Z.F.); (N.S.); (A.T.); (P.D.L.)
| | - Amytis Towfighi
- Keck School of Medicine, The University of Southern California, Los Angeles, CA 90033, USA; (C.Z.); (A.P.); (G.K.); (J.X.); (Z.F.); (N.S.); (A.T.); (P.D.L.)
| | - Patrick D. Lyden
- Keck School of Medicine, The University of Southern California, Los Angeles, CA 90033, USA; (C.Z.); (A.P.); (G.K.); (J.X.); (Z.F.); (N.S.); (A.T.); (P.D.L.)
- Zilkha Neurogenetic Institute, Keck School of Medicine, The University of Southern California, Los Angeles, CA 90033, USA
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11
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Zhang Y, Wang L, Kuang X, Tang D, Zhang P. Diagnostic and Prognostic Value of C1q in Sepsis-Induced Coagulopathy. Clin Appl Thromb Hemost 2024; 30:10760296241257517. [PMID: 38778544 PMCID: PMC11113060 DOI: 10.1177/10760296241257517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/27/2024] [Accepted: 05/10/2024] [Indexed: 05/25/2024] Open
Abstract
Early identification of biomarkers that can predict the onset of sepsis-induced coagulopathy (SIC) in septic patients is clinically important. This study endeavors to examine the diagnostic and prognostic utility of serum C1q in the context of SIC. Clinical data from 279 patients diagnosed with sepsis at the Departments of Intensive Care, Respiratory Intensive Care, and Infectious Diseases at the Renmin Hospital of Wuhan University were gathered spanning from January 2022 to January 2024. These patients were categorized into two groups: the SIC group comprising 108 cases and the non-SIC group consisting of 171 cases, based on the presence of SIC. Within the SIC group, patients were further subdivided into a survival group (43 cases) and non-survival group (65 cases). The concentration of serum C1q in the SIC group was significantly lower than that in the non-SIC group. Furthermore, A significant correlation was observed between serum C1q levels and both SIC score and coagulation indices. C1q demonstrated superior diagnostic and prognostic performance for SIC patients, as indicated by a higher area under the curve (AUC). Notably, when combined with CRP, PCT, and SOFA score, C1q displayed the most robust diagnostic efficacy for SIC. Moreover, the combination of C1q with the SOFA score heightened predictive value concerning the 28-day mortality of SIC patients.
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Affiliation(s)
- Ye Zhang
- Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan, PR China
| | - Li Wang
- Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan, PR China
| | - Xiandong Kuang
- Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan, PR China
| | - Dongling Tang
- Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan, PR China
| | - Pingan Zhang
- Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan, PR China
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Rydenfelt K, Kjøsen G, Horneland R, Krey Ludviksen J, Jenssen TG, Line PD, Tønnessen TI, Mollnes TE, Haugaa H, Pischke SE. Local Postoperative Graft Inflammation in Pancreas Transplant Patients With Early Graft Thrombosis. Transplant Direct 2024; 10:e1567. [PMID: 38094132 PMCID: PMC10715763 DOI: 10.1097/txd.0000000000001567] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/18/2023] [Accepted: 10/07/2023] [Indexed: 02/11/2025] Open
Abstract
BACKGROUND Graft thrombosis is the main cause of early graft loss following pancreas transplantation, and is more frequent in pancreas transplant alone (PTA) compared with simultaneous pancreas-kidney (SPK) recipients. Ischemia-reperfusion injury during transplantation triggers a local thromboinflammatory response. We aimed to evaluate local graft inflammation and its potential association with early graft thrombosis. METHODS In this observational study, we monitored 67 pancreas-transplanted patients using microdialysis catheters placed on the pancreatic surface during the first postoperative week. We analyzed 6 cytokines, interleukin-1 receptor antagonist (IL-1ra), IL-6, IL-8, interferon gamma-induced protein 10 (IP-10), macrophage inflammatory protein 1β (MIP-1β), IL-10, and the complement activation product complement activation product 5a (C5a) in microdialysis fluid. We compared the dynamic courses between patients with pancreas graft thrombosis and patients without early complications (event-free) and between PTA and SPK recipients. Levels of the local inflammatory markers, and plasma markers C-reactive protein, pancreas amylase, and lipase were evaluated on the day of thrombosis diagnosis compared with the first week in event-free patients. RESULTS IL-10 and C5a were not detectable. Patients with no early complications (n = 34) demonstrated high IL-1ra, IL-6, IL-8, IP-10, and MIP-1β concentrations immediately after surgery, which decreased to steady low levels during the first 2 postoperative days (PODs). Patients with early graft thrombosis (n = 17) demonstrated elevated IL-6 (P = 0.003) concentrations from POD 1 and elevated IL-8 (P = 0.027) concentrations from POD 2 and throughout the first postoperative week compared with patients without complications. IL-6 (P < 0.001) and IL-8 (P = 0.003) were higher on the day of thrombosis diagnosis compared with patients without early complications. No differences between PTA (n = 35) and SPK (n = 32) recipients were detected. CONCLUSIONS Local pancreas graft inflammation was increased in patients experiencing graft thrombosis, with elevated postoperative IL-6 and IL-8 concentrations, but did not differ between PTA and SPK recipients. Investigating the relationship between the local cytokine response and the formation of graft thrombosis warrants further research.
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Affiliation(s)
- Kristina Rydenfelt
- Division of Emergencies and Critical Care, Department of Anesthesia and Intensive Care Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Gisle Kjøsen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Division of Emergencies and Critical Care, Department of Research and Development, Oslo University Hospital, Oslo, Norway
| | - Rune Horneland
- Department of Transplantation Medicine, Section of Transplantation Surgery, Oslo University Hospital, Oslo, Norway
| | | | - Trond Geir Jenssen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Transplantation Medicine, Section of Nephrology, Oslo University Hospital, Oslo, Norway
| | - Pål-Dag Line
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Transplantation Medicine, Section of Transplantation Surgery, Oslo University Hospital, Oslo, Norway
| | - Tor Inge Tønnessen
- Division of Emergencies and Critical Care, Department of Anesthesia and Intensive Care Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Tom Eirik Mollnes
- Research Laboratory, Nordland Hospital, Bodø, Norway
- Department of Immunology, Oslo University Hospital and University of Oslo, Oslo, Norway
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway
| | - Håkon Haugaa
- Division of Emergencies and Critical Care, Department of Anesthesia and Intensive Care Medicine, Oslo University Hospital, Oslo, Norway
- Division of Emergencies and Critical Care, Department of Research and Development, Oslo University Hospital, Oslo, Norway
- Department of Intensive Care Nursing, Lovisenberg University College, Oslo, Norway
| | - Søren Erik Pischke
- Division of Emergencies and Critical Care, Department of Anesthesia and Intensive Care Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Immunology, Oslo University Hospital and University of Oslo, Oslo, Norway
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Lu C, Luo ZF, Tang D, Zheng F, Li S, Liu S, Qiu J, Liu F, Dai Y, Sui WG, Yan Q. Proteomic analysis of glomeruli, tubules and renal interstitium in idiopathic membranous nephropathy (IMN): A statistically observational study. Medicine (Baltimore) 2023; 102:e36476. [PMID: 38115247 PMCID: PMC10727647 DOI: 10.1097/md.0000000000036476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 10/03/2023] [Accepted: 11/14/2023] [Indexed: 12/21/2023] Open
Abstract
Idiopathic membranous nephropathy (IMN) is a common type of primary glomerulonephritis, which pathogenesis are highly involved protein and immune regulation. Therefore, we investigated protein expression in different microregions of the IMN kidney tissue. We used laser capture microdissection and mass spectrometry to identify the proteins in the kidney tissue. Using MSstats software to identify the differently expressed protein (DEP). Gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were used to predict and enrich the potential functions of the DEPs, and DEPs were compared to the Public data in the gene expression omnibus (GEO) database for screening biomarkers of IMN. Immune infiltration analysis was used to analyze the immune proportion in IMN. Three significantly up-regulated proteins were identified in the glomeruli of patients with IMN; 9 significantly up-regulated and 6 significantly down-regulated proteins were identified in the interstitium of patients with IMN. Gene ontology analysis showed that the DEPs in the glomerulus and interstitium were mostly enriched in "biological regulation, the immune system, and metabolic processes." Kyoto Encyclopedia of Genes and Genomes analysis showed that the DEPs in the glomerulus and interstitium were mostly enriched in the "immune system" and the "complement and coagulation cascades. " According to the public information of the GEO database, DEPs in our study, Coatomer subunit delta Archain 1, Laminin subunit alpha-5, and Galectin-1 were highly expressed in the IMN samples from the GEO database; in the immune infiltration analysis, the proportion of resting memory CD4 T cells and activated NK cells in IMN were significantly higher than in the normal group. This study confirmed that there were significant differences in protein expression in different micro-regions of patients with IMN, The protein Coatomer subunit delta Archain 1, Laminin subunit alpha 5, Galectin-1 are potential biomarkers of IMN, the memory T cells CD4 and NK cells, maybe involved in the immunologic mechanism in the development of IMN.
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Affiliation(s)
- Chang Lu
- The Organ Transplantation Department of No.924 Hospital of PLA Joint Logistic Support Force, Medical quality specialty of the Joint Logistic Support Force, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin, Guangxi, P.R. China
| | - Zhi-Feng Luo
- The Organ Transplantation Department of No.924 Hospital of PLA Joint Logistic Support Force, Medical quality specialty of the Joint Logistic Support Force, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin, Guangxi, P.R. China
- The Second Department of Urology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, P.R. China
| | - Donge Tang
- The Organ Transplantation Department of No.924 Hospital of PLA Joint Logistic Support Force, Medical quality specialty of the Joint Logistic Support Force, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin, Guangxi, P.R. China
- Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen Engineering Research Center of Autoimmune Disease, The Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen, Guangdong, P.R. China
| | - Fengping Zheng
- The Organ Transplantation Department of No.924 Hospital of PLA Joint Logistic Support Force, Medical quality specialty of the Joint Logistic Support Force, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin, Guangxi, P.R. China
| | - Shanshan Li
- The Organ Transplantation Department of No.924 Hospital of PLA Joint Logistic Support Force, Medical quality specialty of the Joint Logistic Support Force, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin, Guangxi, P.R. China
| | - Shizhen Liu
- Institute of Nephrology and Blood Purification, the First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, P.R. China
| | - Jing Qiu
- The Organ Transplantation Department of No.924 Hospital of PLA Joint Logistic Support Force, Medical quality specialty of the Joint Logistic Support Force, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin, Guangxi, P.R. China
| | - Fanna Liu
- Institute of Nephrology and Blood Purification, the First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, P.R. China
| | - Yong Dai
- The Organ Transplantation Department of No.924 Hospital of PLA Joint Logistic Support Force, Medical quality specialty of the Joint Logistic Support Force, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin, Guangxi, P.R. China
- Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen Engineering Research Center of Autoimmune Disease, The Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen, Guangdong, P.R. China
| | - Wei-Guo Sui
- The Second Department of Urology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, P.R. China
| | - Qiang Yan
- Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen Engineering Research Center of Autoimmune Disease, The Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen, Guangdong, P.R. China
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Padilla S, Prado R, Anitua E. An evolutionary history of F12 gene: Emergence, loss, and vulnerability with the environment as a driver. Bioessays 2023; 45:e2300077. [PMID: 37750435 DOI: 10.1002/bies.202300077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 09/08/2023] [Accepted: 09/14/2023] [Indexed: 09/27/2023]
Abstract
In the context of macroevolutionary transitions, environmental changes prompted vertebrates already bearing genetic variations to undergo gradual adaptations resulting in profound anatomical, physiological, and behavioral adaptations. The emergence of new genes led to the genetic variation essential in metazoan evolution, just as was gene loss, both sources of genetic variation resulting in adaptive phenotypic diversity. In this context, F12-coding protein with defense and hemostatic roles emerged some 425 Mya, and it might have contributed in aquatic vertebrates to the transition from water-to-land. Conversely, the F12 loss in marine, air-breathing mammals like cetaceans has been associated with phenotypic adaptations in some terrestrial mammals in their transition to aquatic lifestyle. More recently, the advent of technological innovations in western lifestyle with blood-contacting devices and harmful environmental nanoparticles, has unfolded new roles of FXII. Environment operates as either a positive or a relaxed selective pressure on genes, and consequently genes are selected or lost. FXII, an old dog facing environmental novelties can learn new tricks and teach us new therapeutic avenues.
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Affiliation(s)
- Sabino Padilla
- BTI-Biotechnology Institute ImasD, Vitoria, Spain
- Eduardo Anitua Foundation for Biomedical Research, Vitoria, Spain
- University Institute for Regenerative Medicine & Oral Implantology - UIRMI (UPV/EHU-Fundación Eduardo Anitua), Vitoria, Spain
| | - Roberto Prado
- BTI-Biotechnology Institute ImasD, Vitoria, Spain
- Eduardo Anitua Foundation for Biomedical Research, Vitoria, Spain
- University Institute for Regenerative Medicine & Oral Implantology - UIRMI (UPV/EHU-Fundación Eduardo Anitua), Vitoria, Spain
| | - Eduardo Anitua
- BTI-Biotechnology Institute ImasD, Vitoria, Spain
- Eduardo Anitua Foundation for Biomedical Research, Vitoria, Spain
- University Institute for Regenerative Medicine & Oral Implantology - UIRMI (UPV/EHU-Fundación Eduardo Anitua), Vitoria, Spain
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Dudler T, Yaseen S, Cummings WJ. Development and characterization of narsoplimab, a selective MASP-2 inhibitor, for the treatment of lectin-pathway-mediated disorders. Front Immunol 2023; 14:1297352. [PMID: 38022610 PMCID: PMC10663225 DOI: 10.3389/fimmu.2023.1297352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 10/25/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction Overactivation of the lectin pathway of complement plays a pathogenic role in a broad range of immune-mediated and inflammatory disorders; mannan-binding lectin-associated serine protease-2 (MASP-2) is the key effector enzyme of the lectin pathway. We developed a fully human monoclonal antibody, narsoplimab, to bind to MASP-2 and specifically inhibit lectin pathway activation. Herein, we describe the preclinical characterization of narsoplimab that supports its evaluation in clinical trials. Methods and results ELISA binding studies demonstrated that narsoplimab interacted with both zymogen and enzymatically active forms of human MASP-2 with high affinity (KD 0.062 and 0.089 nM, respectively) and a selectivity ratio of >5,000-fold relative to closely related serine proteases C1r, C1s, MASP-1, and MASP-3. Interaction studies using surface plasmon resonance and ELISA demonstrated approximately 100-fold greater binding affinity for intact narsoplimab compared to a monovalent antigen binding fragment, suggesting an important contribution of functional bivalency to high-affinity binding. In functional assays conducted in dilute serum under pathway-specific assay conditions, narsoplimab selectively inhibited lectin pathway-dependent activation of C5b-9 with high potency (IC50 ~ 1 nM) but had no observable effect on classical pathway or alternative pathway activity at concentrations up to 500 nM. In functional assays conducted in 90% serum, narsoplimab inhibited lectin pathway activation in human serum with high potency (IC50 ~ 3.4 nM) whereas its potency in cynomolgus monkey serum was approximately 10-fold lower (IC50 ~ 33 nM). Following single dose intravenous administration to cynomolgus monkeys, narsoplimab exposure increased in an approximately dose-proportional manner. Clear dose-dependent pharmacodynamic responses were observed at doses >1.5 mg/kg, as evidenced by a reduction in lectin pathway activity assessed ex vivo that increased in magnitude and duration with increasing dose. Analysis of pharmacokinetic and pharmacodynamic data revealed a well-defined concentration-effect relationship with an ex vivo EC50 value of approximately 6.1 μg/mL, which was comparable to the in vitro functional potency (IC50 33 nM; ~ 5 μg/mL). Discussion Based on these results, narsoplimab has been evaluated in clinical trials for the treatment of conditions associated with inappropriate lectin pathway activation, such as hematopoietic stem cell transplantation-associated thrombotic microangiopathy.
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Affiliation(s)
- Thomas Dudler
- Discovery, Omeros Corporation, Seattle, WA, United States
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Poblete RA, Yaceczko S, Aliakbar R, Saini P, Hazany S, Breit H, Louie SG, Lyden PD, Partikian A. Optimization of Nutrition after Brain Injury: Mechanistic and Therapeutic Considerations. Biomedicines 2023; 11:2551. [PMID: 37760993 PMCID: PMC10526443 DOI: 10.3390/biomedicines11092551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 09/13/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Emerging science continues to establish the detrimental effects of malnutrition in acute neurological diseases such as traumatic brain injury, stroke, status epilepticus and anoxic brain injury. The primary pathological pathways responsible for secondary brain injury include neuroinflammation, catabolism, immune suppression and metabolic failure, and these are exacerbated by malnutrition. Given this, there is growing interest in novel nutritional interventions to promote neurological recovery after acute brain injury. In this review, we will describe how malnutrition impacts the biomolecular mechanisms of secondary brain injury in acute neurological disorders, and how nutritional status can be optimized in both pediatric and adult populations. We will further highlight emerging therapeutic approaches, including specialized diets that aim to resolve neuroinflammation, immunodeficiency and metabolic crisis, by providing pre-clinical and clinical evidence that their use promotes neurologic recovery. Using nutrition as a targeted treatment is appealing for several reasons that will be discussed. Given the high mortality and both short- and long-term morbidity associated with acute brain injuries, novel translational and clinical approaches are needed.
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Affiliation(s)
- Roy A. Poblete
- Department of Neurology, Keck School of Medicine, The University of Southern California, 1540 Alcazar Street, Suite 215, Los Angeles, CA 90033, USA; (R.A.); (P.S.); (H.B.)
| | - Shelby Yaceczko
- UCLA Health, University of California, 100 Medical Plaza, Suite 345, Los Angeles, CA 90024, USA;
| | - Raya Aliakbar
- Department of Neurology, Keck School of Medicine, The University of Southern California, 1540 Alcazar Street, Suite 215, Los Angeles, CA 90033, USA; (R.A.); (P.S.); (H.B.)
| | - Pravesh Saini
- Department of Neurology, Keck School of Medicine, The University of Southern California, 1540 Alcazar Street, Suite 215, Los Angeles, CA 90033, USA; (R.A.); (P.S.); (H.B.)
| | - Saman Hazany
- Department of Radiology, Keck School of Medicine, The University of Southern California, 1500 San Pablo Street, Los Angeles, CA 90033, USA;
| | - Hannah Breit
- Department of Neurology, Keck School of Medicine, The University of Southern California, 1540 Alcazar Street, Suite 215, Los Angeles, CA 90033, USA; (R.A.); (P.S.); (H.B.)
| | - Stan G. Louie
- Department of Clinical Pharmacy, School of Pharmacy, The University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA;
| | - Patrick D. Lyden
- Department of Neurology, Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, The University of Southern California, 1540 Alcazar Street, Suite 215, Los Angeles, CA 90033, USA;
| | - Arthur Partikian
- Department of Neurology, Department of Pediatrics, Keck School of Medicine, The University of Southern California, 2010 Zonal Avenue, Building B, 3P61, Los Angeles, CA 90033, USA;
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Golomingi M, Kohler J, Lamers C, Pouw RB, Ricklin D, Dobó J, Gál P, Pál G, Kiss B, Dopler A, Schmidt CQ, Hardy ET, Lam W, Schroeder V. Complement inhibition can decrease the haemostatic response in a microvascular bleeding model at multiple levels. Front Immunol 2023; 14:1226832. [PMID: 37771595 PMCID: PMC10525698 DOI: 10.3389/fimmu.2023.1226832] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 08/23/2023] [Indexed: 09/30/2023] Open
Abstract
Background Haemostasis is a crucial process by which the body stops bleeding. It is achieved by the formation of a platelet plug, which is strengthened by formation of a fibrin mesh mediated by the coagulation cascade. In proinflammatory and prothrombotic conditions, multiple interactions of the complement system and the coagulation cascade are known to aggravate thromboinflammatory processes and increase the risk of arterial and venous thrombosis. Whether those interactions also play a relevant role during the physiological process of haemostasis is not yet completely understood. The aim of this study was to investigate the potential role of complement components and activation during the haemostatic response to mechanical vessel injury. Methods We used a microvascular bleeding model that simulates a blood vessel, featuring human endothelial cells, perfusion with fresh human whole blood, and an inducible mechanical injury to the vessel. We studied the effects of complement inhibitors against components of the lectin (MASP-1, MASP-2), classical (C1s), alternative (FD) and common pathways (C3, C5), as well as a novel triple fusion inhibitor of all three complement pathways (TriFu). Effects on clot formation were analysed by recording of fibrin deposition and the platelet activation marker CD62P at the injury site in real time using a confocal microscope. Results With the inhibitors targeting MASP-2 or C1s, no significant reduction of fibrin formation was observed, while platelet activation was significantly reduced in the presence of the FD inhibitor. Both common pathway inhibitors targeting C3 or C5, respectively, were associated with a substantial reduction of fibrin formation, and platelet activation was also reduced in the presence of the C3 inhibitor. Triple inhibition of all three activation pathways at the C3-convertase level by TriFu reduced both fibrin formation and platelet activation. When several complement inhibitors were directly compared in two individual donors, TriFu and the inhibitors of MASP-1 and C3 had the strongest effects on clot formation. Conclusion The observed impact of complement inhibition on reducing fibrin clot formation and platelet activation suggests a role of the complement system in haemostasis, with modulators of complement initiation, amplification or effector functions showing distinct profiles. While the interactions between complement and coagulation might have evolved to support haemostasis and protect against bleeding in case of vessel injury, they can turn harmful in pathological conditions when aggravating thromboinflammation and promoting thrombosis.
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Affiliation(s)
- Murielle Golomingi
- Experimental Haemostasis Group, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Jessie Kohler
- Experimental Haemostasis Group, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Christina Lamers
- Molecular Pharmacy Group, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
| | - Richard B. Pouw
- Molecular Pharmacy Group, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
| | - Daniel Ricklin
- Molecular Pharmacy Group, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
| | - József Dobó
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary
| | - Péter Gál
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary
| | - Gábor Pál
- Department of Biochemistry, Eötvös Loránd University, Budapest, Hungary
| | - Bence Kiss
- Department of Biochemistry, Eötvös Loránd University, Budapest, Hungary
| | - Arthur Dopler
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, University of Ulm Medical Center, Ulm, Germany
| | - Christoph Q. Schmidt
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, University of Ulm Medical Center, Ulm, Germany
| | - Elaissa Trybus Hardy
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
- Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, Atlanta, GA, United States
- Department of Pediatrics, Emory University, Atlanta, GA, United States
| | - Wilbur Lam
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
- Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, Atlanta, GA, United States
- Department of Pediatrics, Emory University, Atlanta, GA, United States
| | - Verena Schroeder
- Experimental Haemostasis Group, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
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Förnvik Jonsson K, Liljedahl E, Osther K, Bengzon J, Melander Skattum L, Nittby Redebrandt H. Complement Components in Peripheral Blood from Adult Patients with IDH Wild-Type Glioblastoma. World Neurosurg 2023; 177:e742-e747. [PMID: 37419318 DOI: 10.1016/j.wneu.2023.06.133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 07/09/2023]
Abstract
BACKGROUND The complement system seems to influence cancer pathophysiology. The primary aim of this study was to explore complement components associated with the classical pathway (CP) of the complement system in peripheral blood from patients with IDH-wild-type (IDH-wt) glioblastoma. METHODS Patients undergoing primary surgery due to glioblastoma in the years 2019-2021 were prospectively included in the present study. Blood samples were collected prior to surgery, and analyzed with regard to CP complement components, as well as standard coagulation tests. RESULTS In total, 40 patients with IDH-wt glioblastomas were included. C1q was reduced in 44% of the cases compared to the reference interval. C1r was reduced in 61% of the analyzed samples. Both C1q and C1r are parts of the initial steps of the classical complement activation pathway, which, however, was not correspondingly altered. Activated pro-thromboplastin time (APTT) was shorter in 82% of the analyzed samples compared to the reference interval. APTT was shorter in those with reduced C1q and C1r levels. C1q is an important link between the innate and acquired immunity, and C1q and C1r also interact with the coagulation system. Patients who displayed reduced levels of both C1q and C1r preoperatively had a significantly shorter overall survival compared with the rest of the cohort. CONCLUSIONS Our findings demonstrate that there are alterations in C1q and C1r concentrations in peripheral blood from patients with IDH1-wt glioblastoma compared with the normal population. Patients who displayed reduced C1q and C1r levels had a significantly shorter survival.
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Affiliation(s)
- Karolina Förnvik Jonsson
- Division of Neurosurgery, Department of Clinical Sciences, The Rausing Laboratory, Lund University, Lund, Sweden
| | - Emma Liljedahl
- Division of Neurosurgery, Department of Clinical Sciences, The Rausing Laboratory, Lund University, Lund, Sweden; Department of Neurosurgery, Skåne University Hospital, Lund, Sweden
| | - Kurt Osther
- Division of Neurosurgery, Department of Clinical Sciences, The Rausing Laboratory, Lund University, Lund, Sweden
| | - Johan Bengzon
- Department of Neurosurgery, Skåne University Hospital, Lund, Sweden; Lund Stem Cell Center, Lund, Sweden
| | - Lillemor Melander Skattum
- Department of Laboratory Medicine, Section of Microbiology, Immunology, and Glycobiology, Lund University, Lund, Sweden; Clinical Immunology and Transfusion Medicine, Region Skåne, Lund, Sweden
| | - Henrietta Nittby Redebrandt
- Division of Neurosurgery, Department of Clinical Sciences, The Rausing Laboratory, Lund University, Lund, Sweden; Department of Neurosurgery, Skåne University Hospital, Lund, Sweden.
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Andersen GR. The lufaxin inhibitor caught in the act. Blood 2023; 141:3017-3018. [PMID: 37347503 DOI: 10.1182/blood.2023020507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/23/2023] Open
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Coss SL, Zhou D, Chua GT, Aziz RA, Hoffman RP, Wu YL, Ardoin SP, Atkinson JP, Yu CY. The complement system and human autoimmune diseases. J Autoimmun 2023; 137:102979. [PMID: 36535812 PMCID: PMC10276174 DOI: 10.1016/j.jaut.2022.102979] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022]
Abstract
Genetic deficiencies of early components of the classical complement activation pathway (especially C1q, r, s, and C4) are the strongest monogenic causal factors for the prototypic autoimmune disease systemic lupus erythematosus (SLE), but their prevalence is extremely rare. In contrast, isotype genetic deficiency of C4A and acquired deficiency of C1q by autoantibodies are frequent among patients with SLE. Here we review the genetic basis of complement deficiencies in autoimmune disease, discuss the complex genetic diversity seen in complement C4 and its association with autoimmune disease, provide guidance as to when clinicians should suspect and test for complement deficiencies, and outline the current understanding of the mechanisms relating complement deficiencies to autoimmunity. We focus primarily on SLE, as the role of complement in SLE is well-established, but will also discuss other informative diseases such as inflammatory arthritis and myositis.
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Affiliation(s)
- Samantha L Coss
- Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University, Columbus, OH, USA.
| | - Danlei Zhou
- Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University, Columbus, OH, USA
| | - Gilbert T Chua
- Department of Pediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Rabheh Abdul Aziz
- Department of Pediatrics, The Ohio State University, Columbus, OH, USA; Department of Allergy, Immunology and Rheumatology, University of Buffalo, NY, USA
| | - Robert P Hoffman
- Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University, Columbus, OH, USA
| | - Yee Ling Wu
- Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University, Columbus, OH, USA; Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL, USA
| | - Stacy P Ardoin
- Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University, Columbus, OH, USA
| | - John P Atkinson
- Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St Louis, MO, USA
| | - Chack-Yung Yu
- Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University, Columbus, OH, USA.
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21
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Rydenfelt K, Kjøsen G, Horneland R, Ludviksen J, Jenssen TG, Line PD, Tønnessen TI, Mollnes TE, Haugaa H, Pischke SE. Thromboinflammatory response is increased in pancreas transplant alone versus simultaneous pancreas-kidney transplantation and early pancreas graft thrombosis is associated with complement activation. Front Immunol 2023; 14:1044444. [PMID: 37063904 PMCID: PMC10090504 DOI: 10.3389/fimmu.2023.1044444] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 03/14/2023] [Indexed: 03/31/2023] Open
Abstract
BACKGROUND Pancreas transplant alone (PTA) recipients are more affected by pancreas graft thrombosis, and graft loss compared to simultaneous pancreas-kidney (SPK) recipients. The pathophysiology is unknown, but an increased immune response has been suggested in the PTA recipients. In this observational study, we compared perioperative thromboinflammation between PTA (n=32) and SPK (n=35) recipients, and between PTA recipients with (n=14) versus without (n=18) early graft thrombosis. METHODS We measured C-reactive protein (CRP), plasma markers of activated coagulation and complement, and cytokines preoperatively and daily during the first postoperative week. RESULTS Preoperatively, coagulation and complement activation markers were comparable between PTA and SPK recipients, while cytokine concentrations were higher in SPK recipients (TNF, IL-8, IP-10, MCP-1, MIP-1α; all p<0.05). On the first postoperative day, PTA recipients had higher coagulation activation, measured as thrombin-antithrombin complex (TAT), than SPK recipients (p=0.008). In the first postoperative week, PTA recipients showed higher relative cytokine release (IL-6, IL-8, G-CSF, IP-10, MCP-1, and MIP-1α; all p<0.05) while SPK recipients showed higher absolute cytokine concentrations (TNF, IL-1ra, IL-8, MIP-1α, and IL-4; all p<0.05). PTA and SPK recipients showed similar terminal complement complex (TCC, sC5b-9) activation. On the first postoperative day, TCC (OR 1.2 [95% CI 1.0-1.5] for 0.1 CAU/ml increase, p=0.02) and CRP (OR 1.2 [95% CI 1.0-1.3] for 10 mg/L increase, p=0.04) were associated with an increased risk of early graft thrombosis. TCC was specific for graft thrombosis, while CRP increased with several complications. PTA recipients with compared to those without graft thrombosis had higher TCC pre- (p=0.04) and postoperatively (p=0.03). CONCLUSION The relative increase in postoperative thromboinflammatory response was more pronounced in PTA recipients. Complement activation was associated with an increased risk of graft thrombosis. This study indicates that innate immune activation rather than elevated levels may affect early postoperative pancreas graft thrombosis. CLINICAL TRIAL REGISTRATION https://clinicaltrials.gov/ct2/show/NCT01957696, identifier NCT01957696.
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Affiliation(s)
- Kristina Rydenfelt
- Department of Anesthesia and Intensive Care Medicine, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Research & Development, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway
| | - Gisle Kjøsen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Research & Development, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway
| | - Rune Horneland
- Department of Transplantation Medicine, Section of Transplantation Surgery, Oslo University Hospital, Oslo, Norway
| | | | - Trond Geir Jenssen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Transplantation Medicine, Section of Nephrology, Oslo University Hospital, Oslo, Norway
| | - Pål-Dag Line
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Transplantation Medicine, Section of Transplantation Surgery, Oslo University Hospital, Oslo, Norway
| | - Tor Inge Tønnessen
- Department of Anesthesia and Intensive Care Medicine, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Tom Eirik Mollnes
- Research Laboratory, Nordland Hospital, Bodø, Norway
- Department of Immunology, Oslo University Hospital, and University of Oslo, Oslo, Norway
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway
| | - Håkon Haugaa
- Department of Anesthesia and Intensive Care Medicine, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway
- Department of Research & Development, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway
- Department of Intensive Care Nursing, Lovisenberg University College, Oslo, Norway
| | - Søren Erik Pischke
- Department of Anesthesia and Intensive Care Medicine, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Immunology, Oslo University Hospital, and University of Oslo, Oslo, Norway
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22
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Fromell K, Johansson U, Abadgar S, Bourzeix P, Lundholm L, Elihn K. The effect of airborne Palladium nanoparticles on human lung cells, endothelium and blood - A combinatory approach using three in vitro models. Toxicol In Vitro 2023; 89:105586. [PMID: 36931534 DOI: 10.1016/j.tiv.2023.105586] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 02/24/2023] [Accepted: 03/13/2023] [Indexed: 03/17/2023]
Abstract
A better understanding of the mechanisms behind adverse health effects caused by airborne fine particles and nanoparticles (NP) is essential to improve risk assessment and identification the most critical particle exposures. While the use of automobile catalytic converters is decreasing the exhausts of harmful gases, concentrations of fine airborne particles and nanoparticles (NPs) from catalytic metals such as Palladium (Pd) are reaching their upper safe level. Here we used a combinatory approach with three in vitro model systems to study the toxicity of Pd particles, to infer their potential effects on human health upon inhalation. The three model systems are 1) a lung system with human lung cells (ALI), 2) an endothelial cell system and 3) a human whole blood loop system. All three model systems were exposed to the exact same type of Pd NPs. The ALI lung cell exposure system showed a clear reduction in cell growth from 24 h onwards and the effect persisted over a longer period of time. In the endothelial cell model, Pd NPs induced apoptosis, but not to the same extent as the most aggressive types of NPs such as TiO2. Similarly, Pd triggered clear coagulation and contact system activation but not as forcefully as the highly thrombogenic TiO2 NPs. In summary, we show that our 3-step in vitro model of the human lung and surrounding vessels can be a useful tool for studying pathological events triggered by airborne fine particles and NPs.
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Affiliation(s)
- Karin Fromell
- Department of Immunology, Genetics and Pathology, Rudbeck laboratory C5:3, Uppsala university, SE-751 85 Uppsala, Sweden.
| | - Ulrika Johansson
- Department of Immunology, Genetics and Pathology, Rudbeck laboratory C5:3, Uppsala university, SE-751 85 Uppsala, Sweden; Linnæus Centre for Biomaterials Chemistry, Linnæus University, SE-391 82 Kalmar, Sweden
| | - Sophia Abadgar
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 91 Stockholm, Sweden; Department of Environmental Science, Stockholm University, 106 91 Stockholm, Sweden
| | - Pauline Bourzeix
- Department of Immunology, Genetics and Pathology, Rudbeck laboratory C5:3, Uppsala university, SE-751 85 Uppsala, Sweden
| | - Lovisa Lundholm
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 91 Stockholm, Sweden
| | - Karine Elihn
- Department of Environmental Science, Stockholm University, 106 91 Stockholm, Sweden
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23
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Gromadziński L, Paukszto Ł, Lepiarczyk E, Skowrońska A, Lipka A, Makowczenko KG, Łopieńska-Biernat E, Jastrzębski JP, Holak P, Smoliński M, Majewska M. Pulmonary artery embolism: comprehensive transcriptomic analysis in understanding the pathogenic mechanisms of the disease. BMC Genomics 2023; 24:10. [PMID: 36624378 PMCID: PMC9830730 DOI: 10.1186/s12864-023-09110-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 01/02/2023] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Pulmonary embolism (PE) is a severe disease that usually originates from deep vein thrombosis (DVT) of the lower extremities. This study set out to investigate the changes in the transcriptome of the pulmonary artery (PA) in the course of the PE in the porcine model. METHODS The study was performed on 11 male pigs: a thrombus was formed in each right femoral vein in six animals, and then was released to induce PE, the remaining five animals served as a control group. In the experimental animals total RNA was isolated from the PA where the blood clot lodged, and in the control group, from the corresponding PA segments. High-throughput RNA sequencing was used to analyse the global changes in the transcriptome of PA with induced PE (PA-E). RESULTS Applied multistep bioinformatics revealed 473 differentially expressed genes (DEGs): 198 upregulated and 275 downregulated. Functional Gene Ontology annotated 347 DEGs into 27 biological processes, 324 to the 11 cellular components and 346 to the 2 molecular functions categories. In the signaling pathway analysis, KEGG 'protein processing in endoplasmic reticulum' was identified for the mRNAs modulated during PE. The same KEGG pathway was also exposed by 8 differentially alternative splicing genes. Within single nucleotide variants, the 61 allele-specific expression variants were localised in the vicinity of the genes that belong to the cellular components of the 'endoplasmic reticulum'. The discovered allele-specific genes were also classified as signatures of the cardiovascular system. CONCLUSIONS The findings of this research provide the first thorough investigation of the changes in the gene expression profile of PA affected by an embolus. Evidence from this study suggests that the disturbed homeostasis in the biosynthesis of proteins in the endoplasmic reticulum plays a major role in the pathogenesis of PE.
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Affiliation(s)
- Leszek Gromadziński
- grid.412607.60000 0001 2149 6795Department of Cardiology and Internal Medicine, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, Warszawska Str 30, 10-082 Olsztyn, Poland
| | - Łukasz Paukszto
- grid.412607.60000 0001 2149 6795Department of Botany and Nature Protection, University of Warmia and Mazury in Olsztyn, Plac Łódzki 1, 10-727 Olsztyn, Poland
| | - Ewa Lepiarczyk
- grid.412607.60000 0001 2149 6795Department of Human Physiology and Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, Warszawska Str 30, 10-082 Olsztyn, Poland
| | - Agnieszka Skowrońska
- grid.412607.60000 0001 2149 6795Department of Human Physiology and Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, Warszawska Str 30, 10-082 Olsztyn, Poland
| | - Aleksandra Lipka
- grid.412607.60000 0001 2149 6795Department of Gynecology, and Obstetrics, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, Żołnierska Str 18, 10-561 Olsztyn, Poland
| | - Karol G. Makowczenko
- grid.412607.60000 0001 2149 6795Department of Animal Anatomy and Physiology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego 1A, 10-719 Olsztyn, Poland
| | - Elżbieta Łopieńska-Biernat
- grid.412607.60000 0001 2149 6795Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego Str 1A, 10-719 Olsztyn, Poland
| | - Jan P. Jastrzębski
- grid.412607.60000 0001 2149 6795Department of Plant Physiology, Genetics and Biotechnology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Oczapowskiego Str 1A, 10-719 Olsztyn-Kortowo, Poland
| | - Piotr Holak
- grid.412607.60000 0001 2149 6795Department of Surgery and Radiology With Clinic, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego Str 14, 10-719 Olsztyn, Poland
| | - Michał Smoliński
- grid.460107.4Clinic of Cardiology and Internal Diseases, University Clinical Hospital in Olsztyn, Warszawska Str 30, 10-082 Olsztyn, Poland
| | - Marta Majewska
- grid.412607.60000 0001 2149 6795Department of Human Physiology and Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, Warszawska Str 30, 10-082 Olsztyn, Poland
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24
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Sotos KE, Goggs R, Stablein AP, Brooks MB. Increased thrombin activatable fibrinolysis inhibitor activity is associated with hypofibrinolysis in dogs with sepsis. Front Vet Sci 2023; 10:1104602. [PMID: 36876005 PMCID: PMC9978197 DOI: 10.3389/fvets.2023.1104602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 01/30/2023] [Indexed: 02/18/2023] Open
Abstract
Introduction Disorders of coagulation are well-recognized in dogs with sepsis, but data regarding fibrinolysis disorders are limited. We aimed to characterize fibrinolysis in dogs with sepsis compared to healthy controls. We hypothesized that dogs with sepsis would be hypofibrinolytic, and that hypofibrinolysis would be associated with non-survival. Methods This was a prospective observational cohort study. We enrolled 20 client-owned dogs with sepsis admitted to the Cornell University Hospital for Animals and 20 healthy pet dogs. Coagulation and fibrinolytic pathway proteins including antiplasmin activity (AP), antithrombin activity (AT), thrombin activatable fibrinolysis inhibitor activity (TAFI), D-dimer concentration, fibrinogen concentration, and plasminogen activity were measured and compared between groups. Overall coagulation potential, overall fibrinolysis potential, and overall hemostatic potential were calculated from the curve of fibrin clot formation and lysis over time. Results Compared to healthy controls, dogs with sepsis had lower AT (P = 0.009), higher AP (P = 0.002), higher TAFI (P = 0.0385), and higher concentrations of fibrinogen (P < 0.0001) and D-dimer (P = 0.0001). Dogs with sepsis also had greater overall coagulation potential (P = 0.003), overall hemostatic potential (P = 0.0015), and lower overall fibrinolysis potential (P = 0.0004). The extent of fibrinolysis was significantly negatively correlated with TAFI. No significant differences were observed between survivors and non-survivors. Discussion Dogs with sepsis were hypercoagulable and hypofibrinolytic compared to healthy dogs, suggesting potential utility of thromboprophylaxis in this patient population. The association between high TAFI and low overall fibrinolysis potential might provide a potential mechanism for this hypofibrinolysis.
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Affiliation(s)
- Katherine E Sotos
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
| | - Robert Goggs
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
| | - Alyssa P Stablein
- Comparative Coagulation Laboratory, Animal Health Diagnostic Center, Cornell University, Ithaca, NY, United States
| | - Marjory B Brooks
- Comparative Coagulation Laboratory, Animal Health Diagnostic Center, Cornell University, Ithaca, NY, United States
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25
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Saad AA. Unveiling the Great Therapeutic Potential of MASPs as Hemostatic Agents. J Hematol 2022; 11:240-245. [PMID: 36632573 PMCID: PMC9822654 DOI: 10.14740/jh1060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 10/31/2022] [Indexed: 01/04/2023] Open
Affiliation(s)
- Ashraf Abdullah Saad
- Unit of Pediatric Hematologic Oncology and BMT, Sultan Qaboos University Hospital, Muscat, Oman.
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26
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Chen X, Wang K, Li D, Zhao M, Huang B, Su W, Yu D. Genetic and immune crosstalk between severe burns and blunt trauma: A study of transcriptomic data. Front Genet 2022; 13:1038222. [PMID: 36246590 PMCID: PMC9561827 DOI: 10.3389/fgene.2022.1038222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 09/15/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Severe burns and blunt trauma can lead to multiple organ dysfunction syndrome, the leading cause of death in intensive care units. In addition to infection, the degree of immune inflammatory response also affects prognosis. However, the characteristics and clinical relevance of the common mechanisms of these major diseases are still underexplored. Methods: In the present study, we performed microarray data analysis to identify immune-related differentially expressed genes (DEGs) involved in both disease progression in burns and blunt trauma. Six analyses were subsequently performed, including gene enrichment analysis, protein‐protein interaction (PPI) network construction, immune cell infiltration analysis, core gene identification, co-expression network analysis, and clinical correlation analysis. Results: A total of 117 common immune-related DEGs was selected for subsequent analyses. Functional analysis emphasizes the important role of Th17 cell differentiation, Th1 and Th2 cell differentiation, Cytokine-cytokine receptor interaction and T cell receptor signaling pathway in these two diseases. Finally, eight core DEGs were identified using cytoHubba, including CD8A, IL10, CCL5, CD28, LCK, CCL4, IL2RB, and STAT1. The correlation analysis showed that the identified core DEGs were more or less significantly associated with simultaneous dysregulation of immune cells in blunt trauma and sepsis patients. Of these, the downregulation of CD8A and CD28 had a worse prognosis. Conclusion: Our analysis lays the groundwork for future studies to elucidate molecular mechanisms shared in burns and blunt trauma. The functional roles of identified core immune-related DEGs and dysregulated immune cell subsets warrant further in-depth study.
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Affiliation(s)
- Xiaoming Chen
- Department of Plastic and burns Surgery, The Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital), Chengdu, China
| | - Kuan Wang
- Department of Cosmetic Plastic and burns Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Dazhuang Li
- Department of Orthopedics, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Mingyue Zhao
- Department of Periodontology, Affiliated Stomatological Hospital of Zunyi MedicalUniversity, Zunyi, China
| | - Biao Huang
- Department of Plastic and burns Surgery, The Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital), Chengdu, China
- *Correspondence: Biao Huang, ; Wenxing Su, ; Daojiang Yu,
| | - Wenxing Su
- Department of Plastic and burns Surgery, The Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital), Chengdu, China
- *Correspondence: Biao Huang, ; Wenxing Su, ; Daojiang Yu,
| | - Daojiang Yu
- Department of Plastic and burns Surgery, The Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital), Chengdu, China
- *Correspondence: Biao Huang, ; Wenxing Su, ; Daojiang Yu,
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27
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Heden TD, Chen C, Leland G, Mashek MM, Najt CP, Shang L, Chow LS, Mashek DG. Isolated and combined impact of dietary olive oil and exercise on markers of health and energy metabolism in female mice. J Nutr Biochem 2022; 107:109040. [PMID: 35533899 PMCID: PMC9626252 DOI: 10.1016/j.jnutbio.2022.109040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 03/04/2022] [Accepted: 03/20/2022] [Indexed: 11/27/2022]
Abstract
An olive oil (OO) rich diet or high-intensity interval training (HIIT) independently improve markers of health and energy metabolism, but it is unknown if combining OO and HIIT synergize to improve these markers. This study characterized the isolated and combined impact of OO and HIIT on markers of health and energy metabolism in various tissues in C57BL/6J female mice. Nine-week-old mice were divided into four groups for a 12-week diet and/or exercise intervention including: (1) Control Diet without HIIT (CD), (2) Control Diet with HIIT (CD+HIIT), (3) OO diet (10% kcal from olive oil) without HIIT, and (4) OO diet with HIIT (OO+HIIT). Neither dietary OO or HIIT altered body weight, glucose tolerance, or serum lipids. HIIT, regardless of diet, increased aerobic capacity and HDL cholesterol levels. In liver and heart tissue, OO resulted in similar adaptations as HIIT including increased mitochondrial content and fatty acid oxidation but combining OO with HIIT did not augment these effects. In skeletal muscle, HIIT increased mitochondrial content in type II fibers similarly between diets. An RNA sequencing analysis on type I fibers revealed OO reduced muscle regeneration and lipid metabolism gene abundance, whereas HIIT increased the abundance of these genes, independent of diet. HIIT training, independent of diet, induced subcutaneous white adipose tissue (sWAT) hypertrophy, whereas OO induced gonadal white adipose tissue (gWAT) hypertrophy, an effect that was augmented with HIIT. These data highlight the pleiotropic effects of OO and HIIT, although their combination does not synergize to further improve most markers of health and energy metabolism.
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Affiliation(s)
- Timothy D Heden
- Department of Biochemistry, Molecular Biology, and Biophysics, Minneapolis, MN
| | - Chen Chen
- Department of Biochemistry, Molecular Biology, and Biophysics, Minneapolis, MN
| | - Grace Leland
- Department of Biochemistry, Molecular Biology, and Biophysics, Minneapolis, MN
| | - Mara M Mashek
- Department of Biochemistry, Molecular Biology, and Biophysics, Minneapolis, MN
| | - Charles P Najt
- Department of Biochemistry, Molecular Biology, and Biophysics, Minneapolis, MN
| | - Linshan Shang
- Department of Biochemistry, Molecular Biology, and Biophysics, Minneapolis, MN
| | - Lisa S Chow
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Minneapolis, MN
| | - Douglas G Mashek
- Department of Biochemistry, Molecular Biology, and Biophysics, Minneapolis, MN; Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Minneapolis, MN.
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28
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McCrae KR, Swaidani S, Diaz-Montero CM, Khorana AA. Old is new again: emergence of thromboembolic complications in cancer patients on immunotherapy. Thromb Res 2022; 213:S51-S57. [PMID: 36061419 PMCID: PMC9435305 DOI: 10.1016/j.thromres.2022.01.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Cancer immunotherapy has emerged as one of the most important new treatments for cancer in many years, moving rapidly to front-line therapy for several cancers. Cancer immunotherapy is based on treatment with immune checkpoint inhibitors (ICI), which are monoclonal antibodies directed toward immunoregulatory proteins including PD-1, PD-L1 and CTLA-4. ICI inhibit interactions between these proteins and their ligands, disabling physiologic immune regulatory networks and enhancing anti-tumor immunity. However, since the immune response cannot be directed specifically to the tumor, ICI are associated with immune-related adverse events (irAEs) resulting from immune-mediated attack of normal tissues. We and others have reported a high incidence of thrombosis in patients treated with ICI, which may approach 20%. Given the rapidly increasing use of ICIs, it is clear that ICI-Associated Thrombosis (IAT) is a major emerging clinical problem. However, there is a remarkable knowledge gap concerning mechanisms of IAT. IAT may be a composite irAE resulting from activation of blood and vascular cells, leading to thromboinflammation. Cancer itself is an inflammatory disorder, and inducing further inflammation through ICI administration may stimulate procoagulant activity by multiple cell types. Moreover, some blood and vascular cells express ICI target proteins. Here, we review the results of several studies describing the clinical manifestations of IAT, as well as our recent studies demonstrating that elevated levels of myeloid derived suppressor cells and inflammatory cytokines may serve as biomarkers of IAT. It is hoped that the concepts reviewed here may stimulate further research into this important clinical problem.
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Affiliation(s)
- Keith R McCrae
- Department of Hematology & Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Shadi Swaidani
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - C Marcela Diaz-Montero
- Center for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Alok A Khorana
- Department of Hematology & Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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29
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Nilsson B, Persson B, Eriksson O, Fromell K, Hultström M, Frithiof R, Lipcsey M, Huber-Lang M, Ekdahl KN. How the Innate Immune System of the Blood Contributes to Systemic Pathology in COVID-19-Induced ARDS and Provides Potential Targets for Treatment. Front Immunol 2022; 13:840137. [PMID: 35350780 PMCID: PMC8957861 DOI: 10.3389/fimmu.2022.840137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/14/2022] [Indexed: 12/22/2022] Open
Abstract
Most SARS-CoV-2 infected patients experience influenza-like symptoms of low or moderate severity. But, already in 2020 early during the pandemic it became obvious that many patients had a high incidence of thrombotic complications, which prompted treatment with high doses of low-molecular-weight heparin (LMWH; typically 150-300IU/kg) to prevent thrombosis. In some patients, the disease aggravated after approximately 10 days and turned into a full-blown acute respiratory distress syndrome (ARDS)-like pulmonary inflammation with endothelialitis, thrombosis and vascular angiogenesis, which often lead to intensive care treatment with ventilator support. This stage of the disease is characterized by dysregulation of cytokines and chemokines, in particular with high IL-6 levels, and also by reduced oxygen saturation, high risk of thrombosis, and signs of severe pulmonary damage with ground glass opacities. The direct link between SARS-CoV-2 and the COVID-19-associated lung injury is not clear. Indirect evidence speaks in favor of a thromboinflammatory reaction, which may be initiated by the virus itself and by infected damaged and/or apoptotic cells. We and others have demonstrated that life-threatening COVID-19 ARDS is associated with a strong activation of the intravascular innate immune system (IIIS). In support of this notion is that activation of the complement and kallikrein/kinin (KK) systems predict survival, the necessity for usage of mechanical ventilation, acute kidney injury and, in the case of MBL, also coagulation system activation with thromboembolism. The general properties of the IIIS can easily be translated into mechanisms of COVID-19 pathophysiology. The prognostic value of complement and KKsystem biomarkers demonstrate that pharmaceuticals, which are licensed or have passed the phase I trial stage are promising candidate drugs for treatment of COVID-19. Examples of such compounds include complement inhibitors AMY-101 and eculizumab (targeting C3 and C5, respectively) as well as kallikrein inhibitors ecallantide and lanadelumab and the bradykinin receptor (BKR) 2 antagonist icatibant. In this conceptual review we discuss the activation, crosstalk and the therapeutic options that are available for regulation of the IIIS.
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Affiliation(s)
- Bo Nilsson
- Department of Immunology Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Barbro Persson
- Department of Immunology Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Oskar Eriksson
- Department of Immunology Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Karin Fromell
- Department of Immunology Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Michael Hultström
- Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden.,Unit for Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Robert Frithiof
- Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden
| | - Miklos Lipcsey
- Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden.,Hedenstierna Laboratory, Anesthesiology and Intensive Care, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Markus Huber-Lang
- Institute for Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, Germany
| | - Kristina N Ekdahl
- Department of Immunology Genetics and Pathology, Uppsala University, Uppsala, Sweden.,Linnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden
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30
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Alteration of Serum Proteome in Levo-Thyroxine-Euthyroid Thyroidectomized Patients. J Clin Med 2022; 11:jcm11061676. [PMID: 35330001 PMCID: PMC8951767 DOI: 10.3390/jcm11061676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/11/2022] [Accepted: 03/14/2022] [Indexed: 11/16/2022] Open
Abstract
The monotherapy with levo-thyroxine (LT4) is the treatment of choice for patients with hypothyroidism after thyroidectomy. However, many athyreotic LT4-treated patients with thyroid hormones in the physiological range experience hypothyroid-like symptoms, showing post-operative, statistically significant lower FT3 levels with respect to that before total thyroidectomy. Since we hypothesized that the lower plasmatic FT3 levels observed in this subgroup could be associated with tissue hypothyroidism, here we compared, by a preliminary proteomic analysis, eight sera of patients with reduced post-surgical FT3 to eight sera from patients with FT3 levels similar to pre-surgery levels, and six healthy controls. Proteomic analysis highlights a different serum protein profile among the considered conditions. By enrichment analysis, differential proteins are involved in coagulation processes (PLMN-1.61, -1.98 in reduced vs. stable FT3, p < 0.02; A1AT fragmentation), complement system activation (CFAH + 1.83, CFAB + 1.5, C1Qb + 1.6, C1S + 7.79 in reduced vs. stable FT3, p < 0.01) and in lipoprotein particles remodeling (APOAI fragmentation; APOAIV + 2.13, p < 0.003), potentially leading to a pro-inflammatory response. This study suggests that LT4 replacement therapy might restore biochemical euthyroid conditions in thyroidectomized patients, but in some cases without re-establishing body tissue euthyroidism. Since our results, this condition is reflected by the serum protein profile.
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Sinkovits G, Réti M, Müller V, Iványi Z, Gál J, Gopcsa L, Reményi P, Szathmáry B, Lakatos B, Szlávik J, Bobek I, Prohászka ZZ, Förhécz Z, Mező B, Csuka D, Hurler L, Kajdácsi E, Cervenak L, Kiszel P, Masszi T, Vályi-Nagy I, Prohászka Z. Associations between the von Willebrand Factor-ADAMTS13 Axis, Complement Activation, and COVID-19 Severity and Mortality. Thromb Haemost 2022; 122:240-256. [PMID: 35062036 PMCID: PMC8820843 DOI: 10.1055/s-0041-1740182] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Background
Endothelial and complement activation were both associated with immunothrombosis, a key determinant of COVID-19 severity, but their interrelation has not yet been investigated.
Objectives
We aimed to determine von Willebrand factor (VWF) antigen (VWF:Ag) concentration, VWF collagen binding activity (VWF:CBA), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity (ADAMTS13:Ac), and their ratios in hospitalized COVID-19 patients, and to investigate how these parameters and their constellation with complement activation relate to disease severity and in-hospital mortality in COVID-19.
Methods
Samples of 102 hospitalized patients with polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 positivity were included in our observational cohort study. Patients were stratified according to the peak severity of COVID-19 disease in agreement with the World Health Organization ordinal scale. Twenty-six convalescent plasma donors with previous COVID-19 disease formed the control group. VWF:Ag concentration and VWF:CBA were determined by enzyme-linked immunosorbent assay (ELISA); ADAMTS13:Ac was determined by fluorescence resonance energy transfer. Complement C3 and C3a were measured by turbidimetry and ELISA, respectively. Clinical covariates and markers of inflammation were extracted from hospital records.
Results
VWF:Ag and VWF:CBA were elevated in all groups of hospitalized COVID-19 patients and increased in parallel with disease severity. ADAMTS13:Ac was decreased in patients with severe COVID-19, with the lowest values in nonsurvivors. High (> 300%) VWF:Ag concentrations or decreased (< 67%) ADAMTS13:Ac were associated with higher risk of severe COVID-19 disease or in-hospital mortality. The concomitant presence of decreased ADAMTS13:Ac and increased C3a/C3 ratio—indicating complement overactivation and consumption—was a strong independent predictor of in-hospital mortality.
Conclusion
Our results suggest that an interaction between the VWF-ADAMTS13 axis and complement overactivation and consumption plays an important role in the pathogenesis of COVID-19.
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Affiliation(s)
- György Sinkovits
- Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
| | - Marienn Réti
- Department of Haematology and Stem Cell Transplantation, Central Hospital of Southern Pest, Institute of Haematology and Infectious Diseases, Budapest, Hungary
| | - Veronika Müller
- Department of Pulmonology, Semmelweis University, Budapest, Hungary
| | - Zsolt Iványi
- Department of Anaesthesiology and Intensive Therapy, Semmelweis University, Budapest, Hungary
| | - János Gál
- Department of Anaesthesiology and Intensive Therapy, Semmelweis University, Budapest, Hungary
| | - László Gopcsa
- Department of Haematology and Stem Cell Transplantation, Central Hospital of Southern Pest, Institute of Haematology and Infectious Diseases, Budapest, Hungary
| | - Péter Reményi
- Department of Haematology and Stem Cell Transplantation, Central Hospital of Southern Pest, Institute of Haematology and Infectious Diseases, Budapest, Hungary
| | - Beáta Szathmáry
- Department of Infectology, Central Hospital of Southern Pest, Institute of Haematology and Infectious Diseases, Budapest, Hungary
| | - Botond Lakatos
- Department of Infectology, Central Hospital of Southern Pest, Institute of Haematology and Infectious Diseases, Budapest, Hungary
| | - János Szlávik
- Department of Infectology, Central Hospital of Southern Pest, Institute of Haematology and Infectious Diseases, Budapest, Hungary
| | - Ilona Bobek
- Department of Anaesthesiology and Intensive Therapy, Central Hospital of Southern Pest, Institute of Haematology and Infectious Diseases, Budapest, Hungary
| | - Zita Z Prohászka
- Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
| | - Zsolt Förhécz
- Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
| | - Blanka Mező
- Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary.,Research Group for Immunology and Haematology, Semmelweis University - Eötvös Loránd Research Network (Office for Supported Research Groups), Budapest, Hungary
| | - Dorottya Csuka
- Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
| | - Lisa Hurler
- Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
| | - Erika Kajdácsi
- Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
| | - László Cervenak
- Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
| | - Petra Kiszel
- Research Group for Immunology and Haematology, Semmelweis University - Eötvös Loránd Research Network (Office for Supported Research Groups), Budapest, Hungary
| | - Tamás Masszi
- Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
| | - István Vályi-Nagy
- Department of Haematology and Stem Cell Transplantation, Central Hospital of Southern Pest, Institute of Haematology and Infectious Diseases, Budapest, Hungary
| | - Zoltán Prohászka
- Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary.,Research Group for Immunology and Haematology, Semmelweis University - Eötvös Loránd Research Network (Office for Supported Research Groups), Budapest, Hungary
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32
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Zou XL, Chen WY, Zhang GY, Ke H, Yang QH, Li XB. Risk Factors, Incidence, and Prognosis of Thromboembolism in Cancer Patients Treated With Immune Checkpoint Inhibitors. Front Pharmacol 2021; 12:747075. [PMID: 34819857 PMCID: PMC8606686 DOI: 10.3389/fphar.2021.747075] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 10/15/2021] [Indexed: 11/16/2022] Open
Abstract
In recent years, immune checkpoint inhibitors (ICIs) have become the standard treatment option for tumors. With the widespread application of ICIs, immune-related adverse events (irAEs) have gradually attracted the attention of researchers. Owing to the characteristics of ICIs, irAEs can affect each organ of the human body. Thromboembolism is uncommon in cancer patients receiving ICIs, but it may affect their survival. Most thromboembolic events do not cause serious effects after early prediction and treatment, but life-threatening toxic reactions are also observed. This condition should not be ignored because of vague and atypical symptoms, which make early diagnosis more challenging. This article focuses on the high-risk factors, underlying mechanisms, incidence, and prognosis of thromboembolism in patients using ICIs and briefly describes the intervention and treatment measures. This information would allow patients to effectively manage the side effects of thromboembolism during Immune checkpoint inhibitors treatment, ensuring the efficacy of ICIs and reducing mortality.
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Affiliation(s)
- Xue-Lin Zou
- Department of Respiratory Medicine, Chengdu Seventh People's Hospital, Chengdu, China
| | - Wei-Yong Chen
- Department of Respiratory Medicine, Chengdu Seventh People's Hospital, Chengdu, China
| | - Guang-Yan Zhang
- Department of Respiratory Medicine, Chengdu Seventh People's Hospital, Chengdu, China
| | - Hua Ke
- Department of Respiratory Medicine, Chengdu Seventh People's Hospital, Chengdu, China
| | - Qiu-Hong Yang
- Department of Respiratory Medicine, Chengdu Seventh People's Hospital, Chengdu, China
| | - Xiao-Bo Li
- Department of Respiratory Medicine, Chengdu Seventh People's Hospital, Chengdu, China
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33
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Freiwald T, Afzali B. Renal diseases and the role of complement: Linking complement to immune effector pathways and therapeutics. Adv Immunol 2021; 152:1-81. [PMID: 34844708 PMCID: PMC8905641 DOI: 10.1016/bs.ai.2021.09.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The complement system is an ancient and phylogenetically conserved key danger sensing system that is critical for host defense against pathogens. Activation of the complement system is a vital component of innate immunity required for the detection and removal of pathogens. It is also a central orchestrator of adaptive immune responses and a constituent of normal tissue homeostasis. Once complement activation occurs, this system deposits indiscriminately on any cell surface in the vicinity and has the potential to cause unwanted and excessive tissue injury. Deposition of complement components is recognized as a hallmark of a variety of kidney diseases, where it is indeed associated with damage to the self. The provenance and the pathophysiological role(s) played by complement in each kidney disease is not fully understood. However, in recent years there has been a renaissance in the study of complement, with greater appreciation of its intracellular roles as a cell-intrinsic system and its interplay with immune effector pathways. This has been paired with a profusion of novel therapeutic agents antagonizing complement components, including approved inhibitors against complement components (C)1, C3, C5 and C5aR1. A number of clinical trials have investigated the use of these more targeted approaches for the management of kidney diseases. In this review we present and summarize the evidence for the roles of complement in kidney diseases and discuss the available clinical evidence for complement inhibition.
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Affiliation(s)
- Tilo Freiwald
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, MD, United States; Department of Nephrology, University Hospital Frankfurt, Goethe-University, Frankfurt am Main, Germany
| | - Behdad Afzali
- Department of Nephrology, University Hospital Frankfurt, Goethe-University, Frankfurt am Main, Germany.
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34
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Crosstalk between the renin-angiotensin, complement and kallikrein-kinin systems in inflammation. Nat Rev Immunol 2021; 22:411-428. [PMID: 34759348 PMCID: PMC8579187 DOI: 10.1038/s41577-021-00634-8] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/24/2021] [Indexed: 12/28/2022]
Abstract
During severe inflammatory and infectious diseases, various mediators modulate the equilibrium of vascular tone, inflammation, coagulation and thrombosis. This Review describes the interactive roles of the renin–angiotensin system, the complement system, and the closely linked kallikrein–kinin and contact systems in cell biological functions such as vascular tone and leakage, inflammation, chemotaxis, thrombosis and cell proliferation. Specific attention is given to the role of these systems in systemic inflammation in the vasculature and tissues during hereditary angioedema, cardiovascular and renal glomerular disease, vasculitides and COVID-19. Moreover, we discuss the therapeutic implications of these complex interactions, given that modulation of one system may affect the other systems, with beneficial or deleterious consequences. The renin–angiotensin, complement and kallikrein–kinin systems comprise a multitude of mediators that modulate physiological responses during inflammatory and infectious diseases. This Review investigates the complex interactions between these systems and how these are dysregulated in various conditions, including cardiovascular diseases and COVID-19, as well as their therapeutic implications.
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35
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Prohászka Z, Frazer-Abel A. Complement multiplex testing: Concept, promises and pitfalls. Mol Immunol 2021; 140:120-126. [PMID: 34688958 DOI: 10.1016/j.molimm.2021.10.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 08/15/2021] [Accepted: 10/06/2021] [Indexed: 10/20/2022]
Abstract
Complement is a complex system. This complexity becomes more obvious when looking at complement analysis in health and disease, where one presentation can require a number of measurements to understand the full role of this cascade in the disease. The current state of clinical testing requires multiple tests to cover the whole of the complement cascade. There is a clear potential for multiplex testing to help address this need for comprehensive analysis of the state of complement deficiency, activation or inhibition. Fortunately, there are a number of potential methods for multiplex analysis, each with advantages and disadvantages that need to be considered in light of the intricacy of the complement cascade and its interconnection to other systems. Despite the complexities of such methods several groups have started utilizing multiplex analysis for research and even for diagnostic testing. The potential methods, current successes, and the type of testing that needs to be streamlined are reviewed in this text.
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Affiliation(s)
- Zoltán Prohászka
- Department of Internal Medicine and Haematology, Semmelweis University, and Research Group for Immunology and Haematology, Semmelweis University- EötvösLoránd Research Network (Office for Supported Research Groups), Budapest, Hungary
| | - Ashley Frazer-Abel
- Exsera BioLabs, University of Colorado School of Medicine, Aurora, CO, USA.
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36
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Padilla S, Nurden AT, Prado R, Nurden P, Anitua E. Healing through the lens of immunothrombosis: Biology-inspired, evolution-tailored, and human-engineered biomimetic therapies. Biomaterials 2021; 279:121205. [PMID: 34710794 DOI: 10.1016/j.biomaterials.2021.121205] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 09/30/2021] [Accepted: 10/20/2021] [Indexed: 12/14/2022]
Abstract
Evolution, from invertebrates to mammals, has yielded and shaped immunoclotting as a defense and repair response against trauma and infection. This mosaic of immediate and local wound-sealing and pathogen-killing mechanisms results in survival, restoration of homeostasis, and tissue repair. In mammals, immunoclotting has been complemented with the neuroendocrine system, platelets, and contact system among other embellishments, adding layers of complexity through interconnecting blood-born proteolytic cascades, blood cells, and the neuroendocrine system. In doing so, immunothrombosis endows humans with survival advantages, but entails vulnerabilities in the current unprecedented and increasingly challenging environment. Immunothrombosis and tissue repair appear to go hand in hand with common mechanisms mediating both processes, a fact that is underlined by recent advances that are deciphering the mechanisms of the repair process and of the biochemical pathways that underpins coagulation, hemostasis and thrombosis. This review is intended to frame both the universal aspects of tissue repair and the therapeutic use of autologous fibrin matrix as a biology-as-a-drug approach in the context of the evolutionary changes in coagulation and hemostasis. In addition, we will try to shed some light on the molecular mechanisms underlying the use of the autologous fibrin matrix as a biology-inspired, evolution-tailored, and human-engineered biomimetic therapy.
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Affiliation(s)
- Sabino Padilla
- Eduardo Anitua Foundation for Biomedical Research, Vitoria, Spain; BTI-Biotechnology Institute ImasD, Vitoria, Spain; University Institute for Regenerative Medicine & Oral Implantology - UIRMI (UPV/EHU-Fundación Eduardo Anitua), Vitoria, Spain.
| | - Alan T Nurden
- Institut Hospitalo-Universitaire LIRYC, Hôpital Xavier Arnozan, Pessac, France
| | - Roberto Prado
- Eduardo Anitua Foundation for Biomedical Research, Vitoria, Spain; BTI-Biotechnology Institute ImasD, Vitoria, Spain; University Institute for Regenerative Medicine & Oral Implantology - UIRMI (UPV/EHU-Fundación Eduardo Anitua), Vitoria, Spain
| | - Paquita Nurden
- Institut Hospitalo-Universitaire LIRYC, Hôpital Xavier Arnozan, Pessac, France
| | - Eduardo Anitua
- Eduardo Anitua Foundation for Biomedical Research, Vitoria, Spain; BTI-Biotechnology Institute ImasD, Vitoria, Spain; University Institute for Regenerative Medicine & Oral Implantology - UIRMI (UPV/EHU-Fundación Eduardo Anitua), Vitoria, Spain.
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37
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Hajishengallis G, Hasturk H, Lambris JD. C3-targeted therapy in periodontal disease: moving closer to the clinic. Trends Immunol 2021; 42:856-864. [PMID: 34483038 PMCID: PMC8487962 DOI: 10.1016/j.it.2021.08.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 08/03/2021] [Accepted: 08/06/2021] [Indexed: 02/07/2023]
Abstract
Complement plays a key role in immunosurveillance and homeostasis. When dysregulated or overactivated, complement can become a pathological effector, as seen in several inflammatory disorders, including periodontal disease. Recently, clinical correlative studies and preclinical mechanistic investigations have collectively demonstrated that complement is hyperactivated during periodontitis and that targeting its central component (C3) provides therapeutic benefit in nonhuman primates (NHPs). The preclinical efficacy of a C3-targeted drug candidate combined with excellent safety and pharmacokinetic profiles supported its use in a recent Phase IIa clinical study in which C3 inhibition resolved gingival inflammation in patients with periodontal disease. We posit that C3-targeted intervention might represent a novel and transformative host-modulation therapy meriting further investigation in Phase III clinical trials for the treatment of periodontitis.
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Affiliation(s)
- George Hajishengallis
- University of Pennsylvania, Penn Dental Medicine, Department of Basic and Translational Sciences, Philadelphia, PA, USA.
| | - Hatice Hasturk
- The Forsyth Institute, Center for Clinical and Translational Research, Cambridge, MA, USA.
| | - John D Lambris
- University of Pennsylvania, Perelman School of Medicine, Department of Pathology and Laboratory Medicine, Philadelphia, USA.
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38
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Ruhoff AM, Hong JK, Gao L, Singh J, Tran C, Mackie G, Waterhouse A. Biomaterial Wettability Affects Fibrin Clot Structure and Fibrinolysis. Adv Healthc Mater 2021; 10:e2100988. [PMID: 34423587 DOI: 10.1002/adhm.202100988] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/29/2021] [Indexed: 12/20/2022]
Abstract
Thrombosis on blood-contacting medical devices can cause patient fatalities through device failure and unstable thrombi causing embolism. The effect of material wettability on fibrin network formation, structure, and stability is poorly understood. Under static conditions, fibrin fiber network volume and density increase in clots formed on hydrophilic compared to hydrophobic polystyrene surfaces. This correlates with reduced plasma clotting time and increased factor XIIa (FXIIa) activity. These structural differences are consistent up to 50 µm away from the material surface and are FXIIa dependent. Fibrin forms fibers immediately at the material interface on hydrophilic surfaces but are incompletely formed in the first 5 µm above hydrophobic surfaces. Additionally, fibrin clots on hydrophobic surfaces have increased susceptibility to fibrinolysis compared to clots formed on hydrophilic surfaces. Under low-flow conditions, clots are still denser on hydrophilic surfaces, but only 5 µm above the surface, showing the combined effect of the surface wettability and coagulation factor dilution with low flow. Overall, wettability affects fibrin fiber formation at material interfaces, which leads to differences in bulk fibrin clot density and susceptibility to fibrinolysis. These findings have implications for thrombus formed in stagnant or low-flow regions of medical devices and the design of nonthrombogenic materials.
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Affiliation(s)
- Alexander M. Ruhoff
- Heart Research Institute 7 Eliza Street Newtown NSW 2042 Australia
- The Charles Perkins Centre The University of Sydney Sydney NSW 2006 Australia
- Faculty of Medicine and Health The University of Sydney Sydney NSW 2006 Australia
| | - Jun Ki Hong
- Heart Research Institute 7 Eliza Street Newtown NSW 2042 Australia
- The Charles Perkins Centre The University of Sydney Sydney NSW 2006 Australia
- School of Chemistry Faculty of Science The University of Sydney Sydney NSW 2006 Australia
- School of Medical Sciences Faculty of Medicine and Health The University of Sydney Sydney NSW 2006 Australia
- The University of Sydney Nano Institute The University of Sydney Sydney NSW 2006 Australia
| | - Lingzi Gao
- Heart Research Institute 7 Eliza Street Newtown NSW 2042 Australia
- The Charles Perkins Centre The University of Sydney Sydney NSW 2006 Australia
- Faculty of Medicine and Health The University of Sydney Sydney NSW 2006 Australia
| | - Jasneil Singh
- Heart Research Institute 7 Eliza Street Newtown NSW 2042 Australia
- The Charles Perkins Centre The University of Sydney Sydney NSW 2006 Australia
- School of Medical Sciences Faculty of Medicine and Health The University of Sydney Sydney NSW 2006 Australia
- School of Biomedical Engineering Faculty of Engineering The University of Sydney Sydney NSW 2006 Australia
| | - Clara Tran
- School of Biomedical Engineering Faculty of Engineering The University of Sydney Sydney NSW 2006 Australia
- School of Physics Faculty of Science The University of Sydney Sydney NSW 2006 Australia
| | - Grace Mackie
- Heart Research Institute 7 Eliza Street Newtown NSW 2042 Australia
- The Charles Perkins Centre The University of Sydney Sydney NSW 2006 Australia
- Faculty of Medicine and Health The University of Sydney Sydney NSW 2006 Australia
| | - Anna Waterhouse
- Heart Research Institute 7 Eliza Street Newtown NSW 2042 Australia
- The Charles Perkins Centre The University of Sydney Sydney NSW 2006 Australia
- School of Medical Sciences Faculty of Medicine and Health The University of Sydney Sydney NSW 2006 Australia
- The University of Sydney Nano Institute The University of Sydney Sydney NSW 2006 Australia
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Bomback AS, Appel GB, Gipson DS, Hladunewich MA, Lafayette R, Nester CM, Parikh SV, Smith RJH, Trachtman H, Heeger PS, Ram S, Rovin BH, Ali S, Arceneaux N, Ashoor I, Bailey-Wickins L, Barratt J, Beck L, Cattran DC, Cravedi P, Erkan E, Fervenza F, Frazer-Abel AA, Fremeaux-Bacchi V, Fuller L, Gbadegesin R, Hogan JJ, Kiryluk K, le Quintrec-Donnette M, Licht C, Mahan JD, Pickering MC, Quigg R, Rheault M, Ronco P, Sarwal MM, Sethna C, Spino C, Stegall M, Vivarelli M, Feldman DL, Thurman JM. Improving Clinical Trials for Anticomplement Therapies in Complement-Mediated Glomerulopathies: Report of a Scientific Workshop Sponsored by the National Kidney Foundation. Am J Kidney Dis 2021; 79:570-581. [PMID: 34571062 DOI: 10.1053/j.ajkd.2021.07.025] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 07/13/2021] [Indexed: 12/25/2022]
Abstract
Blocking the complement system as a therapeutic strategy has been proposed for numerous glomerular diseases but presents myriad questions and challenges, not the least of which is demonstrating efficacy and safety. In light of these potential issues and because there are an increasing number of anticomplement therapy trials either planned or under way, the National Kidney Foundation facilitated an all-virtual scientific workshop entitled "Improving Clinical Trials for Anti-Complement Therapies in Complement-Mediated Glomerulopathies." Attended by patient representatives and experts in glomerular diseases, complement physiology, and clinical trial design, the aim of this workshop was to develop standards applicable for designing and conducting clinical trials for anticomplement therapies across a wide spectrum of complement-mediated glomerulopathies. Discussions focused on study design, participant risk assessment and mitigation, laboratory measurements and biomarkers to support these studies, and identification of optimal outcome measures to detect benefit, specifically for trials in complement-mediated diseases. This report summarizes the discussions from this workshop and outlines consensus recommendations.
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Affiliation(s)
- Andrew S Bomback
- Division of Nephrology, Columbia University Irving Medical Center, New York.
| | - Gerald B Appel
- Division of Nephrology, New York University Langone Health, New York
| | - Debbie S Gipson
- Department of Pediatrics, Division of Nephrology, University of Michigan, Ann Arbor, Michigan
| | | | | | - Carla M Nester
- Division of Nephrology, University of Iowa, Iowa City, Iowa
| | - Samir V Parikh
- Division of Nephrology, The Ohio State University College of Medicine, Columbus, Ohio
| | - Richard J H Smith
- Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa
| | - Howard Trachtman
- Division of Nephrology, New York University Langone Health, New York
| | - Peter S Heeger
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York
| | - Sanjay Ram
- Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Brad H Rovin
- Division of Nephrology, The Ohio State University College of Medicine, Columbus, Ohio
| | | | | | - Isa Ashoor
- Division of Nephrology, Louisiana State University Health, New Orleans, Louisiana
| | | | | | - Laurence Beck
- Division of Nephrology, Boston University School of Medicine, Boston, Massachusetts
| | - Daniel C Cattran
- Division of Nephrology, University of Toronto, Toronto, ON, Canada
| | - Paolo Cravedi
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York
| | - Elif Erkan
- Division of Nephrology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | | | - Ashley A Frazer-Abel
- Division of Nephrology, University of Colorado School of Medicine, Aurora, Colorado
| | | | | | | | - Jonathan J Hogan
- Division of Nephrology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Krzysztof Kiryluk
- Division of Nephrology, Columbia University Irving Medical Center, New York
| | | | - Christoph Licht
- Division of Nephrology, University of Toronto, Toronto, ON, Canada
| | - John D Mahan
- Division of Nephrology, The Ohio State University College of Medicine, Columbus, Ohio
| | | | - Richard Quigg
- Division of Nephrology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York
| | - Michelle Rheault
- Division of Nephrology, University of Minnesota, Minneapolis, Minnesota
| | - Pierre Ronco
- Division of Nephrology, Sorbonne Université, Université Pierre et Marie Curie, Paris
| | - Minnie M Sarwal
- Division of Nephrology, University of California, San Francisco, California
| | - Christine Sethna
- Division of Nephrology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York
| | - Cathie Spino
- Department of Biostatistics, University of Michigan, Ann Arbor, Michigan
| | | | - Marina Vivarelli
- Division of Nephrology, Bambino Gesu Children's Hospital, Rome, Italy
| | | | - Joshua M Thurman
- Division of Nephrology, University of Colorado School of Medicine, Aurora, Colorado
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Nilsson PH, Johnson C, Quach QH, Macpherson A, Durrant O, Pischke SE, Fure H, Landsem A, Bergseth G, Schjalm C, Haugaard-Kedström LM, Huber-Lang M, van den Elsen J, Brekke OL, Mollnes TE. A Conformational Change of Complement C5 Is Required for Thrombin-Mediated Cleavage, Revealed by a Novel Ex Vivo Human Whole Blood Model Preserving Full Thrombin Activity. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2021; 207:1641-1651. [PMID: 34380648 PMCID: PMC8428748 DOI: 10.4049/jimmunol.2001471] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 07/09/2021] [Indexed: 11/19/2022]
Abstract
Thrombin activation of C5 connects thrombosis to inflammation. Complement research in whole blood ex vivo necessitates anticoagulation, which potentially interferes with the inflammatory modulation by thrombin. We challenged the concept of thrombin as an activator of native C5 by analyzing complement activation and C5 cleavage in human whole blood anticoagulated with Gly-Pro-Arg-Pro (GPRP), a peptide targeting fibrin polymerization downstream of thrombin, allowing complete endogenous thrombin generation. GPRP dose-dependently inhibited coagulation but allowed for platelet activation in accordance with thrombin generation. Spontaneous and bacterial-induced complement activation by Escherichia coli and Staphylococcus aureus, analyzed at the level of C3 and C5, were similar in blood anticoagulated with GPRP and the thrombin inhibitor lepirudin. In the GPRP model, endogenous thrombin, even at supra-physiologic concentrations, did not cleave native C5, despite efficiently cleaving commercially sourced purified C5 protein, both in buffer and when added to C5-deficient serum. In normal serum, only exogenously added, commercially sourced C5 was cleaved, whereas the native plasma C5 remained intact. Crucially, affinity-purified C5, eluted under mild conditions using an MgCl2 solution, was not cleaved by thrombin. Acidification of plasma to pH ≤ 6.8 by hydrochloric or lactic acid induced a C5 antigenic change, nonreversible by pH neutralization, that permitted cleavage by thrombin. Circular dichroism on purified C5 confirmed the structural change during acidification. Thus, we propose that pH-induced conformational change allows thrombin-mediated cleavage of C5 and that, contrary to previous reports, thrombin does not cleave plasma C5 in its native form, suggesting that thrombin cleavage of C5 may be restricted to certain pathophysiological conditions.
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Affiliation(s)
- Per H Nilsson
- Department of Immunology, University of Oslo and Oslo University Hospital Rikshospitalet, Oslo, Norway
- Linnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden
- Department of Chemistry and Biomedical Sciences, Linnaeus University, Kalmar, Sweden
| | - Christina Johnson
- Department of Immunology, University of Oslo and Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Quang Huy Quach
- Department of Immunology, University of Oslo and Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Alex Macpherson
- UCB, Slough, UK
- Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
| | - Oliver Durrant
- UCB, Slough, UK
- Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
| | - Soeren E Pischke
- Department of Immunology, University of Oslo and Oslo University Hospital Rikshospitalet, Oslo, Norway
- Clinic for Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway
| | - Hilde Fure
- Research Laboratory, Nordland Hospital, Bodø, Norway
| | - Anne Landsem
- Research Laboratory, Nordland Hospital, Bodø, Norway
- Faculty of Health Sciences, K. G. Jebsen Thrombosis Research Center, University of Tromsø - The Arctic University of Norway, Tromsø, Norway
| | | | - Camilla Schjalm
- Department of Immunology, University of Oslo and Oslo University Hospital Rikshospitalet, Oslo, Norway
| | | | - Markus Huber-Lang
- Department of Orthopedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany
| | - Jean van den Elsen
- Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
- Centre for Therapeutic Innovation, University of Bath, Bath, UK; and
| | - Ole-Lars Brekke
- Research Laboratory, Nordland Hospital, Bodø, Norway
- Faculty of Health Sciences, K. G. Jebsen Thrombosis Research Center, University of Tromsø - The Arctic University of Norway, Tromsø, Norway
| | - Tom Eirik Mollnes
- Department of Immunology, University of Oslo and Oslo University Hospital Rikshospitalet, Oslo, Norway;
- Research Laboratory, Nordland Hospital, Bodø, Norway
- Faculty of Health Sciences, K. G. Jebsen Thrombosis Research Center, University of Tromsø - The Arctic University of Norway, Tromsø, Norway
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway
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Elevated plasma concentration of complement factor C5 is associated with risk of future venous thromboembolism. Blood 2021; 138:2129-2137. [PMID: 34339498 DOI: 10.1182/blood.2021010822] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 07/05/2021] [Indexed: 11/20/2022] Open
Abstract
The role of complement in the pathogenesis of venous thromboembolism (VTE) is unclear. We aimed to (i) investigate whether plasma complement component C5 levels are influenced by genetic variants or chronic inflammation, and (ii) investigate the association between plasma C5 and risk of future VTE in a nested case-control study with 415 VTE patients and 848 age- and sex-matched controls derived from the Tromsø study. Plasma C5 levels were measured at inclusion. Odds ratios (ORs) with 95% confidence intervals (95% CI) for provoked and unprovoked VTE across tertiles of C5 concentrations were estimated using logistic regression. C-reactive protein (CRP) was adjusted for as a proxy for general inflammation. Whole exome sequencing and protein quantitative trait loci analyses were performed to assess genetic influence on C5 concentrations. There was no association between genome-wide or C5-related gene variants and C5 levels. The association between plasma C5 levels and VTE risk displayed a threshold effect, where subjects with C5 levels above the lowest tertile had increased VTE risk. Subjects in tertile 3 (highest C5 levels) had an age and sex-adjusted OR of 1.45 (95% CI 1.07-1.96) compared to tertile 1 (lowest). This was more pronounced for unprovoked VTE (OR 1.70, 95% CI 1.11-2.60). Adjustments for body mass index and CRP had minor impact on risk estimates. The ORs increased substantially with shorter time between blood sampling and VTE event. In conclusion, plasma C5 was associated with risk of future VTE. C5 levels were not genetically regulated and only slightly influenced by chronic inflammation.
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Mannes M, Schmidt CQ, Nilsson B, Ekdahl KN, Huber-Lang M. Complement as driver of systemic inflammation and organ failure in trauma, burn, and sepsis. Semin Immunopathol 2021; 43:773-788. [PMID: 34191093 PMCID: PMC8243057 DOI: 10.1007/s00281-021-00872-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 05/23/2021] [Indexed: 02/08/2023]
Abstract
Complement is one of the most ancient defense systems. It gets strongly activated immediately after acute injuries like trauma, burn, or sepsis and helps to initiate regeneration. However, uncontrolled complement activation contributes to disease progression instead of supporting healing. Such effects are perceptible not only at the site of injury but also systemically, leading to systemic activation of other intravascular cascade systems eventually causing dysfunction of several vital organs. Understanding the complement pathomechanism and its interplay with other systems is a strict requirement for exploring novel therapeutic intervention routes. Ex vivo models exploring the cross-talk with other systems are rather limited, which complicates the determination of the exact pathophysiological roles that complement has in trauma, burn, and sepsis. Literature reporting on these three conditions is often controversial regarding the importance, distribution, and temporal occurrence of complement activation products further hampering the deduction of defined pathophysiological pathways driven by complement. Nevertheless, many in vitro experiments and animal models have shown beneficial effects of complement inhibition at different levels of the cascade. In the future, not only inhibition but also a complement reconstitution therapy should be considered in prospective studies to expedite how meaningful complement-targeted interventions need to be tailored to prevent complement augmented multi-organ failure after trauma, burn, and sepsis. This review summarizes clinically relevant studies investigating the role of complement in the acute diseases trauma, burn, and sepsis with important implications for clinical translation.
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Affiliation(s)
- Marco Mannes
- Institute of Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Helmholtzstr. 8/2, 89081, Ulm, Germany
| | - Christoph Q Schmidt
- Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany
| | - Bo Nilsson
- Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden
| | - Kristina N Ekdahl
- Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden.,Linnaeus Center of Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Helmholtzstr. 8/2, 89081, Ulm, Germany.
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Nossent EJ, Schuurman AR, Reijnders TDY, Saris A, Jongerius I, Blok SG, de Vries H, Duitman J, Vonk Noordegraaf A, Meijboom LJ, Lutter R, Heunks L, Bogaard HJ, van der Poll T. Pulmonary Procoagulant and Innate Immune Responses in Critically Ill COVID-19 Patients. Front Immunol 2021; 12:664209. [PMID: 34054832 PMCID: PMC8160522 DOI: 10.3389/fimmu.2021.664209] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 04/30/2021] [Indexed: 12/14/2022] Open
Abstract
Rationale Systemic activation of procoagulant and inflammatory mechanisms has been implicated in the pathogenesis of COVID-19. Knowledge of activation of these host response pathways in the lung compartment of COVID-19 patients is limited. Objectives To evaluate local and systemic activation of coagulation and interconnected inflammatory responses in critically ill COVID-19 patients with persistent acute respiratory distress syndrome. Methods Paired bronchoalveolar lavage fluid and plasma samples were obtained from 17 patients with COVID-19 related persistent acute respiratory distress syndrome (mechanical ventilation > 7 days) 1 and 2 weeks after start mechanical ventilation and compared with 8 healthy controls. Thirty-four host response biomarkers stratified into five functional domains (coagulation, complement system, cytokines, chemokines and growth factors) were measured. Measurements and Main Results In all patients, all functional domains were activated, especially in the bronchoalveolar compartment, with significantly increased levels of D-dimers, thrombin-antithrombin complexes, soluble tissue factor, C1-inhibitor antigen and activity levels, tissue type plasminogen activator, plasminogen activator inhibitor type I, soluble CD40 ligand and soluble P-selectin (coagulation), next to activation of C3bc and C4bc (complement) and multiple interrelated cytokines, chemokines and growth factors. In 10 patients in whom follow-up samples were obtained between 3 and 4 weeks after start mechanical ventilation many bronchoalveolar and plasma host response biomarkers had declined. Conclusions Critically ill, ventilated patients with COVID-19 show strong responses relating to coagulation, the complement system, cytokines, chemokines and growth factors in the bronchoalveolar compartment. These results suggest a local pulmonary rather than a systemic procoagulant and inflammatory “storm” in severe COVID-19.
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Affiliation(s)
- Esther J Nossent
- Department of Pulmonary Medicine, Amsterdam UMC, Free University Amsterdam, Amsterdam, Netherlands.,Amsterdam Cardiovascular Sciences Research Institute, Amsterdam UMC, Amsterdam, Netherlands
| | - Alex R Schuurman
- Center for Experimental and Molecular Medicine, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.,Amsterdam Infection & Immunity Institute, Amsterdam UMC, Amsterdam, Netherlands
| | - Tom D Y Reijnders
- Center for Experimental and Molecular Medicine, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.,Amsterdam Infection & Immunity Institute, Amsterdam UMC, Amsterdam, Netherlands
| | - Anno Saris
- Center for Experimental and Molecular Medicine, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.,Amsterdam Infection & Immunity Institute, Amsterdam UMC, Amsterdam, Netherlands
| | - Ilse Jongerius
- Department of Immunopathology, Sanquin Research, Amsterdam and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.,Emma Children's Hospital, Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Siebe G Blok
- Department of Pulmonary Medicine, Amsterdam UMC, Free University Amsterdam, Amsterdam, Netherlands
| | - Heder de Vries
- Amsterdam Cardiovascular Sciences Research Institute, Amsterdam UMC, Amsterdam, Netherlands.,Department of Intensive Care Medicine, Amsterdam UMC, Free University Amsterdam, Amsterdam, Netherlands
| | - JanWillem Duitman
- Center for Experimental and Molecular Medicine, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.,Amsterdam Infection & Immunity Institute, Amsterdam UMC, Amsterdam, Netherlands
| | - Anton Vonk Noordegraaf
- Department of Pulmonary Medicine, Amsterdam UMC, Free University Amsterdam, Amsterdam, Netherlands.,Amsterdam Cardiovascular Sciences Research Institute, Amsterdam UMC, Amsterdam, Netherlands
| | - Lilian J Meijboom
- Amsterdam Cardiovascular Sciences Research Institute, Amsterdam UMC, Amsterdam, Netherlands.,Department of Radiology and Nuclear Medicine, Amsterdam UMC, Free University Amsterdam, Amsterdam, Netherlands
| | - René Lutter
- Department of Pulmonary Medicine, Amsterdam UMC, Free University Amsterdam, Amsterdam, Netherlands.,Amsterdam Infection & Immunity Institute, Amsterdam UMC, Amsterdam, Netherlands.,Department of Experimental Immunology, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Leo Heunks
- Amsterdam Cardiovascular Sciences Research Institute, Amsterdam UMC, Amsterdam, Netherlands.,Department of Intensive Care Medicine, Amsterdam UMC, Free University Amsterdam, Amsterdam, Netherlands
| | - Harm Jan Bogaard
- Department of Pulmonary Medicine, Amsterdam UMC, Free University Amsterdam, Amsterdam, Netherlands.,Amsterdam Cardiovascular Sciences Research Institute, Amsterdam UMC, Amsterdam, Netherlands
| | - Tom van der Poll
- Center for Experimental and Molecular Medicine, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.,Amsterdam Infection & Immunity Institute, Amsterdam UMC, Amsterdam, Netherlands.,Department of Infectious Diseases, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
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RNA-Seq analysis reveals critical transcriptome changes caused by sodium butyrate in DN mouse models. Biosci Rep 2021; 41:228173. [PMID: 33779731 PMCID: PMC8035627 DOI: 10.1042/bsr20203005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 03/09/2021] [Accepted: 03/25/2021] [Indexed: 12/11/2022] Open
Abstract
Diabetic nephropathy (DN)—a common complication of diabetes—is the primary cause of end-stage renal disease. Sodium butyrate (NaB) is a short-chain fatty acid (SCFA) that is a metabolic product of intestinal bacterium, and its protective effect on the kidney has been reported in cases of DN. However, its underlying mechanism remains unclear. The aim of the present study was to investigate the effect of NaB on globe transcriptome changes in DN. In our study, 8-week-old male db/db mice suffering from DN were randomly divided into two groups: the DN+NaB group (DN mice treated with NaB, 5 g/kg/day) and the DN group (DN mice treated with saline). Further, normal db/m mice were used as the normal control (NC) group. The blood glucose, body weight, urinary microalbumin and urinary creatinine of mice were measured for all three groups. Whole-transcriptome analysis was performed by RNA sequencing (RNA-Seq) to evaluate the profiling of long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs). Bioinformatics analysis was performed to predict the potential NaB-related lncRNAs and genes in DN. The expressions of lncRNAs and mRNAs were tested using the quantitative real-time polymerase chain reactions (qRT-PCRs) in renal tissues and mesangial cells treated with NaB. The results of the present study demonstrated that NaB ameliorated renal dysfunction in DN mice. Moreover, RNA-Seq results identified that some lncRNAs and mRNAs were reversely changed in the DN+NaB group in comparison to those in the DN group. Additionally, the integrated co-expression networks of NaB-related lncRNAs revealed that these lncRNAs interacted with 155 key mRNAs. Furthermore, the co-expression network of inflammation-related lncRNAs and mRNAs demonstrated that those reversed lncRNAs and mRNAs also play essential roles in the inflammatory response. In summary, the present study suggests that NaB ameliorates diabetes-induced renal dysfunction and regulates transcriptome changes in DN.
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45
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Roopkumar J, Swaidani S, Kim AS, Thapa B, Gervaso L, Hobbs BP, Wei W, Alban TJ, Funchain P, Kundu S, Sangwan N, Rayman P, Pavicic PG, Diaz-Montero CM, Barnard J, McCrae KR, Khorana AA. Increased Incidence of Venous Thromboembolism with Cancer Immunotherapy. MED 2021; 2:423-434. [PMID: 34036293 PMCID: PMC8143033 DOI: 10.1016/j.medj.2021.02.002] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Cancer immunotherapy is associated with several immune-related adverse events, but the relationship between immunotherapy and venous thromboembolism has not been thoroughly studied. METHODS We conducted a retrospective cohort study of 1,686 patients who received immunotherapy for a variety of malignancies to determine the incidence of venous thromboembolism and the impact of venous thromboembolism on survival. To examine the potential role of inflammation in venous thromboembolism, we also profiled immune cells and plasma cytokines in blood samples obtained prior to initiation of immunotherapy in a sub-cohort of patients treated on clinical trials who subsequently did (N = 15), or did not (N = 10) develop venous thromboembolism. FINDINGS Venous thromboembolism occurred while on immunotherapy in 404/1686 patients (24%) and was associated with decreased overall survival [HR=1.22 (95% CI 1.06-1.41), p<0.008]. Patients that developed venous thromboembolism had significantly higher pretreatment levels of myeloid-derived suppressor cells (5.382 ± 0.873 vs. 3.341 ± 0.3402, mean ± SEM; p=0.0045), interleukin 8 (221.2 ± 37.53 vs. 111.6 ± 25.36, mean ± SEM; p=0.016), and soluble vascular cell adhesion protein 1 (1210 ± 120.6 vs. 895.5 ± 53.34, mean ± SEM; p=0.0385). CONCLUSIONS These findings demonstrate that venous thromboembolism is an underappreciated and important immune-related adverse event associated with cancer immunotherapy, and may implicate an interleukin 8 and myeloid-derived suppressor cell-driven pathway in pathogenesis.
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Affiliation(s)
- Joanna Roopkumar
- Department of Hematology & Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
| | - Shadi Swaidani
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Ann S. Kim
- Department of Hematology & Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
| | - Bicky Thapa
- Department of Hematology & Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
| | - Lorenzo Gervaso
- Department of Hematology & Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
| | - Brian P. Hobbs
- Department of Hematology & Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
| | - Wei Wei
- Department of Hematology & Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
| | - Tyler J Alban
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Pauline Funchain
- Department of Hematology & Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
| | - Suman Kundu
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Naseer Sangwan
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Patricia Rayman
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Paul G. Pavicic
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - C. Marcela Diaz-Montero
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - John Barnard
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Keith R. McCrae
- Department of Hematology & Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
| | - Alok A. Khorana
- Department of Hematology & Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
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Garred P, Tenner AJ, Mollnes TE. Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics. Pharmacol Rev 2021; 73:792-827. [PMID: 33687995 PMCID: PMC7956994 DOI: 10.1124/pharmrev.120.000072] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The complement system was discovered at the end of the 19th century as a heat-labile plasma component that "complemented" the antibodies in killing microbes, hence the name "complement." Complement is also part of the innate immune system, protecting the host by recognition of pathogen-associated molecular patterns. However, complement is multifunctional far beyond infectious defense. It contributes to organ development, such as sculpting neuron synapses, promoting tissue regeneration and repair, and rapidly engaging and synergizing with a number of processes, including hemostasis leading to thromboinflammation. Complement is a double-edged sword. Although it usually protects the host, it may cause tissue damage when dysregulated or overactivated, such as in the systemic inflammatory reaction seen in trauma and sepsis and severe coronavirus disease 2019 (COVID-19). Damage-associated molecular patterns generated during ischemia-reperfusion injuries (myocardial infarction, stroke, and transplant dysfunction) and in chronic neurologic and rheumatic disease activate complement, thereby increasing damaging inflammation. Despite the long list of diseases with potential for ameliorating complement modulation, only a few rare diseases are approved for clinical treatment targeting complement. Those currently being efficiently treated include paroxysmal nocturnal hemoglobinuria, atypical hemolytic-uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorders. Rare diseases, unfortunately, preclude robust clinical trials. The increasing evidence for complement as a pathogenetic driver in many more common diseases suggests an opportunity for future complement therapy, which, however, requires robust clinical trials; one ongoing example is COVID-19 disease. The current review aims to discuss complement in disease pathogenesis and discuss future pharmacological strategies to treat these diseases with complement-targeted therapies. SIGNIFICANCE STATEMENT: The complement system is the host's defense friend by protecting it from invading pathogens, promoting tissue repair, and maintaining homeostasis. Complement is a double-edged sword, since when dysregulated or overactivated it becomes the host's enemy, leading to tissue damage, organ failure, and, in worst case, death. A number of acute and chronic diseases are candidates for pharmacological treatment to avoid complement-dependent damage, ranging from the well established treatment for rare diseases to possible future treatment of large patient groups like the pandemic coronavirus disease 2019.
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Affiliation(s)
- Peter Garred
- Laboratory of Molecular Medicine, Department of Clinical Immunology, Rigshospitalet, Copenhagen, Denmark, and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (P.G.); Departments of Molecular Biology and Biochemistry, Neurobiology and Behavior, and Pathology and Laboratory Medicine, University of California, Irvine, California (A.J.T.); and Research Laboratory, Nordland Hospital, Bodø, Norway, Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway (T.E.M.); Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway (T.E.M.); and Department of Immunology, Oslo University Hospital and University of Oslo, Oslo, Norway (T.E.M.)
| | - Andrea J Tenner
- Laboratory of Molecular Medicine, Department of Clinical Immunology, Rigshospitalet, Copenhagen, Denmark, and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (P.G.); Departments of Molecular Biology and Biochemistry, Neurobiology and Behavior, and Pathology and Laboratory Medicine, University of California, Irvine, California (A.J.T.); and Research Laboratory, Nordland Hospital, Bodø, Norway, Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway (T.E.M.); Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway (T.E.M.); and Department of Immunology, Oslo University Hospital and University of Oslo, Oslo, Norway (T.E.M.)
| | - Tom E Mollnes
- Laboratory of Molecular Medicine, Department of Clinical Immunology, Rigshospitalet, Copenhagen, Denmark, and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (P.G.); Departments of Molecular Biology and Biochemistry, Neurobiology and Behavior, and Pathology and Laboratory Medicine, University of California, Irvine, California (A.J.T.); and Research Laboratory, Nordland Hospital, Bodø, Norway, Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway (T.E.M.); Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway (T.E.M.); and Department of Immunology, Oslo University Hospital and University of Oslo, Oslo, Norway (T.E.M.)
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48
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Hu W, Wang X, Su G. Infective endocarditis complicated by embolic events: Pathogenesis and predictors. Clin Cardiol 2021; 44:307-315. [PMID: 33527443 PMCID: PMC7943911 DOI: 10.1002/clc.23554] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 01/15/2021] [Accepted: 01/20/2021] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND Infective endocarditis (IE) continues to be associated with great challenges. Embolic events (EE) are frequent and life-threatening complications in IE patients. It remains challenging to predict and assess the embolic risk in individual patients with IE accurately. HYPOTHESIS Accurate prediction of embolization is critical in the early identification and treatment of risky and potentially embolic lesions in patients with IE. METHODS We searched the PubMed, Web of Science, and Google Scholar databases using a range of related search terms, and reviewed the literatures about the pathogenesis and embolic predictors of IE. RESULTS The development of IE and its complications is widely accepted as the result of complex interactions between microorganisms, valve endothelium, and host immune responses. The predictive value of echocardiographic characteristics is the most powerful for EE. In addition, both easily obtained blood biomarkers such as C-reactive protein, mean platelet volume, neutrophil-to-lymphocyte ratio, anti-β2-glycoprotein I antibodies, D-Dimer, troponin I, matrix metalloproteinases, and several microbiological or clinical characteristics might be promising as potential predictors of EE. CONCLUSION Our review provides a synthesis of current knowledge regarding the pathogenesis and predictors of embolism in IE along with a review of potentially emerging biomarkers.
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Affiliation(s)
- Wangling Hu
- Department of CardiologyUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Xindi Wang
- Department of HematologyUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Guanhua Su
- Department of CardiologyUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
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Lipcsey M, Persson B, Eriksson O, Blom AM, Fromell K, Hultström M, Huber-Lang M, Ekdahl KN, Frithiof R, Nilsson B. The Outcome of Critically Ill COVID-19 Patients Is Linked to Thromboinflammation Dominated by the Kallikrein/Kinin System. Front Immunol 2021; 12:627579. [PMID: 33692801 PMCID: PMC7937878 DOI: 10.3389/fimmu.2021.627579] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 01/18/2021] [Indexed: 01/08/2023] Open
Abstract
An important manifestation of severe COVID-19 is the ARDS-like lung injury that is associated with vascular endothelialitis, thrombosis, and angiogenesis. The intravascular innate immune system (IIIS), including the complement, contact, coagulation, and fibrinolysis systems, which is crucial for recognizing and eliminating microorganisms and debris in the body, is likely to be involved in the pathogenesis of COVID-19 ARDS. Biomarkers for IIIS activation were studied in the first 66 patients with COVID-19 admitted to the ICU in Uppsala University Hospital, both cross-sectionally on day 1 and in 19 patients longitudinally for up to a month, in a prospective study. IIIS analyses were compared with biochemical parameters and clinical outcome and survival. Blood cascade systems activation leading to an overreactive conjunct thromboinflammation was demonstrated, reflected in consumption of individual cascade system components, e.g., FXII, prekallikrein, and high molecular weight kininogen and in increased levels of activation products, e.g., C4d, C3a, C3d,g, sC5b-9, TAT, and D-dimer. Strong associations were found between the blood cascade systems and organ damage, illness severity scores, and survival. We show that critically ill COVID-19 patients display a conjunct activation of the IIIS that is linked to organ damage of the lung, heart, kidneys, and death. We present evidence that the complement and in particular the kallikrein/kinin system is strongly activated and that both systems are prognostic markers of the outcome of the patients suggesting their role in driving the inflammation. Already licensed kallikrein/kinin inhibitors are potential drugs for treatment of critically ill patients with COVID-19.
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Affiliation(s)
- Miklós Lipcsey
- Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden
- Hedenstierna Laboratory, Anesthesiology and Intensive Care, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Barbro Persson
- Department of Immunology Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Oskar Eriksson
- Department of Immunology Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Anna M. Blom
- Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Karin Fromell
- Department of Immunology Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Michael Hultström
- Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden
- Unit for Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Markus Huber-Lang
- Institute for Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, Germany
| | - Kristina N. Ekdahl
- Department of Immunology Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Linnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden
| | - Robert Frithiof
- Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden
| | - Bo Nilsson
- Department of Immunology Genetics and Pathology, Uppsala University, Uppsala, Sweden
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Complement 5 Inhibition Ameliorates Hepatic Ischemia/reperfusion Injury in Mice, Dominantly via the C5a-mediated Cascade. Transplantation 2021; 104:2065-2077. [PMID: 32384381 DOI: 10.1097/tp.0000000000003302] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Hepatic ischemia/reperfusion injury (IRI) is a serious complication in liver surgeries, including transplantation. Complement activation seems to be closely involved in hepatic IRI; however, no complement-targeted intervention has been clinically applied. We investigated the therapeutic potential of Complement 5 (C5)-targeted regulation in hepatic IRI. METHODS C5-knockout (B10D2/oSn) and their corresponding wild-type mice (WT, B10D2/nSn) were exposed to 90-minute partial (70%) hepatic ischemia/reperfusion with either anti-mouse-C5 monoclonal antibody (BB5.1) or corresponding control immunoglobulin administration 30 minutes before ischemia. C5a receptor 1 antagonist was also given to WT to identify which cascade, C5a or C5b-9, is dominant. RESULTS C5-knockout and anti-C5-Ab administration to WT both significantly reduced serum transaminase release and histopathological damages from 2 hours after reperfusion. This improvement was characterized by significantly reduced CD41+ platelet aggregation, maintained F4/80+ cells, and decreased high-mobility group box 1 release. After 6 hours of reperfusion, the infiltration of CD11+ and Ly6-G+ cells, cytokine/chemokine expression, single-stranded DNA+ cells, and cleaved caspase-3 expression were all significantly alleviated by anti-C5-Ab. C5a receptor 1 antagonist was as effective as anti-C5-Ab for reducing transaminases. CONCLUSIONS Anti-C5 antibody significantly ameliorated hepatic IRI, predominantly via the C5a-mediated cascade, not only by inhibiting platelet aggregation during the early phase but also by attenuating the activation of infiltrating macrophages/neutrophils and hepatocyte apoptosis in the late phase of reperfusion. Given its efficacy, clinical availability, and controllability, C5-targeted intervention may provide a novel therapeutic strategy against hepatic IRI.
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