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Shin J, Nahmias J, Chen P, Chen J, Lekawa M, Nguyen L, Grigorian A. Identifying the Influence of Lung-Related Injuries and Other Factors on Delirium in Traumatic Brain Injury Patients: A National Analysis. J Head Trauma Rehabil 2025:00001199-990000000-00185. [PMID: 40326920 DOI: 10.1097/htr.0000000000000992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/07/2025]
Abstract
Traumatic brain injury (TBI) is a known risk factor for delirium, a condition associated with prolonged hospitalization and cognitive deterioration. Although the relationship between TBI and delirium is established, the influence of traumatic lung injuries on delirium development is less understood. Respiratory disorders can significantly influence the central nervous system, with sequelae such as hypoxia and hypercapnia causing neurologic dysfunction. Therefore, we hypothesized that TBI patients suffering lung-associated conditions, stemming either from traumatic lung injury (TLI) or subsequent pulmonary surgery will be associated with an increased risk of developing delirium. METHODS The 2021 Trauma Quality Improvement Program database was queried for patients with TBI, excluding those with pre-existing dementia. TBI patients developing delirium were compared to those without delirium. A multivariable logistic regression analysis was performed to determine pulmonary and neurogenic-associated risk factors for delirium. RESULTS Among 155,252 TBI patients, 3244 (2.1%) developed delirium. Delirium-afflicted patients showed elevated rates of TLI (25.0% vs 13.3%, p < .001), severe head trauma (51.4% vs 37.8%, p < .001), sepsis (3.1% vs 0.5%, p < .001) and more commonly underwent pulmonary operations (21.8% vs 6.6%, p < .001). The strongest associated risk factors for delirium included unplanned intubation (OR 2.79, CI 2.47-3.16, p < .001), pulmonary surgery (OR 1.47, CI 1.32-1.63, p < .001), COPD (OR 1.52, CI 1.34-1.72, p < .001), TLI (OR 1.25, CI 1.14-1.38, p < .001), and severe head injury (OR 1.12, CI 1.04-1.22, p = .003). CONCLUSION Delirium affects approximately 2% of the national TBI population. Our study reveals an influence of lung-related conditions for delirium onset. These results emphasize the intimate relationship of the brain and pulmonary system. Future prospective studies are needed to validate these findings as they may impact TBI management and outcomes.
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Affiliation(s)
- Jordan Shin
- Author Affiliations: Department of Surgery, Division of Trauma, Burns and Surgical Critical Care, University of California, Irvine, Orange, California
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Sarkar S. Pathological role of RAGE underlying progression of various diseases: its potential as biomarker and therapeutic target. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:3467-3487. [PMID: 39589529 DOI: 10.1007/s00210-024-03595-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 10/31/2024] [Indexed: 11/27/2024]
Abstract
The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor with several structural types, performing a myriad of molecular mechanisms. The RAGE-ligand interactions play important roles in maintaining latent chronic inflammation, and oxidative damage underlying various pathological conditions like metabolic syndrome (MetS), neurodegenerative diseases, stroke, cardiovascular disorders, pulmonary disorders, cancer and infections. RAGE is thoroughly explored in knockout animals and human trials, targeted by small molecule inhibitors, peptides, diet, and natural compounds. But it is yet to be incorporated in the mainstream management of any ailment. This review performs an appraisal of the pathological mechanisms influenced by RAGE to uncover its prospects as a biomarker while also assessing its power to become a promising therapeutic target.
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Affiliation(s)
- Sinjini Sarkar
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS Deemed-to-be-University, V.L. Mehta Road, Vile Parle (W), Mumbai, 400056, India.
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Lim SH, Jung H, Youn DH, Kim TY, Han SW, Kim BJ, Lee JJ, Jeon JP. Mild Traumatic Brain Injury and Subsequent Acute Pulmonary Inflammatory Response. J Korean Neurosurg Soc 2022; 65:680-687. [PMID: 35574585 PMCID: PMC9452391 DOI: 10.3340/jkns.2021.0310] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/21/2022] [Indexed: 11/27/2022] Open
Abstract
Objective The influence of moderate-to-severe traumatic brain injury (TBI) on acute pulmonary injury is well established, but the association between acute pulmonary injury and mild TBI has not been well studied. Here, we evaluated the histological changes and fluctuations in inflammatory markers in the lungs to determine whether an acute pulmonary inflammatory response occurred after mild TBI.
Methods Mouse models of mild TBI (n=24) were induced via open-head injuries using a stereotaxic impactor. The brain and lungs were examined 6, 24, and 72 hours after injury and compared to sham-operated controls (n=24). Fluoro-Jade B staining and Astra blue and hematoxylin staining were performed to assess cerebral neuronal degeneration and pulmonary histological architecture. Quantitative real-time polymerase chain reaction analysis was done to measure inflammatory cytokines.
Results Increased neuronal degeneration and the mRNA expression of interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-10, and transforming growth factor (TGF)-β were observed after mild TBI. The IL-6, TNF-α, and TGF-β levels in mice with mild TBI were significantly different compared to those of sham-operated mice 24 hours after injury, and this was more pronounced at 72 hours. Mild TBI induced acute pulmonary interstitial edema with cell infiltration and alveolar morphological changes. In particular, a significant infiltration of mast cells was observed. Among the inflammatory cytokines, TNF-α was significantly increased in the lungs at 6 hours, but there was no significant difference 24 and 72 hours after injury.
Conclusion Mild TBI induced acute pulmonary interstitial inflammation and alveolar structural changes, which are likely to worsen the patient’s prognosis.
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Luo W, Tao Y, Chen S, Luo H, Li X, Qu S, Chen K, Zeng C. Rosmarinic Acid Ameliorates Pulmonary Ischemia/Reperfusion Injury by Activating the PI3K/Akt Signaling Pathway. Front Pharmacol 2022; 13:860944. [PMID: 35645792 PMCID: PMC9132383 DOI: 10.3389/fphar.2022.860944] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/30/2022] [Indexed: 01/01/2023] Open
Abstract
Pulmonary ischemia/reperfusion (IR) injury is the leading cause of acute lung injury, which is mainly attributed to reactive oxygen species (ROS) induced cell injuries and apoptosis. Since rosmarinic acid (RA) has been identified as an antioxidant natural ester, this natural compound might protect against pulmonary IR injury. In this study, the mice were given RA daily (50, 75, or 100 mg/kg) by gavage for 7 days before the pulmonary IR injury. We found that hypoxemia, pulmonary edema, and serum inflammation cytokines were aggravated in pulmonary IR injury. RA pretreatment (75 and 100 mg/kg) effectively reversed these parameters, while 50 mg/kg RA pretreatment was less pronounced. Our data also indicated RA pretreatment mitigated the upregulation of pro-oxidant NADPH oxidases (NOX2 and NOX4) and the downregulation of anti-oxidant superoxide dismutases (SOD1 and SOD2) upon IR injury. In vitro studies showed RA preserved the viability of anoxia/reoxygenation (AR)-treated A549 cells (a human lung epithelial cell line), and the results showed the protective effect of RA started at 5 μM concentration, reached its maximum at 15 μM, and gradually decreased at 20–25 μM. Besides, RA pretreatment (15 μM) greatly reduced the lactate dehydrogenase release levels subjected to AR treatment. Moreover, the results of our research revealed that RA eliminated ROS production and reduced alveolar epithelial cell apoptosis through activating the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway, which was supported by using wortmannin, because in the presence of wortmannin, the RA-mediated protection was blocked. Meanwhile, wortmannin also reversed the protective effects of RA in mice. Together, our results demonstrate the beneficial role of RA in pulmonary IR injury via PI3K/Akt-mediated anti-oxidation and anti-apoptosis, which could be a promising therapeutic intervention for pulmonary IR injury.
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Affiliation(s)
- Wenbin Luo
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
| | - Yu Tao
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
| | - Shengnan Chen
- Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, China
- Department of Cardiology, Chongqing General Hospital, Chongqing, China
| | - Hao Luo
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
| | - Xiaoping Li
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
| | - Shuang Qu
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
| | - Ken Chen
- Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, China
- *Correspondence: Ken Chen, ; Chunyu Zeng,
| | - Chunyu Zeng
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China
- Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, China
- Department of Cardiology, Chongqing General Hospital, Chongqing, China
- Heart Center of Fujian Province, Union Hospital, Fujian Medical University, Fuzhou, China
- *Correspondence: Ken Chen, ; Chunyu Zeng,
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Zhang CN, Li FJ, Zhao ZL, Zhang JN. The role of extracellular vesicles in traumatic brain injury-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 2021; 321:L885-L891. [PMID: 34549593 DOI: 10.1152/ajplung.00023.2021] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Acute lung injury (ALI), a common complication after traumatic brain injury (TBI), can evolve into acute respiratory distress syndrome (ARDS) and has a mortality rate of 30%-40%. Secondary ALI after TBI exhibits the following typical pathological features: infiltration of neutrophils into the alveolar and interstitial space, alveolar septal thickening, alveolar edema, and hemorrhage. Extracellular vesicles (EVs) were recently identified as key mediators in TBI-induced ALI. Due to their small size and lipid bilayer, they can pass through the disrupted blood-brain barrier (BBB) into the peripheral circulation and deliver their contents, such as genetic material and proteins, to target cells through processes such as fusion, receptor-mediated interactions, and uptake. Acting as messengers, EVs contribute to mediating brain-lung cross talk after TBI. In this review, we aim to summarize the mechanism of EVs in TBI-induced ALI, which may provide new ideas for clinical treatment.
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Affiliation(s)
- Chao-Nan Zhang
- Department of Neurosurgery, Tianjin Institute of Neurology, grid.412645.0Tianjin Medical University General Hospital, Tianjin, China
| | - Fan-Jian Li
- Department of Neurosurgery, Tianjin Institute of Neurology, grid.412645.0Tianjin Medical University General Hospital, Tianjin, China
| | - Zi-Long Zhao
- Department of Neurosurgery, Tianjin Institute of Neurology, grid.412645.0Tianjin Medical University General Hospital, Tianjin, China
| | - Jian-Ning Zhang
- Department of Neurosurgery, Tianjin Institute of Neurology, grid.412645.0Tianjin Medical University General Hospital, Tianjin, China
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Abstract
The appreciation of human microbiome is gaining strong grounds in biomedical research. In addition to gut-brain axis, is the lung-brain axis, which is hypothesised to link pulmonary microbes to neurodegenerative disorders and behavioural changes. There is a need for analysis based on emerging studies to map out the prospects for lung-brain axis. In this review, relevant English literature and researches in the field of 'lung-brain axis' is reported. We recommend all the highlighted prospective studies to be integrated with an interdisciplinary approach. This might require conceptual research approaches based on physiology and pathophysiology. Multimodal aspects should include experimental animal units, while exploring the research gaps and making reference to the already existing human data. The overall microbiome medicine is gaining more ground. Aetiological paths and experimental recommendations as per prospective studies in this review will be an important guideline to develop effective treatments for any lung induced neurodegenerative diseases. An in-depth knowledge of the bi-directional communication between host and microbiome in the lung could help treatment to respiratory infections, alleviate stress, anxiety and enhanced neurological effects. The timely prevention and treatment of neurodegenerative diseases requires paradigm shift of the aetiology and more innovative experimentation.Impact statementThe overall microbiome medicine is gaining more ground. An in-depth knowledge of the bi-directional communication between host and microbiome in the lung could confer treatment to respiratory infections, alleviate stress, anxiety and enhanced neurological effects. Based on this review, we recommend all the highlighted prospective studies to be integrated and be given an interdisciplinary approach. This might require conceptual research approaches based on physiology and pathophysiology. Multimodal aspects should include experimental animal units; while exploring the research gaps and making reference to the already existing human data.
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Affiliation(s)
- Ousman Bajinka
- Department of Medical Microbiology, Central South University, Changsha, Hunan Provinces, China.,China-Africa Research Center of Infectious Diseases, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.,School of Medicine and Allied Health Sciences, University of The Gambia, Banjul, Gambia
| | - Lucette Simbilyabo
- Department of Neurosurgery, Xiangya Hospital of Central South University, Changsha, Hunan Provinces, China
| | - Yurong Tan
- Department of Medical Microbiology, Central South University, Changsha, Hunan Provinces, China.,China-Africa Research Center of Infectious Diseases, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China
| | - John Jabang
- School of Medicine and Allied Health Sciences, University of The Gambia, Banjul, Gambia
| | - Shakeel Ahmed Saleem
- Department of Neurosurgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan Provinces, China
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Saber M, Rice AD, Christie I, Roberts RG, Knox KS, Nakaji P, Rowe RK, Wang T, Lifshitz J. Remote Ischemic Conditioning Reduced Acute Lung Injury After Traumatic Brain Injury in the Mouse. Shock 2021; 55:256-267. [PMID: 32769821 PMCID: PMC8878575 DOI: 10.1097/shk.0000000000001618] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
ABSTRACT Traumatic brain injury (TBI) can induce acute lung injury (ALI). The exact pathomechanism of TBI-induced ALI is poorly understood, limiting treatment options. Remote ischemic conditioning (RIC) can mitigate detrimental outcomes following transplants, cardiac arrests, and neurological injuries. In this study, we hypothesized that RIC would reduce TBI-induced ALI by regulating the sphingosine-1-phosphate (S1P)-dependent pathway, a central regulator of endothelial barrier integrity, lymphocyte, and myokine trafficking. Male mice were subjected to either diffuse TBI by midline fluid percussion or control sham injury and randomly assigned among four groups: sham, TBI, sham RIC, or TBI RIC; RIC was performed 1 h prior to TBI. Mice were euthanized at 1-h postinjury or 7 days post-injury (DPI) and lung tissue, bronchoalveolar lavage (BAL) fluid, and blood were collected. Lung tissue was analyzed for histopathology, irisin myokine levels, and S1P receptor levels. BAL fluid and blood were analyzed for cellularity and myokine/S1P levels, respectively. One-hour postinjury, TBI damaged lung alveoli and increased neutrophil infiltration; RIC preserved alveoli. BAL from TBI mice had more neutrophils and higher neutrophil/monocyte ratios compared with sham, where TBI RIC mice showed no injury-induced change. Further, S1P receptor 3 and irisin-associated protein levels were significantly increased in the lungs of TBI mice compared with sham, which was prevented by RIC. However, there was no RIC-associated change in plasma irisin or S1P. At 7 DPI, ALI in TBI mice was largely resolved, with evidence for residual lung pathology. Thus, RIC may be a viable intervention for TBI-induced ALI to preserve lung function and facilitate clinical management.
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Affiliation(s)
- Maha Saber
- Child Health, University of Arizona College of Medicine – Phoenix, Phoenix, AZ
- Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ
| | - Amanda D. Rice
- Internal Medicine, University of Arizona College of Medicine - Phoenix, Phoenix, AZ
| | - Immaculate Christie
- Child Health, University of Arizona College of Medicine – Phoenix, Phoenix, AZ
- Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ
| | - Rebecca G. Roberts
- Internal Medicine, University of Arizona College of Medicine - Phoenix, Phoenix, AZ
| | - Kenneth S. Knox
- Internal Medicine, University of Arizona College of Medicine - Phoenix, Phoenix, AZ
| | - Peter Nakaji
- Neurosurgery, University of Arizona College of Medicine - Phoenix, Phoenix, AZ
| | - Rachel K. Rowe
- Child Health, University of Arizona College of Medicine – Phoenix, Phoenix, AZ
- Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ
- Phoenix VA Health Care System, Phoenix, AZ
| | - Ting Wang
- Internal Medicine, University of Arizona College of Medicine - Phoenix, Phoenix, AZ
| | - Jonathan Lifshitz
- Child Health, University of Arizona College of Medicine – Phoenix, Phoenix, AZ
- Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ
- Phoenix VA Health Care System, Phoenix, AZ
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Xu B, Chandrasekar A, olde Heuvel F, Powerski M, Nowak A, Noack L, Omari J, Huber-Lang M, Roselli F, Relja B. Ethanol Intoxication Alleviates the Inflammatory Response of Remote Organs to Experimental Traumatic Brain Injury. Int J Mol Sci 2020; 21:ijms21218181. [PMID: 33142949 PMCID: PMC7663496 DOI: 10.3390/ijms21218181] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 10/19/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022] Open
Abstract
Traumatic brain injury (TBI) may cause damage to distant organs. Acute ethanol intoxication (EI) induces complex local and systemic anti-inflammatory effects and influences the early outcomes of traumatized patients. Here, we evaluated its effects on the BI-induced expression of local inflammatory mediators in the trauma-remote organs the lungs and liver. Male mice were exposed to ethanol as a single oral dose (5g·kg–1, 32%) before inducing a moderate blunt TBI. Sham groups underwent the same procedures without TBI. Ether 3 or 6h after the TBI, the lung and liver were collected. The gene expression of HMGB1, IL-6, MMP9, IL-1β, and TNF as well as the homogenate protein levels of receptor for advanced glycation end products (RAGE), IL-6, IL-1β, and IL-10 were analyzed. Liver samples were immunohistologically stained for HMGB1. EI decreased the gene expressions of the proinflammatory markers HMGB1, IL-6, and MMP9 in the liver upon TBI. In line with the reduced gene expression, the TBI-induced protein expression of IL-6 in liver tissue homogenates was significantly reduced by EI at 3h after TBI. While the histological HMGB1 expression was enhanced by TBI, the RAGE protein expression in the liver tissue homogenates was diminished after TBI. EI reduced the histological HMGB1 expression and enhanced the hepatic RAGE protein expression at 6h post TBI. With regard to the lungs, EI significantly reduced the gene expressions of HMGB1, IL-6, IL-1β, and TNF upon TBI, without significantly affecting the protein expression levels of inflammatory markers (RAGE, IL-6, IL-1β, and IL-10). At the early stage of TBI-induced inflammation, the gene expression of inflammatory mediators in both the lungs and liver is susceptible to ethanol-induced remote effects. Taken together, EI may alleviate the TBI-induced pro-inflammatory response in the trauma-distant organs, the lungs and liver, via the HMGB1-RAGE axis.
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Affiliation(s)
- Baolin Xu
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto von Guericke University, 39120 Magdeburg, Germany; (B.X.); (M.P.); (A.N.); (L.N.); (J.O.)
| | - Akila Chandrasekar
- Department of Neurology, Ulm University, 89081 Ulm, Germany; (A.C.); (F.o.H.)
| | - Florian olde Heuvel
- Department of Neurology, Ulm University, 89081 Ulm, Germany; (A.C.); (F.o.H.)
| | - Maciej Powerski
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto von Guericke University, 39120 Magdeburg, Germany; (B.X.); (M.P.); (A.N.); (L.N.); (J.O.)
| | - Aleksander Nowak
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto von Guericke University, 39120 Magdeburg, Germany; (B.X.); (M.P.); (A.N.); (L.N.); (J.O.)
| | - Laurens Noack
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto von Guericke University, 39120 Magdeburg, Germany; (B.X.); (M.P.); (A.N.); (L.N.); (J.O.)
| | - Jazan Omari
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto von Guericke University, 39120 Magdeburg, Germany; (B.X.); (M.P.); (A.N.); (L.N.); (J.O.)
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma-Immunology, University Hospital Ulm, Ulm University, 89081 Ulm, Germany;
| | - Francesco Roselli
- German Center for Neurodegenerative Diseases (DZNE)-Ulm, 89081 Ulm, Germany;
| | - Borna Relja
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto von Guericke University, 39120 Magdeburg, Germany; (B.X.); (M.P.); (A.N.); (L.N.); (J.O.)
- Correspondence:
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9
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Willows S, Alam SB, Sandhu JK, Kulka M. A Canadian perspective on severe acute respiratory syndrome coronavirus 2 infection and treatment: how prevalent underlying inflammatory disease contributes to pathogenesis. Biochem Cell Biol 2020; 99:173-194. [PMID: 33027600 DOI: 10.1139/bcb-2020-0341] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19), a serious respiratory illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a global pandemic. Canada reported its first case of COVID-19 on the 25th January 2020. By March 2020, the virus had spread within Canadian communities reaching the most frail and vulnerable elderly population in long-term care facilities. The majority of cases were reported in the provinces of Quebec, Ontario, Alberta, and British Columbia, and the highest mortality was seen among individuals aged 65 years or older. Canada has the highest prevalence and incidence rates of several chronic inflammatory diseases, such as multiple sclerosis, inflammatory bowel disease, and Parkinson's disease. Many elderly Canadians also live with comorbid medical illnesses, such as hypertension, diabetes, cardiovascular disease, and chronic lung disease, and are more likely to suffer from severe COVID-19 with a poor prognosis. It is becoming increasingly evident that underlying inflammatory disease contributes to the pathogenesis of SARS-CoV-2. Here, we review the mechanisms behind SARS-CoV-2 infection, and the host inflammatory responses that lead to resolution or progression to severe COVID-19 disease. Furthermore, we discuss the landscape of COVID-19 therapeutics that are currently in development in Canada.
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Affiliation(s)
- Steven Willows
- Nanotechnology Research Centre, National Research Council Canada, 11421 Saskatchewan Drive, Edmonton, AB T6G 2A3, Canada.,Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Syed Benazir Alam
- Nanotechnology Research Centre, National Research Council Canada, 11421 Saskatchewan Drive, Edmonton, AB T6G 2A3, Canada.,Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Jagdeep K Sandhu
- Human Health Therapeutics Research Centre, National Research Council Canada, 1200 Montreal Road, Ottawa, ON K1A 0R6, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Marianna Kulka
- Nanotechnology Research Centre, National Research Council Canada, 11421 Saskatchewan Drive, Edmonton, AB T6G 2A3, Canada.,Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
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10
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Doran SJ, Henry RJ, Shirey KA, Barrett JP, Ritzel RM, Lai W, Blanco JC, Faden AI, Vogel SN, Loane DJ. Early or Late Bacterial Lung Infection Increases Mortality After Traumatic Brain Injury in Male Mice and Chronically Impairs Monocyte Innate Immune Function. Crit Care Med 2020; 48:e418-e428. [PMID: 32149839 PMCID: PMC7541908 DOI: 10.1097/ccm.0000000000004273] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Respiratory infections in the postacute phase of traumatic brain injury impede optimal recovery and contribute substantially to overall morbidity and mortality. This study investigated bidirectional innate immune responses between the injured brain and lung, using a controlled cortical impact model followed by secondary Streptococcus pneumoniae infection in mice. DESIGN Experimental study. SETTING Research laboratory. SUBJECTS Adult male C57BL/6J mice. INTERVENTIONS C57BL/6J mice were subjected to sham surgery or moderate-level controlled cortical impact and infected intranasally with S. pneumoniae (1,500 colony-forming units) or vehicle (phosphate-buffered saline) at 3 or 60 days post-injury. MAIN RESULTS At 3 days post-injury, S. pneumoniae-infected traumatic brain injury mice (TBI + Sp) had a 25% mortality rate, in contrast to no mortality in S. pneumoniae-infected sham (Sham + Sp) animals. TBI + Sp mice infected 60 days post-injury had a 60% mortality compared with 5% mortality in Sham + Sp mice. In both studies, TBI + Sp mice had poorer motor function recovery compared with TBI + PBS mice. There was increased expression of pro-inflammatory markers in cortex of TBI + Sp compared with TBI + PBS mice after both early and late infection, indicating enhanced post-traumatic neuroinflammation. In addition, monocytes from lungs of TBI + Sp mice were immunosuppressed acutely after traumatic brain injury and could not produce interleukin-1β, tumor necrosis factor-α, or reactive oxygen species. In contrast, after delayed infection monocytes from TBI + Sp mice had higher levels of interleukin-1β, tumor necrosis factor-α, and reactive oxygen species when compared with Sham + Sp mice. Increased bacterial burden and pathology was also found in lungs of TBI + Sp mice. CONCLUSIONS Traumatic brain injury causes monocyte functional impairments that may affect the host's susceptibility to respiratory infections. Chronically injured mice had greater mortality following S. pneumoniae infection, which suggests that respiratory infections even late after traumatic brain injury may pose a more serious threat than is currently appreciated.
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Affiliation(s)
- Sarah J Doran
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD
| | - Rebecca J Henry
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD
| | - Kari Ann Shirey
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD
| | - James P Barrett
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD
| | - Rodney M Ritzel
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD
| | - Wendy Lai
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD
| | | | - Alan I Faden
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD
| | - Stefanie N Vogel
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD
| | - David J Loane
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland
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11
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New Answers to Old Conundrums: What Antibodies, Exosomes and Inflammasomes Bring to the Conversation. Canadian National Transplant Research Program International Summit Report. Transplantation 2018; 102:209-214. [PMID: 28731910 PMCID: PMC5802265 DOI: 10.1097/tp.0000000000001872] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Antibody-mediated injury is a major cause of allograft dysfunction and loss. Antibodies to ABH(O) blood group antigens are classic mediators of ABO-incompatible graft rejection, whereas donor-specific anti-HLA antibodies and, more recently, autoantibodies are appreciated as important contributors to allograft inflammation and dysfunction. In August 2016, the International Summit of the Canadian National Transplant Research Program focused on recent advances in the field of antibody-mediated rejection. Here, we describe work presented and discussed at the meeting, with a focus on 3 major themes: the importance of (1) natural antibodies and autoantibodies, (2) tissue injury-derived exosomes and autoimmunity, (3) inflammasome activation and innate immune responses in regulating allograft inflammation and dysfunction. Finally, we explore novel areas of therapeutic intervention that have recently emerged from these 3 major and overlapping fields of transplantation research.
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12
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Li Y, Yang Z, Chavko M, Liu B, Aderemi OA, Simovic MO, Dubick MA, Cancio LC. Complement inhibition ameliorates blast-induced acute lung injury in rats: Potential role of complement in intracellular HMGB1-mediated inflammation. PLoS One 2018; 13:e0202594. [PMID: 30133517 PMCID: PMC6105023 DOI: 10.1371/journal.pone.0202594] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Accepted: 08/05/2018] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Complement activation as an early and important inflammatory process contributes to multiple organ dysfunction after trauma. We have recently shown that complement inhibition by decay-accelerating factor (DAF) protects brain from blast-overpressure (BOP)-induced damage. This study was conducted to determine the effect of DAF on acute lung injury induced by BOP exposure and to elucidate its possible mechanisms of action. METHODS Anesthetized adult male Sprague-Daley rats were exposed to BOP (120 kPa) from a compressed air-driven shock tube. Rats were randomly assigned to three experimental groups: 1) Control (no BOP and no DAF treatment), 2) BOP (120 kPa BOP exposure), and 3) BOP followed by treatment with rhDAF (500μg/kg, i.v) at 30 minutes after blast. After a recovery period of 3, 24, or 48 hours, animals were euthanized followed by the collection of blood and tissues at each time point. Samples were subjected to the assessment of cytokines and histopathology as well as for the interaction of high-mobility-group box 1 (HMGB1) protein, NF-κB, receptor for advanced glycation end products (RAGE), C3a, and C3aR. RESULTS BOP exposure significantly increased in the production of systemic pro- and anti-inflammatory cytokines, and obvious pathological changes as characterized by pulmonary edema, inflammation, endothelial damage and hemorrhage in the lungs. These alterations were ameliorated by early administration of rhDAF. The rhDAF treatment not only significantly reduced the expression levels of HMGB1, RAGE, NF-κB, C3a, and C3aR, but also reversed the interaction of C3a-C3aR and nuclear translocation of HMGB1 in the lungs. CONCLUSIONS Our findings indicate that early administration of DAF efficiently inhibits systemic and local inflammation, and mitigates blast-induced lung injury. The underlying mechanism might be attributed to its potential modulation of C3a-C3aR-HMGB1-transcriptional factor axis. Therefore, complement and/or HMGB1 may be potential therapeutic targets in amelioration of acute lung injury after blast injury.
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Affiliation(s)
- Yansong Li
- Department of Multiple Organ Support Technology, US Army Institute of Surgical Research, JBSA Fort Sam Houston, San Antonio, Texas, United States of America
- * E-mail:
| | - Zhangsheng Yang
- Department of Multiple Organ Support Technology, US Army Institute of Surgical Research, JBSA Fort Sam Houston, San Antonio, Texas, United States of America
| | - Mikulas Chavko
- Department of Neurotrauma, Naval Medical Research Center, Silver Spring, Maryland, United States of America
| | - Bin Liu
- Department of Blood Research, US Army Institute of Surgical Research, JBSA Fort Sam Houston, San Antonio, Texas, United States of America
| | - Olawale A. Aderemi
- Department of Multiple Organ Support Technology, US Army Institute of Surgical Research, JBSA Fort Sam Houston, San Antonio, Texas, United States of America
| | - Milomir O. Simovic
- Department of Multiple Organ Support Technology, US Army Institute of Surgical Research, JBSA Fort Sam Houston, San Antonio, Texas, United States of America
| | - Michael A. Dubick
- Department of Damage Control Resuscitation, US Army Institute of Surgical Research, JBSA Fort Sam Houston, San Antonio, Texas, United States of America
| | - Leopoldo C. Cancio
- Department of Multiple Organ Support Technology, US Army Institute of Surgical Research, JBSA Fort Sam Houston, San Antonio, Texas, United States of America
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13
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NLRP3/ASC-mediated alveolar macrophage pyroptosis enhances HMGB1 secretion in acute lung injury induced by cardiopulmonary bypass. J Transl Med 2018; 98:1052-1064. [PMID: 29884910 DOI: 10.1038/s41374-018-0073-0] [Citation(s) in RCA: 115] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 03/16/2018] [Accepted: 04/02/2018] [Indexed: 11/09/2022] Open
Abstract
Our previous study showed that high levels of HMGB1 existed in rats following cardiopulmonary bypass (CPB)-induced acute lung injury (ALI) and neutralization of high-mobility group box 1(HMGB1) reduced CPB-induced ALI. However, the mechanism by which CPB increases HMGB1 secretion is unclear. Recent studies have shown that inflammasome-mediated cell pyroptosis promotes HMGB1 secretion. This study aimed to investigate the relationship between inflammasome-mediated pyroptosis and HMGB1 in CPB-related ALI. We employed oxygen-glucose deprivation (OGD)-induced alveolar macrophage (AM) NR8383 pyroptosis to measure HMGB1 secretion. We found that OGD significantly increased the levels of caspase-1 cleaved p10, IL-1β and ASC expression, caspase-1 activity and the frequency of pyroptotic AM, and promoted the cytoplasm transportation and secretion of HMGB1, which were significantly mitigated by ASC silencing or pre-treatment with glyburide (a Nlrp3 inhibitor) in AM. CPB also increased the expression levels of Nlrp3, ASC, caspase-1 P10, and IL-1β, and the percentages of AM pyroptosis in the lungs of experimental rats accompanied by increased levels of serum and bronchoalveolar lavage fluid (BALF) HMGB1. Treatment with glyburide significantly mitigated the CPB-increased ASC, caspase-1 p10 and IL-1β expression, and the percentages of AM pyroptosis in the lungs, as well as the levels of HMGB1 in serum and BALF in rats. Therefore, our data indicated that the Nlrp3/ASC-mediated AM pyroptosis increased HMGB1 secretion in ALI induced by CPB. These findings may provide a therapeutic strategy to reduce lung injury and inflammatory responses during CPB.
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14
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Wang Y, Wang C, Zhang D, Wang H, Bo L, Deng X. Dexmedetomidine Protects Against Traumatic Brain Injury-Induced Acute Lung Injury in Mice. Med Sci Monit 2018; 24:4961-4967. [PMID: 30013022 PMCID: PMC6067036 DOI: 10.12659/msm.908133] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Background Traumatic brain injury (TBI) leads to acute lung injury (ALI), in which the inflammatory response plays an important role in its pathophysiology. Recent studies suggest that dexmedetomidine (Dex) plays a protective role in acute inflammatory diseases. However, whether Dex has a protective effect on TBI-induced ALI is not clear. The aim of this study was to investigate the effect of Dex on TBI-induced ALI in mice. Material/Methods Mice were randomly divided into 5 groups: 1) sham group; 2) TBI group; 3) TBI+Dex group; 4) TBI+atipamezole (Atip) group; and 5) TBI+Dex+Atip group. Dex (50 μg/kg) was intraperitoneal injected immediately after TBI. The α2 adrenergic antagonist Atip (250 μg/kg) was intraperitoneal injected 15 minutes prior to Dex treatment. Then 24 hours later, the protein concentration in the bronchoalveolar lavage fluid (BALF), lung wet to dry weight ratio, hematoxylin and eosin (H&E) staining of lungs, the level of high-mobility group box protein 1(HMGB1) in serum, and the receptor for advanced glycation end products (RAGE) expression in lung were detected. Results Dex ameliorated the score of lung histological examination, as well as the severity of pulmonary edema and permeability. Moreover, Dex was observed to significantly suppress the expression of HMGBI and RAGE. However, the protective effects of Dex were partially reversed by the administration of Atip. Conclusions Dex may protect against TBI-induced ALI via the HMGB1-RAGE signal pathway, and this protective effect is partly dependent on its α2 adrenoceptor agonist action.
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Affiliation(s)
- Yuanyuan Wang
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China (mainland).,Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China (mainland)
| | - Changli Wang
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China (mainland)
| | - Dan Zhang
- Department of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China (mainland).,Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China (mainland)
| | - Huihui Wang
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China (mainland)
| | - Lulong Bo
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China (mainland)
| | - Xiaoming Deng
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China (mainland).,Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China (mainland)
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15
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Lee H, Lee J, Hong SH, Rahman I, Yang SR. Inhibition of RAGE Attenuates Cigarette Smoke-Induced Lung Epithelial Cell Damage via RAGE-Mediated Nrf2/DAMP Signaling. Front Pharmacol 2018; 9:684. [PMID: 30013476 PMCID: PMC6036614 DOI: 10.3389/fphar.2018.00684] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 06/06/2018] [Indexed: 12/13/2022] Open
Abstract
The oxidative stress and cellular apoptosis by environmental factor including cigarette smoke induces alveolar airway remodeling leading to chronic obstructive pulmonary disease (COPD). Recently, the receptor for advanced glycan end products (RAGE) which is highly expressed in alveolar epithelium is emerging as a biomarker for COPD susceptibility or progression. However, it still remains unknown how RAGE plays a role in cigarette smoke extract (CSE)-exposed human alveolar type II epithelial cell line. Therefore, we determined the efficacy of RAGE-specific antagonist FPS-ZM1 in response to CSE-induced lung epithelial cells. CSE induced the elevated generation of RONS and release of pro-inflammatory cytokines, and impaired the cellular antioxidant defense system. Further, CSE induced the alteration of RAGE distribution via the activation of redox-sensitive DAMP (Damage-associated molecular patterns) signaling through Nrf2 in cells. Although pre-treatment with SB202190 (p38 inhibitor) or SP600125 (JNK inhibitor) failed to recover the alteration of RAGE distribution, treatment of FPS-ZM1 significantly exhibited anti-inflammatory and anti-oxidative/nitrosative effects, also inhibited the activation of redox-sensitive DAMP signaling through Nrf2 (nuclear factor erythroid 2-related factor 2) migration in the presence of CSE. Taken together, our data demonstrate that RAGE and Nrf2 play a pivotal role in maintenance of alveolar epithelial integrity.
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Affiliation(s)
- Hanbyeol Lee
- Department of Thoracic and Cardiovascular Surgery, Kangwon National University, Chuncheon, South Korea
| | - Jooyeon Lee
- Department of Thoracic and Cardiovascular Surgery, Kangwon National University, Chuncheon, South Korea
| | - Seok-Ho Hong
- Department of Internal Medicine, Kangwon National University, Chuncheon, South Korea
| | - Irfan Rahman
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, United States
| | - Se-Ran Yang
- Department of Thoracic and Cardiovascular Surgery, Kangwon National University, Chuncheon, South Korea,*Correspondence: Se-Ran Yang,
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Kerr NA, de Rivero Vaccari JP, Abbassi S, Kaur H, Zambrano R, Wu S, Dietrich WD, Keane RW. Traumatic Brain Injury-Induced Acute Lung Injury: Evidence for Activation and Inhibition of a Neural-Respiratory-Inflammasome Axis. J Neurotrauma 2018; 35:2067-2076. [PMID: 29648974 DOI: 10.1089/neu.2017.5430] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Approximately 20-25% of traumatic brain injury (TBI) subjects develop acute lung injury (ALI), but the pathomechanisms of TBI-induced ALI remain poorly defined. Our previous work has shown that the inflammasome plays a critical role in TBI-induced secondary pathophysiology and that inflammasome proteins are released in extracellular vesicles (EV) after TBI. Here we investigated whether EV-mediated inflammasome signaling contributed to the etiology of TBI-induced ALI. C57/BL6 male mice were subjected to controlled cortical impact (CCI), and the brains and lungs were examined for inflammasome activation and ALI at 4 and 24 h after TBI. We show that TBI releases EV containing inflammasome proteins into serum that target the lung to cause ALI, supporting activation of a neural-respiratory-inflammasome axis. Administration of a low-molecular-weight heparin (enoxaparin, a blocker of EV uptake) or treatment with a monoclonal antibody against apoptosis speck-like staining protein containing a caspase recruitment domain (anti-ASC) after adoptive transfer of EV isolated from TBI-injured mice significantly inhibited inflammasome activation in the lungs of recipient mice resulting in improved ALI scores.This axis constitutes an important arm of the innate inflammatory response in lung pathology after TBI and targeting this axis represents a novel therapeutic treatment for TBI-induced ALI.
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Affiliation(s)
- Nadine A Kerr
- 1 Department of Neurological Surgery, University of Miami Miller School of Medicine , Miami, Florida.,2 Department of Physiology and Biophysics, University of Miami Miller School of Medicine , Miami, Florida
| | - Juan Pablo de Rivero Vaccari
- 1 Department of Neurological Surgery, University of Miami Miller School of Medicine , Miami, Florida.,2 Department of Physiology and Biophysics, University of Miami Miller School of Medicine , Miami, Florida
| | - Sam Abbassi
- 2 Department of Physiology and Biophysics, University of Miami Miller School of Medicine , Miami, Florida
| | - Harmanpreet Kaur
- 1 Department of Neurological Surgery, University of Miami Miller School of Medicine , Miami, Florida
| | - Ronald Zambrano
- 3 Department of Pediatrics, University of Miami Miller School of Medicine , Miami, Florida
| | - Shu Wu
- 3 Department of Pediatrics, University of Miami Miller School of Medicine , Miami, Florida
| | - W Dalton Dietrich
- 1 Department of Neurological Surgery, University of Miami Miller School of Medicine , Miami, Florida
| | - Robert W Keane
- 1 Department of Neurological Surgery, University of Miami Miller School of Medicine , Miami, Florida.,2 Department of Physiology and Biophysics, University of Miami Miller School of Medicine , Miami, Florida
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Hu PJ, Pittet JF, Kerby JD, Bosarge PL, Wagener BM. Acute brain trauma, lung injury, and pneumonia: more than just altered mental status and decreased airway protection. Am J Physiol Lung Cell Mol Physiol 2017; 313:L1-L15. [PMID: 28408366 DOI: 10.1152/ajplung.00485.2016] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 03/24/2017] [Accepted: 04/07/2017] [Indexed: 01/25/2023] Open
Abstract
Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Even when patients survive the initial insult, there is significant morbidity and mortality secondary to subsequent pulmonary edema, acute lung injury (ALI), and nosocomial pneumonia. Whereas the relationship between TBI and secondary pulmonary complications is recognized, little is known about the mechanistic interplay of the two phenomena. Changes in mental status secondary to acute brain injury certainly impair airway- and lung-protective mechanisms. However, clinical and translational evidence suggests that more specific neuronal and cellular mechanisms contribute to impaired systemic and lung immunity that increases the risk of TBI-mediated lung injury and infection. To better understand the cellular mechanisms of that immune impairment, we review here the current clinical data that support TBI-induced impairment of systemic and lung immunity. Furthermore, we also review the animal models that attempt to reproduce human TBI. Additionally, we examine the possible role of damage-associated molecular patterns, the chlolinergic anti-inflammatory pathway, and sex dimorphism in post-TBI ALI. In the last part of the review, we discuss current treatments and future pharmacological therapies, including fever control, tracheostomy, and corticosteroids, aimed to prevent and treat pulmonary edema, ALI, and nosocomial pneumonia after TBI.
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Affiliation(s)
- Parker J Hu
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Jean-Francois Pittet
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama.,Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.,Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Jeffrey D Kerby
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Patrick L Bosarge
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Brant M Wagener
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and
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HMGB1, IL-1α, IL-33 and S100 proteins: dual-function alarmins. Cell Mol Immunol 2016; 14:43-64. [PMID: 27569562 PMCID: PMC5214941 DOI: 10.1038/cmi.2016.34] [Citation(s) in RCA: 344] [Impact Index Per Article: 38.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 05/16/2016] [Accepted: 05/17/2016] [Indexed: 02/08/2023] Open
Abstract
Our immune system is based on the close collaboration of the innate and adaptive immune systems for the rapid detection of any threats to the host. Recognition of pathogen-derived molecules is entrusted to specific germline-encoded signaling receptors. The same receptors have now also emerged as efficient detectors of misplaced or altered self-molecules that signal tissue damage and cell death following, for example, disruption of the blood supply and subsequent hypoxia. Many types of endogenous molecules have been shown to provoke such sterile inflammatory states when released from dying cells. However, a group of proteins referred to as alarmins have both intracellular and extracellular functions which have been the subject of intense research. Indeed, alarmins can either exert beneficial cell housekeeping functions, leading to tissue repair, or provoke deleterious uncontrolled inflammation. This group of proteins includes the high-mobility group box 1 protein (HMGB1), interleukin (IL)-1α, IL-33 and the Ca2+-binding S100 proteins. These dual-function proteins share conserved regulatory mechanisms, such as secretory routes, post-translational modifications and enzymatic processing, that govern their extracellular functions in time and space. Release of alarmins from mesenchymal cells is a highly relevant mechanism by which immune cells can be alerted of tissue damage, and alarmins play a key role in the development of acute or chronic inflammatory diseases and in cancer development.
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Koutsoukou A, Katsiari M, Orfanos SE, Kotanidou A, Daganou M, Kyriakopoulou M, Koulouris NG, Rovina N. Respiratory mechanics in brain injury: A review. World J Crit Care Med 2016; 5:65-73. [PMID: 26855895 PMCID: PMC4733457 DOI: 10.5492/wjccm.v5.i1.65] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Revised: 10/08/2015] [Accepted: 12/11/2015] [Indexed: 02/06/2023] Open
Abstract
Several clinical and experimental studies have shown that lung injury occurs shortly after brain damage. The responsible mechanisms involve neurogenic pulmonary edema, inflammation, the harmful action of neurotransmitters, or autonomic system dysfunction. Mechanical ventilation, an essential component of life support in brain-damaged patients (BD), may be an additional traumatic factor to the already injured or susceptible to injury lungs of these patients thus worsening lung injury, in case that non lung protective ventilator settings are applied. Measurement of respiratory mechanics in BD patients, as well as assessment of their evolution during mechanical ventilation, may lead to preclinical lung injury detection early enough, allowing thus the selection of the appropriate ventilator settings to avoid ventilator-induced lung injury. The aim of this review is to explore the mechanical properties of the respiratory system in BD patients along with the underlying mechanisms, and to translate the evidence of animal and clinical studies into therapeutic implications regarding the mechanical ventilation of these critically ill patients.
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