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Zerikiotis S, Efentakis P, Dapola D, Agapaki A, Seiradakis G, Kostomitsopoulos N, Skaltsounis AL, Tseti I, Triposkiadis F, Andreadou I. Synergistic Pulmonoprotective Effect of Natural Prolyl Oligopeptidase Inhibitors in In Vitro and In Vivo Models of Acute Respiratory Distress Syndrome. Int J Mol Sci 2023; 24:14235. [PMID: 37762537 PMCID: PMC10531912 DOI: 10.3390/ijms241814235] [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: 08/23/2023] [Revised: 09/13/2023] [Accepted: 09/15/2023] [Indexed: 09/29/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a highly morbid inflammatory lung disease with limited pharmacological interventions. The present study aims to evaluate and compare the potential pulmonoprotective effects of natural prolyl oligopeptidase (POP) inhibitors namely rosmarinic acid (RA), chicoric acid (CA), epigallocatechin-3-gallate (EGCG) and gallic acid (GA), against lipopolysaccharide (LPS)-induced ARDS. Cell viability and expression of pro-inflammatory mediators were measured in RAW264.7 cells and in primary murine lung epithelial and bone marrow cells. Nitric oxide (NO) production was also assessed in unstimulated and LPS-stimulated RAW264.7 cells. For subsequent in vivo experiments, the two natural products (NPs) with the most favorable effects, RA and GA, were selected. Protein, cell content and lipid peroxidation levels in bronchoalveolar lavage fluid (BALF), as well as histopathological changes and respiratory parameters were evaluated in LPS-challenged mice. Expression of key mediators involved in ARDS pathophysiology was detected by Western blotting. RA and GA favorably reduced gene expression of pro-inflammatory mediators in vitro, while GA decreased NO production in macrophages. In LPS-challenged mice, RA and GA co-administration improved respiratory parameters, reduced cell and protein content and malondialdehyde (MDA) levels in BALF, decreased vascular cell adhesion molecule-1 (VCAM-1) and the inducible nitric oxide synthase (iNOS) protein expression, activated anti-apoptotic mechanisms and down-regulated POP in the lung. Conclusively, these synergistic pulmonoprotective effects of RA and GA co-administration could render them a promising prophylactic/therapeutic pharmacological intervention against ARDS.
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Affiliation(s)
- Stelios Zerikiotis
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 157 71 Athens, Greece; (S.Z.); (P.E.); (D.D.); (G.S.)
| | - Panagiotis Efentakis
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 157 71 Athens, Greece; (S.Z.); (P.E.); (D.D.); (G.S.)
| | - Danai Dapola
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 157 71 Athens, Greece; (S.Z.); (P.E.); (D.D.); (G.S.)
| | - Anna Agapaki
- Histochemistry Facility, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece;
| | - Georgios Seiradakis
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 157 71 Athens, Greece; (S.Z.); (P.E.); (D.D.); (G.S.)
| | - Nikolaos Kostomitsopoulos
- Laboratory Animal Facility, Centre of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece;
| | - Alexios-Leandros Skaltsounis
- Section of Pharmacognosy and Natural Product Chemistry Faculty of Pharmacy, National and Kapodistrian University of Athens, 157 71 Athens, Greece;
| | | | - Filippos Triposkiadis
- Department of Cardiology, University General Hospital of Larissa, 413 34 Larissa, Greece;
- Faculty of Health Sciences, University of Thessaly, 413 34 Larissa, Greece
| | - Ioanna Andreadou
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 157 71 Athens, Greece; (S.Z.); (P.E.); (D.D.); (G.S.)
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Zyrianova T, Zou K, Lopez B, Liao A, Gu C, Olcese R, Schwingshackl A. Activation of Endothelial Large Conductance Potassium Channels Protects against TNF-α-Induced Inflammation. Int J Mol Sci 2023; 24:4087. [PMID: 36835507 PMCID: PMC9961193 DOI: 10.3390/ijms24044087] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 01/30/2023] [Accepted: 02/09/2023] [Indexed: 02/22/2023] Open
Abstract
Elevated TNF-α levels in serum and broncho-alveolar lavage fluid of acute lung injury patients correlate with mortality rates. We hypothesized that pharmacological plasma membrane potential (Em) hyperpolarization protects against TNF-α-induced CCL-2 and IL-6 secretion from human pulmonary endothelial cells through inhibition of inflammatory Ca2+-dependent MAPK pathways. Since the role of Ca2+ influx in TNF-α-mediated inflammation remains poorly understood, we explored the role of L-type voltage-gated Ca2+ (CaV) channels in TNF-α-induced CCL-2 and IL-6 secretion from human pulmonary endothelial cells. The CaV channel blocker, Nifedipine, decreased both CCL-2 and IL-6 secretion, suggesting that a fraction of CaV channels is open at the significantly depolarized resting Em of human microvascular pulmonary endothelial cells (-6 ± 1.9 mV), as shown by whole-cell patch-clamp measurements. To further explore the role of CaV channels in cytokine secretion, we demonstrated that the beneficial effects of Nifedipine could also be achieved by Em hyperpolarization via the pharmacological activation of large conductance K+ (BK) channels with NS1619, which elicited a similar decrease in CCL-2 but not IL-6 secretion. Using functional gene enrichment analysis tools, we predicted and validated that known Ca2+-dependent kinases, JNK-1/2 and p38, are the most likely pathways to mediate the decrease in CCL-2 secretion.
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Affiliation(s)
- Tatiana Zyrianova
- Departments of Pediatrics, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Kathlyn Zou
- Departments of Pediatrics, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Benjamin Lopez
- Departments of Pediatrics, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Andy Liao
- Departments of Pediatrics, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Charles Gu
- Departments of Pediatrics, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Riccardo Olcese
- Departments of Anesthesiology and Perioperative Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
- Departments of Physiology, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Andreas Schwingshackl
- Departments of Pediatrics, University of California Los Angeles, Los Angeles, CA 90095, USA
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McElvaney OJ, McEvoy NL, Boland F, McElvaney OF, Hogan G, Donnelly K, Friel O, Browne E, Fraughen DD, Murphy MP, Clarke J, Choileáin ON, O'Connor E, McGuinness R, Boylan M, Kelly A, Hayden JC, Collins AM, Cullen A, Hyland D, Carroll TP, Geoghegan P, Laffey JG, Hennessy M, Martin-Loeches I, McElvaney NG, Curley GF. A randomized, double-blind, placebo-controlled trial of intravenous alpha-1 antitrypsin for acute respiratory distress syndrome secondary to COVID-19. MED 2022; 3:233-248.e6. [PMID: 35291694 PMCID: PMC8913266 DOI: 10.1016/j.medj.2022.03.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/11/2022] [Accepted: 03/07/2022] [Indexed: 11/16/2022]
Abstract
Background Patients with severe coronavirus disease 2019 (COVID-19) develop a febrile pro-inflammatory cytokinemia with accelerated progression to acute respiratory distress syndrome (ARDS). Here we report the results of a phase 2, multicenter, randomized, double-blind, placebo-controlled trial of intravenous (IV) plasma-purified alpha-1 antitrypsin (AAT) for moderate to severe ARDS secondary to COVID-19 (EudraCT 2020-001391-15). Methods Patients (n = 36) were randomized to receive weekly placebo, weekly AAT (Prolastin, Grifols, S.A.; 120 mg/kg), or AAT once followed by weekly placebo. The primary endpoint was the change in plasma interleukin (IL)-6 concentration at 1 week. In addition to assessing safety and tolerability, changes in plasma levels of IL-1β, IL-8, IL-10, and soluble tumor necrosis factor receptor 1 (sTNFR1) and clinical outcomes were assessed as secondary endpoints. Findings Treatment with IV AAT resulted in decreased inflammation and was safe and well tolerated. The study met its primary endpoint, with decreased circulating IL-6 concentrations at 1 week in the treatment group. This was in contrast to the placebo group, where IL-6 was increased. Similarly, plasma sTNFR1 was substantially decreased in the treatment group while remaining unchanged in patients receiving placebo. IV AAT did not definitively reduce levels of IL-1β, IL-8, and IL-10. No difference in mortality or ventilator-free days was observed between groups, although a trend toward decreased time on ventilator was observed in AAT-treated patients. Conclusions In patients with COVID-19 and moderate to severe ARDS, treatment with IV AAT was safe, feasible, and biochemically efficacious. The data support progression to a phase 3 trial and prompt further investigation of AAT as an anti-inflammatory therapeutic. Funding ECSA-2020-009; Elaine Galwey Research Bursary.
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Affiliation(s)
- Oliver J McElvaney
- Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
- Beaumont Hospital, Dublin, Ireland
| | - Natalie L McEvoy
- Department of Anaesthesia and Critical Care, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Fiona Boland
- Data Science Centre, Division of Biostatistics and Population Health Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Oisín F McElvaney
- Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
- Beaumont Hospital, Dublin, Ireland
| | - Grace Hogan
- Department of Anaesthesia and Critical Care, Royal College of Surgeons in Ireland, Dublin, Ireland
| | | | | | | | - Daniel D Fraughen
- Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
- Beaumont Hospital, Dublin, Ireland
| | - Mark P Murphy
- Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Jennifer Clarke
- Beaumont Hospital, Dublin, Ireland
- Department of Anaesthesia and Critical Care, Royal College of Surgeons in Ireland, Dublin, Ireland
| | | | | | | | | | | | - John C Hayden
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Ann M Collins
- RCSI Education and Research Centre, Beaumont Hospital, Dublin, Ireland
| | - Ailbhe Cullen
- RCSI Education and Research Centre, Beaumont Hospital, Dublin, Ireland
| | - Deirdre Hyland
- RCSI Education and Research Centre, Beaumont Hospital, Dublin, Ireland
| | - Tomás P Carroll
- Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | | | - John G Laffey
- Department of Anaesthesia, Galway University Hospitals, SAOLTA University Health Group, Galway, Ireland
| | - Martina Hennessy
- Department of Critical Care Medicine, St. James' Hospital, Dublin, Ireland
| | | | - Noel G McElvaney
- Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
- Beaumont Hospital, Dublin, Ireland
| | - Gerard F Curley
- Beaumont Hospital, Dublin, Ireland
- Department of Anaesthesia and Critical Care, Royal College of Surgeons in Ireland, Dublin, Ireland
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Hwang D, Ryu HW, Park JW, Kim JH, Kim DY, Oh JH, Kwon OK, Han SB, Ahn KS. Effects of 3'-isovaleryl-4'-senecioylkhellactone from Peucedanum japonicum Thunberg on PMA-Stimulated Inflammatory Response in A549 Human Lung Epithelial Cells. J Microbiol Biotechnol 2022; 32:81-90. [PMID: 34818666 PMCID: PMC9628833 DOI: 10.4014/jmb.2107.07001] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 11/10/2021] [Accepted: 11/12/2021] [Indexed: 12/15/2022]
Abstract
Peucedanum japonicum Thunberg (PJT) has been used in traditional medicine to treat colds, coughs, fevers, and other inflammatory diseases. The goal of this study was to investigate whether 3'-isovaleryl-4'-senecioylkhellactone (IVSK) from PJT has anti-inflammatory effects on lung epithelial cells. The anti-inflammatory effects of IVSK were evaluated using phorbol 12-myristate 13-acetate (PMA)-stimulated A549 cells and regular human lung epithelial cells as a reference. IVSK reduced the secretion of the inflammatory mediators interleukin (IL)-8 and monocyte chemoattractant protein-1 (MCP-1), and the mRNA expression of IL-6, IL-8, MCP-1, and IL-1β. Additionally, it inhibited the phosphorylation of IκB kinase (IKK), p65, Iκ-Bα, and mitogen-activated protein kinases (MAPKs) p38, JNK, and ERK in A549 cells stimulated with PMA. Moreover, the binding affinity of activator protein-1 (AP-1) and nuclear factor-κB (NF-κB) was significantly reduced in the luciferase assay, while nuclear translocation was markedly inhibited by IVSK in the immunocytochemistry. These findings indicate that IVSK can protect against inflammation through the AP-1 and NF-κB pathway and could possibly be used as a lead compound for the treatment of inflammatory lung diseases.
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Affiliation(s)
- Daseul Hwang
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea,College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea
| | - Hyung Won Ryu
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea
| | - Ji-Won Park
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea
| | - Jung-Hee Kim
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea
| | - Doo-Young Kim
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea
| | - Jae-Hoon Oh
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea,College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea
| | - Ok-Kyoung Kwon
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea,
O.K. Kwon E-mail:
| | - Sang-Bae Han
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea,Corresponding authors S.B. Han E-mail:
| | - Kyung-Seop Ahn
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea,
K.S. Ahn E-mail: Phone: +82-43-240-6134 Fax: +82-43-240-6129
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5
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Zhao Y, Cui L, Yang XX, Sun X, Liu Y, Yang Z, Zhu L, Peng C, Li D, Cai J, Ma Y. Sinoacutine inhibits inflammatory responses to attenuates acute lung injury by regulating NF-κB and JNK signaling pathways. BMC Complement Med Ther 2021; 21:284. [PMID: 34801005 PMCID: PMC8605577 DOI: 10.1186/s12906-021-03458-0] [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: 07/05/2021] [Accepted: 11/03/2021] [Indexed: 12/22/2022] Open
Abstract
Background Stephania yunnanensis H. S. Lo is widely used as an antipyretic, analgesic and anti-inflammatory herbal medicine in SouthWest China. In this study, we investigated the anti-inflammatory activity and mechanism of sinoacutine (sino), one of the primary components extracted from this plant. Methods A RAW264.7 cell model was established using lipopolysaccharide (LPS) induced for estimation of cytokines in vitro, qPCR was used to estimate gene expression, western blot analysis was used to estimate protein level and investigate the regulation of NF- κB, JNK and MAPK signal pathway. In addition, an acute lung injury model was established to determine lung index and levels of influencing factors. Results Using the RAW264.7 model, we found that sino reduced levels of nitric oxide (NO), tumour necrosis factor-α (TNF-α), interleukin (IL)-1β and prostaglandin E2 (PGE2) but increased levels of IL-6. qPCR analysis revealed that sino (50, 25 μg/ml) inhibited gene expression of nitric oxide synthase (iNOS). western blot analysis showed that sino significantly inhibited protein levels of both iNOS and COX-2. Further signalling pathway analysis validated that sino also inhibited phosphorylation of p65 in the NF-κB and c-Jun NH2 terminal kinase (JNK) signalling pathways but promoted the phosphorylation of extracellular signal regulated kinase (ERK) and p38 in the MAPK signalling pathway. In addition, in a mouse model induced by LPS, we determined that sino reduced the lung index and the levels of myeloperoxidase (MPO), NO, IL-6 and TNF-α in lung tissues and bronchoalveolar lavage fluid (BALF) in acute lung injury (ALI). Conclusion Taken together, our results demonstrate that sino is a promising drug to alleviate LPS-induced inflammatory reactions. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-021-03458-0.
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Affiliation(s)
- Yuancui Zhao
- School of Chinese Material Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China.,Key Laboratory of External Drug Delivery System and Preparation Technology in University of Yunnan, Kunming, 650500, China
| | - Lili Cui
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, China
| | - Xing Xin Yang
- Key Laboratory of Southern Medicine Utilization, Kunming, 650500, China
| | - Xingqian Sun
- School of Chinese Material Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China.,Yunnan Key Laboratory of Dai and Yi Medicine, School of Chinese Material Medicine Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Yunkuan Liu
- School of Chinese Material Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China.,Key Laboratory of External Drug Delivery System and Preparation Technology in University of Yunnan, Kunming, 650500, China
| | - Zixian Yang
- School of Chinese Material Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Liyuan Zhu
- School of Chinese Material Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Chaorui Peng
- School of Chinese Material Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Danye Li
- School of Chinese Material Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Junfei Cai
- School of Chinese Material Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Yunshu Ma
- School of Chinese Material Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China. .,Yunnan Key Laboratory of Dai and Yi Medicine, School of Chinese Material Medicine Yunnan University of Chinese Medicine, Kunming, 650500, China.
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α1-Antitrypsin: Key Player or Bystander in Acute Respiratory Distress Syndrome? Anesthesiology 2021; 134:792-808. [PMID: 33721888 DOI: 10.1097/aln.0000000000003727] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Acute respiratory distress syndrome is characterized by hypoxemia, altered alveolar-capillary permeability, and neutrophil-dominated inflammatory pulmonary edema. Despite decades of research, an effective drug therapy for acute respiratory distress syndrome remains elusive. The ideal pharmacotherapy for acute respiratory distress syndrome should demonstrate antiprotease activity and target injurious inflammatory pathways while maintaining host defense against infection. Furthermore, a drug with a reputable safety profile, low possibility of off-target effects, and well-known pharmacokinetics would be desirable. The endogenous 52-kd serine protease α1-antitrypsin has the potential to be a novel treatment option for acute respiratory distress syndrome. The main function of α1-antitrypsin is as an antiprotease, targeting neutrophil elastase in particular. However, studies have also highlighted the role of α1-antitrypsin in the modulation of inflammation and bacterial clearance. In light of the current SARS-CoV-2 pandemic, the identification of a treatment for acute respiratory distress syndrome is even more pertinent, and α1-antitrypsin has been implicated in the inflammatory response to SARS-CoV-2 infection.
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7
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Vitiello A, Ferrara F. Colchicine and SARS-CoV-2: Management of the hyperinflammatory state. Respir Med 2021; 178:106322. [PMID: 33550151 PMCID: PMC7848559 DOI: 10.1016/j.rmed.2021.106322] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/25/2021] [Accepted: 01/27/2021] [Indexed: 12/15/2022]
Abstract
The global COVID-19 pandemic is currently underway. In December 2020, the European Agency of Medicine (EMA) licensed the first Sars-CoV-2 vaccine. Therapeutic management of the COVID-19 positive patient should primarily aim to avoid the severe complications and organ injury caused by generalized inflammation caused by a cytokine storm and occurring in the most severe stages of viral infection. Current knowledge of the pathophysiological mechanisms of SARS- CoV-2 suggests a central role for exaggerated activation of the innate immune system as an important contributor to the adverse outcomes of COVID-19. Several studies have shown that blocking the cytokine storm or acting early with prevention of it can be effective; studies are underway to evaluate agents that may be able to reduce this hyperinflammatory state. The search for effective management strategies for COVID-19 continues to evolve. The actions of colchicine, one of the oldest anti-inflammatory therapies, target multiple targets associated with excessive COVID-19 inflammation. Colchicine is easily administered, generally well tolerated, and inexpensive. This article reports the scientific and molecular rationale for the use of colchicine as monotherapy or in combination in the various stages of SARS-CoV-2 infection to modulate and control the inflammatory state. Low-dose colchicine may be considered safe and effective for the treatment and prevention of cytokine storm in patients with SARS-CoV-2 infection, particularly as an adjunctive remedy to other therapeutic agents. Well-organized clinical studies are needed in this direction.
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Affiliation(s)
- Antonio Vitiello
- Pharmaceutical Department, Usl Umbria 1, A.Migliorati Street, 06132, Perugia, Italy.
| | - Francesco Ferrara
- Pharmaceutical Department, Usl Umbria 1, A.Migliorati Street, 06132, Perugia, Italy.
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8
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Gardin C, Ferroni L, Chachques JC, Zavan B. Could Mesenchymal Stem Cell-Derived Exosomes Be a Therapeutic Option for Critically Ill COVID-19 Patients? J Clin Med 2020; 9:E2762. [PMID: 32858940 PMCID: PMC7565764 DOI: 10.3390/jcm9092762] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 08/25/2020] [Indexed: 01/08/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is a pandemic viral disease originated in Wuhan, China, in December 2019, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The severe form of the disease is often associated with acute respiratory distress syndrome (ARDS), and most critically ill patients require mechanical ventilation and support in intensive care units. A significant portion of COVID-19 patients also develop complications of the cardiovascular system, primarily acute myocardial injury, arrhythmia, or heart failure. To date, no specific antiviral therapy is available for patients with SARS-CoV-2 infection. Exosomes derived from mesenchymal stem cells (MSCs) are being explored for the management of a number of diseases that currently have limited or no therapeutic options, thanks to their anti-inflammatory, immunomodulatory, and pro-angiogenic properties. Here, we briefly introduce the pathogenesis of SARS-CoV-2 and its implications in the heart and lungs. Next, we describe some of the most significant clinical evidence of the successful use of MSC-derived exosomes in animal models of lung and heart injuries, which might strengthen our hypothesis in terms of their utility for also treating critically ill COVID-19 patients.
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Affiliation(s)
- Chiara Gardin
- Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola (RA), Italy; (C.G.); (L.F.)
- Department of Morphology, Experimental Medicine and Surgery, University of Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy
| | - Letizia Ferroni
- Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola (RA), Italy; (C.G.); (L.F.)
- Department of Morphology, Experimental Medicine and Surgery, University of Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy
| | - Juan Carlos Chachques
- Department of Cardiac Surgery Pompidou Hospital, Laboratory of Biosurgical Research, Carpentier Foundation, University Paris Descartes, 75015 Paris, France;
| | - Barbara Zavan
- Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola (RA), Italy; (C.G.); (L.F.)
- Department of Morphology, Experimental Medicine and Surgery, University of Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy
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9
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Ashley SL, Sjoding MW, Popova AP, Cui TX, Hoostal MJ, Schmidt TM, Branton WR, Dieterle MG, Falkowski NR, Baker JM, Hinkle KJ, Konopka KE, Erb-Downward JR, Huffnagle GB, Dickson RP. Lung and gut microbiota are altered by hyperoxia and contribute to oxygen-induced lung injury in mice. Sci Transl Med 2020; 12:eaau9959. [PMID: 32801143 PMCID: PMC7732030 DOI: 10.1126/scitranslmed.aau9959] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 06/14/2019] [Accepted: 01/21/2020] [Indexed: 12/27/2022]
Abstract
Inhaled oxygen, although commonly administered to patients with respiratory disease, causes severe lung injury in animals and is associated with poor clinical outcomes in humans. The relationship between hyperoxia, lung and gut microbiota, and lung injury is unknown. Here, we show that hyperoxia conferred a selective relative growth advantage on oxygen-tolerant respiratory microbial species (e.g., Staphylococcus aureus) as demonstrated by an observational study of critically ill patients receiving mechanical ventilation and experiments using neonatal and adult mouse models. During exposure of mice to hyperoxia, both lung and gut bacterial communities were altered, and these communities contributed to oxygen-induced lung injury. Disruption of lung and gut microbiota preceded lung injury, and variation in microbial communities correlated with variation in lung inflammation. Germ-free mice were protected from oxygen-induced lung injury, and systemic antibiotic treatment selectively modulated the severity of oxygen-induced lung injury in conventionally housed animals. These results suggest that inhaled oxygen may alter lung and gut microbial communities and that these communities could contribute to lung injury.
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Affiliation(s)
- Shanna L Ashley
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Michael W Sjoding
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA
- Michigan Center for Integrative Research in Critical Care, Ann Arbor, MI, USA
| | - Antonia P Popova
- Division of Pediatric Pulmonology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Tracy X Cui
- Division of Pediatric Pulmonology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Matthew J Hoostal
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Thomas M Schmidt
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - William R Branton
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Michael G Dieterle
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Nicole R Falkowski
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Jennifer M Baker
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Kevin J Hinkle
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Kristine E Konopka
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - John R Erb-Downward
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Gary B Huffnagle
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
- Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, MI, USA
| | - Robert P Dickson
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
- Michigan Center for Integrative Research in Critical Care, Ann Arbor, MI, USA
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA
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10
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Zhang X, Ding J, Li Y, Song Q, Li S, Hayat MA, Zhang J, Wang H. The changes of inflammatory mediators and vasoactive substances in dairy cows' plasma with pasture-associated laminitis. BMC Vet Res 2020; 16:119. [PMID: 32326962 PMCID: PMC7178631 DOI: 10.1186/s12917-020-02319-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 03/16/2020] [Indexed: 11/20/2022] Open
Abstract
Background Hoof disease is one of the three major diseases that often occur in dairy cows. The impact of this disease on dairy farming is second only to mastitis. Laminitis is a diffuse, aseptic, serous, non-purulent inflammation of the dermal papillae and vascular layers of the cow’s hoof wall. In the pasture, laminitis occurs mostly in the laminae, that is, inside the hoof shell. No lesions can be seen on the surface. Therefore, laminitis cannot attract the attention of veterinarians. However, laminitis has become a major factor that seriously affects the health and welfare of dairy cows, making it an important cause of hindering the performance of dairy cows. Methods The study was conducted at a dairy farm in Harbin, Heilongjiang province, China. We selected a sample of the laminitis cows based on the veterinary diagnosis, took blood from the jugular vein and then separated the plasma, and measured the index with the Elisa kit. In this study, the markers of inflammatory and vasoactive substances status in dairy cows consisted of subclinical laminitis (SCL, n = 20), chronic laminitis (CL, n = 20) and healthy dairy cows (CON, n = 20) under the local management conditions were investigated. Results Compared with healthy cattle, HIS, IL-6, LPS, and TNF-α in subclinical laminitis group significantly increased (P < 0.05), especially HIS, LPS, TNF-α (P < 0.01); in chronic laminitis cows, COX-2, HIS, IL-6, LPS, and TNF-α increased significantly (P < 0.05), especially COX-2, HIS, TNF-α (P < 0.01). iNOS (P < 0.05), TXB2 (P < 0.01) in chronic laminitis cows had significantly increased. Conclusion This study reported for the first time that pasture laminitis was divided into subclinical laminitis and clinical chronic laminitis. Through research on the inflammatory factors and vasoactive substances of dairy cows, it is found that there is a close relationship between them, which affects the metabolic cycle of dairy cows. These indicators are abnormally expressed and cause hoof microcirculation disorders.
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Affiliation(s)
- Xianhao Zhang
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, P. R. China
| | - Jiafeng Ding
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, P. R. China
| | - Yuepeng Li
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, P. R. China
| | - Qiaozhi Song
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, P. R. China
| | - Shuaichen Li
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, P. R. China
| | - Muhammad Abid Hayat
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, P. R. China
| | - Jiantao Zhang
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, P. R. China
| | - Hongbin Wang
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, P. R. China.
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11
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Mascarenhas JB, Tchourbanov AY, Danilov SM, Zhou T, Wang T, Garcia JGN. The Splicing Factor hnRNPA1 Regulates Alternate Splicing of the MYLK Gene. Am J Respir Cell Mol Biol 2019; 58:604-613. [PMID: 29077485 DOI: 10.1165/rcmb.2017-0141oc] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Profound lung vascular permeability is a cardinal feature of acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI), two syndromes known to centrally involve the nonmuscle isoform of myosin light chain kinase (nmMLCK) in vascular barrier dysregulation. Two main splice variants, nmMLCK1 and nmMLCK2, are well represented in human lung endothelial cells and encoded by MYLK, and they differ only in the presence of exon 11 in nmMLCK1, which contains critical phosphorylation sites (Y464 and Y471) that influence nmMLCK enzymatic activity, cellular translocation, and localization in response to vascular agonists. We recently demonstrated the functional role of SNPs in altering MYLK splicing, and in the present study we sought to identify the role of splicing factors in the generation of nmMLCK1 and nmMLCK2 spliced variants. Using bioinformatic in silico approaches, we identified a putative binding site for heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), a recognized splicing factor. We verified hnRNPA1 binding to MYLK by gel shift analyses and that hnRNPA1 gene and protein expression is upregulated in mouse lungs obtained from preclinical models of ARDS and VILI and in human endothelial cells exposed to 18% cyclic stretch, a model that reproduces the excessive mechanical stress observed in VILI. Using an MYLK minigene approach, we established a direct role of hnRNPA1 in MYLK splicing and in the context of 18% cyclic stretch. In summary, these data indicate an important regulatory role for hnRNPA1 in MYLK splicing, and they increase understanding of MYLK splicing in the regulation of lung vascular integrity during acute lung inflammation and excessive mechanical stress, such as that observed in ARDS and VILI.
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Affiliation(s)
| | | | - Sergei M Danilov
- 1 Department of Medicine, College of Medicine, and.,3 Department of Anesthesiology, University of Illinois at Chicago, Chicago, Illinois; and
| | - Tong Zhou
- 4 Department of Physiology and Cell Biology, The University of Nevada, Reno School of Medicine, Reno, Nevada
| | - Ting Wang
- 1 Department of Medicine, College of Medicine, and
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12
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Jones-Nelson O, Hilliard JJ, DiGiandomenico A, Warrener P, Alfaro A, Cheng L, Stover CK, Cohen TS, Sellman BR. The Neutrophilic Response to Pseudomonas Damages the Airway Barrier, Promoting Infection by Klebsiella pneumoniae. Am J Respir Cell Mol Biol 2019; 59:745-756. [PMID: 30109945 DOI: 10.1165/rcmb.2018-0107oc] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Pseudomonas aeruginosa and Klebsiella pneumoniae are two common gram-negative pathogens that are associated with bacterial pneumonia and can often be isolated from the same patient. We used a mixed-pathogen pneumonia infection model in which mice were infected with sublethal concentrations of P. aeruginosa and K. pneumoniae, resulting in significant lethality, outgrowth of both bacteria in the lung, and systemic dissemination of K. pneumoniae. Inflammation, induced by P. aeruginosa activation of Toll-like receptor 5, results in prolonged neutrophil recruitment to the lung and increased levels of neutrophil elastase in the airway, resulting in lung damage and epithelial barrier dysfunction. Live P. aeruginosa was not required to potentiate K. pneumoniae infection, and flagellin alone was sufficient to induce lethality when delivered along with Klebsiella. Prophylaxis with an anti-Toll-like receptor 5 antibody or Sivelestat, a neutrophil elastase inhibitor, reduced neutrophil influx, inflammation, and mortality. Furthermore, pathogen-specific monoclonal antibodies targeting P. aeruginosa or K. pneumoniae prevented the outgrowth of both bacteria and reduced host inflammation and lethality. These findings suggest that coinfection with P. aeruginosa may enable the outgrowth and dissemination of K. pneumoniae, and that a pathogen- or host-specific prophylactic approach targeting P. aeruginosa may prevent or limit the severity of such infections by reducing neutrophil-induced lung damage.
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Affiliation(s)
| | | | | | | | - Alex Alfaro
- 2 Department of Laboratory Animal Research, and
| | - Lily Cheng
- 3 Department of Translational Science, MedImmune, LLC, Gaithersburg, Maryland
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13
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Brazee PL, Dada LA. Splice Wars: The Role of MLCK Isoforms in Ventilation-induced Lung Injury. Am J Respir Cell Mol Biol 2019; 58:549-550. [PMID: 29714632 DOI: 10.1165/rcmb.2017-0385ed] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Affiliation(s)
- Patricia L Brazee
- 1 Division of Pulmonary and Critical Care Northwestern University Chicago, Illinois
| | - Laura A Dada
- 1 Division of Pulmonary and Critical Care Northwestern University Chicago, Illinois
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14
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Gui X, Qiu X, Tian Y, Xie M, Li H, Gao Y, Zhuang Y, Cao M, Ding H, Ding J, Zhang Y, Cai H. Prognostic value of IFN-γ, sCD163, CCL2 and CXCL10 involved in acute exacerbation of idiopathic pulmonary fibrosis. Int Immunopharmacol 2019; 70:208-215. [PMID: 30851700 DOI: 10.1016/j.intimp.2019.02.039] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 02/24/2019] [Accepted: 02/24/2019] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is of concern because of its propensity for rapid deterioration and high mortality. Its aetiology and mechanism are still unclear. The aims of this study were to clarify the pathophysiology differences between AE-IPF and stable IPF (S-IPF) by comparing the serum levels of various cytokines and chemokines in the two groups and to identify those involvement in the occurrence of acute exacerbation and associated with mortality. METHODS The study included 28 patients with AE-IPF, 32 patients with S-IPF, and 18 healthy control subjects. We measured the serum cytokine and chemokine levels in all cases by multiplex assay. Serum levels of cytokines and chemokines were compared between AE-IPF and S-IPF subjects. Logistic regression analysis was applied to identify the ability of these variables to predict acute exacerbation. Kaplan-Meier curves were used to analyse survival and Cox proportional hazard regression was used to identify predictors of survival. RESULTS Levels of several cytokines and chemokines were significantly higher in both patient groups with IPF (with the exception of interleukin-2 [IL-2], chemokine cc-motif ligand 3, and RANTES [regulation upon activation normal T-cell express sequence]) than in healthy controls. Serum IL-1β (p = 0.008) and interferon (IFN)-γ (p = 0.007) levels tended to be higher in patients with AE-IPF than in those with S-IPF. The concentration of chemokine cc-motif ligand (CCL) 2 was significantly higher in bronchoalveolar lavage fluid than in serum (p = 0.001). Higher C-reactive protein, lactate dehydrogenase, percent forced vital capacity, percent diffusing capacity of the lung for carbon monoxide, and IFN-γ values in the patients with IPF were correlated with acute exacerbation status, with respective odds ratios of 1.241 (p = 0.011), 1.050 (p = 0.004), 1.043 (p = 0.001), 0.927 (p = 0.014), and 0.929 (p = 0.020). Acute exacerbation status was associated with an increased risk of mortality (hazard ratio 0.107, 95% confidence interval 0.036-0.314; p < 0.001). Univariate Cox regression demonstrated an association of IFN-γ, CCL2, C-X-C motif chemokine 10 (CXCL10) and sCD163 levels with an increased mortality risk (p = 0.015, p = 0.002, p = 0.001, and p = 0.030, respectively). CONCLUSIONS Our data demonstrate that serum levels of some pro-inflammatory cytokines and macrophage chemokines are upregulated during acute exacerbations of IPF and that these exacerbations are associated with the serum IFN-γ level. Chemokines and protein such as sCD163, CCL2, and CXCL10 are associated with activation of macrophages and may have a serious impact on overall survival in patients with IPF.
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Affiliation(s)
- Xianhua Gui
- Department of Respiratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, Jiangsu, PR China
| | - Xiaohua Qiu
- Department of Respiratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, Jiangsu, PR China
| | - Yaqiong Tian
- Department of Respiratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, Jiangsu, PR China
| | - Miaomiao Xie
- Department of Respiratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, Jiangsu, PR China
| | - Hui Li
- Department of Respiratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, Jiangsu, PR China
| | - Yujuan Gao
- Department of Respiratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, Jiangsu, PR China
| | - Yi Zhuang
- Department of Respiratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, Jiangsu, PR China
| | - Mengshu Cao
- Department of Respiratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, Jiangsu, PR China
| | - Hui Ding
- Department of Respiratory Medicine, Yixing People Hospital, Affiliated Jiangsu University, No. 75 Tongzhenguan Road, Yixing 214200, Jiangsu, PR China
| | - Jingjing Ding
- Department of Respiratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, Jiangsu, PR China.
| | - Yingwei Zhang
- Department of Respiratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, Jiangsu, PR China.
| | - Hourong Cai
- Department of Respiratory Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, Jiangsu, PR China.
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15
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Huang WC, Wu LY, Hu S, Wu SJ. Spilanthol Inhibits COX-2 and ICAM-1 Expression via Suppression of NF-κB and MAPK Signaling in Interleukin-1β-Stimulated Human Lung Epithelial Cells. Inflammation 2019; 41:1934-1944. [PMID: 29959625 DOI: 10.1007/s10753-018-0837-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Spilanthol a phytochemical derived from the Spilanthes acmella plant has antimicrobial, antioxidant, and anti-inflammatory properties. This study evaluated its effects on the expression of intercellular adhesion molecule 1 (ICAM-1) and inflammation-related mediators in IL-1β-stimulated human lung epithelial A549 cells. Human lung epithelial A549 cells were pretreated with various concentrations of spilanthol (3-100 μM) followed by treatment with IL-1β to induce inflammation. The protein levels of pro-inflammatory cytokines, chemokines, and prostaglandin E2 (PGE2) were measured using ELISA. Cyclooxygenase-2 (COX-2), heme oxygenase (HO-1), nuclear transcription factor kappa-B (NF-κB), and mitogen-activated protein kinase (MAPK) were measured by immunoblotting. The mRNA expression levels of ICAM-1 and MUC5AC were determined by real-time polymerase chain reaction. Spilanthol decreased the expression of PGE2, COX-2, TNF-α, and MCP-1. It also decreased ICAM-1 expression and suppressed monocyte adhesion to IL-1β-stimulated A549 cells. Spilanthol also significantly inhibited the phosphorylation of MAPK and I-κB. These results suggest that spilanthol exerts anti-inflammatory effects by inhibiting the expression of the pro-inflammatory cytokines, COX-2, and ICAM-1 by inhibiting the NF-κB and MAPK signaling pathways. Graphical Abstract ᅟ.
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Affiliation(s)
- Wen-Chung Huang
- Graduate Institute of Health Industry Technology, Research Center for Industry of Human Ecology, Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, No.261, Wenhua 1st Rd., Guishan Dist., Taoyuan, 33303, Taiwan.,Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Guishan Dist., Taoyuan, 33303, Taiwan
| | - Ling-Yu Wu
- Department of Nutrition and Health Sciences, Research Center for Food and Cosmetic Safety, and Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, No.261, Wenhua 1st Rd., Guishan Dist., Taoyuan, 33303, Taiwan
| | - Sindy Hu
- Aesthetic Medical Center, Department of Dermatology, Chang Gung Memorial Hospital, Guishan Dist., Taoyuan, 33303, Taiwan.,Department of Cosmetic Science, Research Center for Food and Cosmetic Safety, and Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, No.261, Wenhua 1st Rd., Guishan Dist., Taoyuan, 33303, Taiwan
| | - Shu-Ju Wu
- Graduate Institute of Health Industry Technology, Research Center for Industry of Human Ecology, Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, No.261, Wenhua 1st Rd., Guishan Dist., Taoyuan, 33303, Taiwan. .,Department of Nutrition and Health Sciences, Research Center for Food and Cosmetic Safety, and Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, No.261, Wenhua 1st Rd., Guishan Dist., Taoyuan, 33303, Taiwan. .,Aesthetic Medical Center, Department of Dermatology, Chang Gung Memorial Hospital, Guishan Dist., Taoyuan, 33303, Taiwan.
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16
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Targeting Cytokines as Evolving Treatment Strategies in Chronic Inflammatory Airway Diseases. Int J Mol Sci 2018; 19:ijms19113402. [PMID: 30380761 PMCID: PMC6275012 DOI: 10.3390/ijms19113402] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 10/25/2018] [Accepted: 10/27/2018] [Indexed: 12/13/2022] Open
Abstract
Cytokines are key players in the initiation and propagation of inflammation in chronic inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis and allergic asthma. This makes them attractive targets for specific novel anti-inflammatory treatment strategies. Recently, both interleukin-1 (IL-1) and IL-6 have been associated with negative health outcomes, mortality and a pro-inflammatory phenotype in COPD. IL-6 in COPD was shown to correlate negatively with lung function, and IL-1beta was induced by cigarette smoke in the bronchial epithelium, causing airway inflammation. Furthermore, IL-8 has been shown to be a pro-inflammatory marker in bronchiectasis, COPD and allergic asthma. Clinical trials using specific cytokine blockade therapies are currently emerging and have contributed to reduce exacerbations and steroid use in COPD. Here, we present a review of the current understanding of the roles of cytokines in the pathophysiology of chronic inflammatory airway diseases. Furthermore, outcomes of clinical trials in cytokine blockade as novel treatment strategies for selected patient populations with those diseases will be discussed.
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17
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Huh JW, Kim WY, Park YY, Lim CM, Koh Y, Kim MJ, Hong SB. Anti-inflammatory Role of Mesenchymal Stem Cells in an Acute Lung Injury Mouse Model. Acute Crit Care 2018; 33:154-161. [PMID: 31723879 PMCID: PMC6786701 DOI: 10.4266/acc.2018.00619] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Revised: 04/06/2018] [Accepted: 07/04/2018] [Indexed: 01/11/2023] Open
Abstract
Background Mesenchymal stem cells (MSCs) attenuate injury in various lung injury models through paracrine effects. We hypothesized that intratracheal transplantation of allogenic MSCs could attenuate lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice, mediated by anti-inflammatory responses. Methods Six-week-old male mice were randomized to either the control or the ALI group. ALI was induced by intratracheal LPS instillation. Four hours after LPS instillation, MSCs or phosphate-buffered saline was randomly intratracheally administered. Neutrophil count and protein concentration in bronchoalveolar lavage fluid (BALF); lung histology; levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and macrophage inflammatory protein-2; and the expression of proliferation cell nuclear antigen (PCNA), caspase-3, and caspase-9 were evaluated at 48 hours after injury. Results Treatment with MSCs attenuated lung injury in ALI mice by decreasing protein level and neutrophil recruitment into the BALF and improving the histologic change. MSCs also decreased the protein levels of proinflammatory cytokines including IL-1β, IL-6, and TNF-α, but had little effect on the protein expression of PCNA, caspase-3, and caspase-9. Conclusions Intratracheal injection of bone marrow-derived allogenic MSCs attenuates LPS-induced ALI via immunomodulatory effects.
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Affiliation(s)
- Jin Won Huh
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Won Young Kim
- Department of Emergency Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | | | - Chae-Man Lim
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Younsuck Koh
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Mi-Jung Kim
- Asan Institute for Life Sciences, Seoul, Korea
| | - Sang-Bum Hong
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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18
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β-Blockade use for Traumatic Injuries and Immunomodulation: A Review of Proposed Mechanisms and Clinical Evidence. Shock 2018; 46:341-51. [PMID: 27172161 DOI: 10.1097/shk.0000000000000636] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Sympathetic nervous system activation and catecholamine release are important events following injury and infection. The nature and timing of different pathophysiologic insults have significant effects on adrenergic pathways, inflammatory mediators, and the host response. Beta adrenergic receptor blockers (β-blockers) are commonly used for treatment of cardiovascular disease, and recent data suggests that the metabolic and immunomodulatory effects of β-blockers can expand their use. β-blocker therapy can reduce sympathetic activation and hypermetabolism as well as modify glucose homeostasis and cytokine expression. It is the purpose of this review to examine either the biologic basis for proposed mechanisms or to describe current available clinical evidence for the use of β-blockers in traumatic brain injury, spinal cord injury, hemorrhagic shock, acute traumatic coagulopathy, erythropoietic dysfunction, metabolic dysfunction, pulmonary dysfunction, burns, immunomodulation, and sepsis.
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19
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Morrison TJ, Jackson MV, Cunningham EK, Kissenpfennig A, McAuley DF, O'Kane CM, Krasnodembskaya AD. Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer. Am J Respir Crit Care Med 2017; 196:1275-1286. [PMID: 28598224 DOI: 10.1164/rccm.201701-0170oc] [Citation(s) in RCA: 556] [Impact Index Per Article: 69.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
RATIONALE Acute respiratory distress syndrome (ARDS) remains a major cause of respiratory failure in critically ill patients. Mesenchymal stromal cells (MSCs) are a promising candidate for a cell-based therapy. However, the mechanisms of MSCs' effects in ARDS are not well understood. In this study, we focused on the paracrine effect of MSCs on macrophage polarization and the role of extracellular vesicle (EV)-mediated mitochondrial transfer. OBJECTIVES To determine the effects of human MSCs on macrophage function in the ARDS environment and to elucidate the mechanisms of these effects. METHODS Human monocyte-derived macrophages (MDMs) were studied in noncontact coculture with human MSCs when stimulated with LPS or bronchoalveolar lavage fluid (BALF) from patients with ARDS. Murine alveolar macrophages (AMs) were cultured ex vivo with/without human MSC-derived EVs before adoptive transfer to LPS-injured mice. MEASUREMENTS AND MAIN RESULTS MSCs suppressed cytokine production, increased M2 macrophage marker expression, and augmented phagocytic capacity of human MDMs stimulated with LPS or ARDS BALF. These effects were partially mediated by CD44-expressing EVs. Adoptive transfer of AMs pretreated with MSC-derived EVs reduced inflammation and lung injury in LPS-injured mice. Inhibition of oxidative phosphorylation in MDMs prevented the modulatory effects of MSCs. Generating dysfunctional mitochondria in MSCs using rhodamine 6G pretreatment also abrogated these effects. CONCLUSIONS In the ARDS environment, MSCs promote an antiinflammatory and highly phagocytic macrophage phenotype through EV-mediated mitochondrial transfer. MSC-induced changes in macrophage phenotype critically depend on enhancement of macrophage oxidative phosphorylation. AMs treated with MSC-derived EVs ameliorate lung injury in vivo.
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Affiliation(s)
- Thomas J Morrison
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom
| | - Megan V Jackson
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom
| | - Erin K Cunningham
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom
| | - Adrien Kissenpfennig
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom
| | - Daniel F McAuley
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom
| | - Cecilia M O'Kane
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom
| | - Anna D Krasnodembskaya
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom
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20
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Wynne BM, Zou L, Linck V, Hoover RS, Ma HP, Eaton DC. Regulation of Lung Epithelial Sodium Channels by Cytokines and Chemokines. Front Immunol 2017; 8:766. [PMID: 28791006 PMCID: PMC5524836 DOI: 10.3389/fimmu.2017.00766] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Accepted: 06/16/2017] [Indexed: 12/20/2022] Open
Abstract
Acute lung injury leading to acute respiratory distress (ARDS) is a global health concern. ARDS patients have significant pulmonary inflammation leading to flooding of the pulmonary alveoli. This prevents normal gas exchange with consequent hypoxemia and causes mortality. A thin fluid layer in the alveoli is normal. The maintenance of this thin layer results from fluid movement out of the pulmonary capillaries into the alveolar interstitium driven by vascular hydrostatic pressure and then through alveolar tight junctions. This is then balanced by fluid reabsorption from the alveolar space mediated by transepithelial salt and water transport through alveolar cells. Reabsorption is a two-step process: first, sodium enters via sodium-permeable channels in the apical membranes of alveolar type 1 and 2 cells followed by active extrusion of sodium into the interstitium by the basolateral Na+, K+-ATPase. Anions follow the cationic charge gradient and water follows the salt-induced osmotic gradient. The proximate cause of alveolar flooding is the result of a failure to reabsorb sufficient salt and water or a failure of the tight junctions to prevent excessive movement of fluid from the interstitium to alveolar lumen. Cytokine- and chemokine-induced inflammation can have a particularly profound effect on lung sodium transport since they can alter both ion channel and barrier function. Cytokines and chemokines affect alveolar amiloride-sensitive epithelial sodium channels (ENaCs), which play a crucial role in sodium transport and fluid reabsorption in the lung. This review discusses the regulation of ENaC via local and systemic cytokines during inflammatory disease and the effect on lung fluid balance.
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Affiliation(s)
- Brandi M Wynne
- Department of Medicine, Nephrology, Emory University, Atlanta, GA, United States.,Department of Physiology, Emory University, Atlanta, GA, United States.,The Center for Cell and Molecular Signaling, Emory University, Atlanta, GA, United States
| | - Li Zou
- Department of Physiology, Emory University, Atlanta, GA, United States
| | - Valerie Linck
- Department of Physiology, Emory University, Atlanta, GA, United States
| | - Robert S Hoover
- Department of Medicine, Nephrology, Emory University, Atlanta, GA, United States.,Department of Physiology, Emory University, Atlanta, GA, United States.,Research Service, Atlanta Veteran's Administration Medical Center, Decatur, GA, United States
| | - He-Ping Ma
- Department of Physiology, Emory University, Atlanta, GA, United States.,The Center for Cell and Molecular Signaling, Emory University, Atlanta, GA, United States
| | - Douglas C Eaton
- Department of Physiology, Emory University, Atlanta, GA, United States.,The Center for Cell and Molecular Signaling, Emory University, Atlanta, GA, United States
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Abstract
Increased levels of tumor necrosis factor (TNF) α have been linked to a number of pulmonary inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), sarcoidosis, and interstitial pulmonary fibrosis (IPF). TNFα plays multiple roles in disease pathology by inducing an accumulation of inflammatory cells, stimulating the generation of inflammatory mediators, and causing oxidative and nitrosative stress, airway hyperresponsiveness and tissue remodeling. TNFα-targeting biologics, therefore, present a potentially highly efficacious treatment option. This review summarizes current knowledge on the role of TNFα in pulmonary disease pathologies, with a focus on the therapeutic potential of TNFα-targeting agents in treating inflammatory lung diseases.
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Affiliation(s)
- Rama Malaviya
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA
| | - Jeffrey D Laskin
- Department of Environmental and Occupational Health, School of Public Health, Rutgers University, Piscataway, NJ, USA
| | - Debra L Laskin
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA.
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22
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Wu G, Wang J, Luo P, Li A, Tian S, Jiang H, Zheng Y, Zhu F, Lu Y, Xia Z. Hydrostatin-SN1, a Sea Snake-Derived Bioactive Peptide, Reduces Inflammation in a Mouse Model of Acute Lung Injury. Front Pharmacol 2017; 8:246. [PMID: 28529485 PMCID: PMC5418923 DOI: 10.3389/fphar.2017.00246] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 04/19/2017] [Indexed: 12/21/2022] Open
Abstract
Snake venom has been used for centuries as a traditional Chinese medicine. Hydrostatin-SN1 (H-SN1), a bioactive peptide extracted from the Hydrophis cyanocinctus venom gland T7 phage display library, was reported to have the ability to reduce inflammation in a dextran sulfate sodium-induced murine colitis model. In this study, we sought to investigate the inhibitory potential of H-SN1 on inflammation in a murine model of lipopolysaccharide (LPS)-induced acute lung injury (ALI), and elucidate the anti-inflammatory mechanism in LPS-stimulated RAW 264.7 cells. In vivo, C57BL/6 male mice were intratracheally instilled with LPS or physiological saline with concurrent intraperitoneal injection of H-SN1 or saline alone. Lung histopathologic changes, lung wet-to-dry weight ratio, and myeloperoxidase activity in lung tissues were assessed. Total cell number, the protein concentration, and cytokine levels were determined in the bronchial alveolar lavage fluid. In vitro, RAW 264.7 cells were treated with various concentrations of H-SN1 for 2 h followed by incubation with or without 1 μg/ml LPS for 0.5 or 24 h. The mRNA expression of inflammatory cytokines was determined via RT-PCR and protein levels in the supernatants were measured via ELISA. Extracellular-signal related kinase 1/2 (ERK1/2) and nuclear factor-κB (NF-κB) pathways were analyzed via western blot. H-SN1 improved pulmonary edema status, decreased vascular permeability, suppressed pro-inflammatory cytokine production, and lessened lung morphological injury. H-SN1 also dose-dependently inhibited the mRNA expression and release of TNF-α, IL-6, and IL-1β in LPS-stimulated RAW 264.7 cells. Moreover, H-SN1 inhibited the LPS-induced phosphorylation of ERK1/2 and the nuclear translocation of NF-κB. Our results suggest that H-SN1 could attenuate LPS-induced ALI in mice, which is associated with the anti-inflammatory effect of H-SN1. The mechanism might involve inhibiting the production of inflammatory cytokines by, at least in part, interfering with the ERK1/2 and NF-κB signaling pathways.
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Affiliation(s)
- Guosheng Wu
- Department of Burn Surgery, Changhai Hospital, Second Military Medical UniversityShanghai, China
| | - Junjie Wang
- Department of Burn Surgery, Changhai Hospital, Second Military Medical UniversityShanghai, China
| | - Pengfei Luo
- Department of Burn Surgery, Changhai Hospital, Second Military Medical UniversityShanghai, China
| | - An Li
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical UniversityShanghai, China
| | - Song Tian
- Department of Burn Surgery, Changhai Hospital, Second Military Medical UniversityShanghai, China
| | - Hailong Jiang
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical UniversityShanghai, China
| | - Yongjun Zheng
- Department of Burn Surgery, Changhai Hospital, Second Military Medical UniversityShanghai, China
| | - Feng Zhu
- Department of Burn Surgery, Changhai Hospital, Second Military Medical UniversityShanghai, China
| | - Yiming Lu
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical UniversityShanghai, China
| | - Zhaofan Xia
- Department of Burn Surgery, Changhai Hospital, Second Military Medical UniversityShanghai, China
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23
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Nguyen Thi Dieu T, Pham Nhat A, Craig TJ, Duong-Quy S. Clinical characteristics and cytokine changes in children with pneumonia requiring mechanical ventilation. J Int Med Res 2017; 45:1805-1817. [PMID: 28703632 PMCID: PMC5805188 DOI: 10.1177/0300060516672766] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Objective To assess clinical characteristics and cytokine levels in children with
severe pneumonia who required ventilatory support. Methods In this prospective, descriptive, cross-sectional study, blood and
endotracheal fluid samples were obtained from patients with severe
pneumonia, aged <5 years, within 24 h following intubation. Blood samples
were also obtained from age-matched healthy controls. Cytokine levels were
investigated using flow cytometry-assisted immunoassay. Results Forty-five patients with severe pneumonia requiring mechanical ventilation
(aged 10 ± 5 months) and 35 healthy age-matched controls were included.
Patients with severe pneumonia had significantly increased serum interleukin
(IL)-6, IL-8, and granulocyte/macrophage colony-stimulating factor
concentrations compared with controls (80.84 pg/ml versus 2.06 pg/ml,
90.03 pg/ml versus 6.62 pg/ml, and 115.58 pg/ml versus 11.47 pg/ml,
respectively). In the severe pneumonia group, serum IL-10 levels were
significantly higher in patients aged <6 months versus those aged 6–12
months. Age-group differences in serum cytokine levels did not correspond to
age-group differences in endotracheal-fluid cytokine levels. Serum IL-6
levels were significantly higher in patients who subsequently died versus
those who survived (267.12 pg/ml versus 20.75 pg/ml, respectively). Conclusion High IL-6 concentrations were associated with mortality in patients <5
years of age with severe pneumonia requiring mechanical ventilation.
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Affiliation(s)
- Thuy Nguyen Thi Dieu
- 1 Department of Immunology, Allergology and Rheumatology, National Hospital of Paediatrics, Hanoi Medical University, Hanoi, Vietnam
| | - An Pham Nhat
- 1 Department of Immunology, Allergology and Rheumatology, National Hospital of Paediatrics, Hanoi Medical University, Hanoi, Vietnam
| | - Timothy J Craig
- 2 Department of Pulmonary, Allergy and Critical Care Medicine, Penn State University, Hershey, PA, USA
| | - Sy Duong-Quy
- 2 Department of Pulmonary, Allergy and Critical Care Medicine, Penn State University, Hershey, PA, USA.,3 Department of Respiratory Diseases, Bio-Medical Research Centre, Lam Dong Medical College, Dalat, Vietnam.,4 Department of Respiratory and Lung Functional Exploration, Cochin Hospital, Paris Descartes University, Paris, France
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TNF α Affects Ciliary Beat Response to Increased Viscosity in Human Pediatric Airway Epithelium. BIOMED RESEARCH INTERNATIONAL 2016; 2016:3628501. [PMID: 28025644 PMCID: PMC5153504 DOI: 10.1155/2016/3628501] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 10/20/2016] [Accepted: 10/30/2016] [Indexed: 01/09/2023]
Abstract
In airway epithelium, mucociliary clearance (MCC) velocity depends on the ciliary beat frequency (CBF), and it is affected by mucus viscoelastic properties. Local inflammation induces secretion of cytokines (TNFα) that can alter mucus viscosity; however airway ciliated cells have an autoregulatory mechanism to prevent the collapse of CBF in response to increase in mucus viscosity, mechanism that is associated with an increment in intracellular Ca+2 level ([Ca2+]i). We studied the effect of TNFα on the autoregulatory mechanism that regulates CBF in response to increased viscosity using dextran solutions, in ciliated cells cultured from human pediatric epithelial adenoid tissue. Cultures were treated with TNFα, before and after the viscous load was changed. TNFα treatment produced a significantly larger decrease in CBF in cultures exposed to dextran. Furthermore, an increment in [Ca2+]i was observed, which was significantly larger after TNFα treatment. In conclusion, although TNFα has deleterious effects on ciliated cells in response to maintaining CBF after increasing viscous loading, it has a positive effect, since increasing [Ca2+]i may prevent the MCC collapse. These findings suggest that augmented levels of TNFα associated with an inflammatory response of the nasopharyngeal epithelium may have dual effects that contribute to maintaining the effectiveness of MCC in the upper airways.
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25
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Rodrigo R, Trujillo S, Bosco C. Biochemical and Ultrastructural Lung Damage Induced by Rhabdomyolysis in the Rat. Exp Biol Med (Maywood) 2016; 231:1430-8. [PMID: 16946412 DOI: 10.1177/153537020623100817] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Rhabdomyolysis-induced oxidative stress is associated with morphological and functional damage to the kidney and other organs, but applications of this model in the lung are still lacking. The aim of the present study was to determine the relationship between oxidative stress and the morphological changes occurring in the lungs of rats subjected to rhabdomyolysis. Rhabdomyolysis was induced by intramuscular glycerol injection (50% v/v, 10 ml/kg), and the control group was injected with saline vehicle. Arterial blood samples were drawn at 0, 2, 4, and 6 hrs for measurement of arterial gases, creatine kinase activity, and plasma free F2-isoprostane levels. Six hours later, the lungs were removed to determine the wet-to-dry weight ratio, reduced glutathione (GSH) and GSH disulfide (GSSG) levels, and activity of antioxidant enzymes (cataiase [CAT], superoxide dismutase [SOD], and GSH peroxidase [GSH-Px]). Protein carbonylation and lipid peroxidation were assessed in the lungs by measurement of carbonyl and malondialdehyde (MDA) production, respectively. Bronchoalveolar lavage, cell counts, and lung ultrastructural studies were also performed. Six hours after glycerol injection, arterial PO2 and PCO2 were 23% and 38% lower, respectively, and plasma free F2-isoprostane levels were 72% higher, compared with control values. In lungs, protein carbonyl and MDA production were 58% and 12% higher, respectively; the GSH:GSSG ratio and GSH-Px activity were 43% and 60% lower, respectively; and activities of CAT and SOD showed no significant differences compared with controls. Rhabdomyolysis-induced ultrastructural impairment of the lung showed Type II cell damage, extracytoplasmic lamellar bodies and lack of tubular myelin reorganization, endothelial cellular edema, and no disruption of the alveolar-capillary barrier. These results provide evidence that rhabdomyolysis could induce tissue injury associated with increased oxidative stress, suggesting the contribution of oxidative stress to the pathogenic mechanism of acute lung injury.
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Affiliation(s)
- Ramón Rodrigo
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, Casilla 70058, Santiago 7, Chile.
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26
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Aisiku IP, Yamal JM, Doshi P, Benoit JS, Gopinath S, Goodman JC, Robertson CS. Plasma cytokines IL-6, IL-8, and IL-10 are associated with the development of acute respiratory distress syndrome in patients with severe traumatic brain injury. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2016; 20:288. [PMID: 27630085 PMCID: PMC5024454 DOI: 10.1186/s13054-016-1470-7] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 08/26/2016] [Indexed: 02/06/2023]
Abstract
Background Patients with severe traumatic brain injury (TBI) are at risk of the development of acute respiratory distress syndrome (ARDS). TBI and ARDS pathophysiologic mechanisms are known to independently involve significant inflammatory responses. The literature on the association between plasma inflammatory cytokines and ARDS in patients with TBI is sparse. Methods The study was a secondary analysis of the safety of a randomized trial of erythropoietin and transfusion threshold in patients with severe TBI. Inflammatory markers within the first 24 hours after injury were compared in patients who developed ARDS and patients without ARDS, using Cox proportional hazards models. Results There were 200 patients enrolled in the study. The majority of plasma and cerebrospinal fluid (CSF) cytokine levels were obtained within 6 hours. Plasma proinflammatory markers IL-6 and IL-8 and anti-inflammatory marker IL-10 were associated with the development of ARDS (adjusted hazard ratio (HR) = 1.55, confidence interval (CI) = 1.14, 2.11, P = 0.005 for IL-6; adjusted HR = 1.32, CI = 1.10, 1.59, P = 0.003 for IL-8). Conclusion Plasma markers of IL-6, IL-8, and IL-10 are associated with ARDS in patients with severe TBI. Trial registration NCT00313716 registered 4/2006
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Affiliation(s)
- Imo P Aisiku
- Department of Emergency Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA.
| | - Jose-Miguel Yamal
- Division of Biostatistics, University of Texas School of Public Health, Houston, TX, USA
| | - Pratik Doshi
- Department of Emergency Medicine and Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Julia S Benoit
- Department of Basic Vision Sciences, College of Optometry Texas Institute for Measurement Evaluation and Statistics, University of Houston, Houston, TX, USA
| | - Shankar Gopinath
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
| | - Jerry C Goodman
- Department of Pathology, Baylor College of Medicine, Houston, TX, USA
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Cavaillon JM, Annane D. Invited review: Compartmentalization of the inflammatory response in sepsis and SIRS. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/09680519060120030301] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Sepsis and systemic inflammatory response syndrome (SIRS) are associated with an exacerbated production of both pro- and anti-inflammatory mediators that are mainly produced within tissues. Although a systemic process, the pathophysiological events differ from organ to organ, and from organ to peripheral blood, leading to the concept of compartmentalization. The nature of the insult ( e.g. burn, hemorrhage, trauma, peritonitis), the cellular composition of each compartment ( e.g . nature of phagocytes, nature of endothelial cells), and its micro-environment ( e.g. local presence of granulocyte-macrophage colony stimulating factor [GM-CSF] in the lungs, low levels of arginine in the liver, release of endotoxin from the gut), and leukocyte recruitment, have a great influence on local inflammation and on tissue injury. High levels of pro-inflammatory mediators ( e.g. interleukin-1 [IL-1], tumor necrosis factor [TNF], gamma interferon [IFN-γ], high mobility group protein-1 [HMGB1], macrophage migration inhibitory factor [MIF]) produced locally and released into the blood stream initiate remote organ injury as a consequence of an organ cross-talk. The inflammatory response within the tissues is greatly influenced by the local delivery of neuromediators by the cholinergic and sympathetic neurons. Acetylcholine and epinephrine contribute with IL-10 and other mediators to the anti-inflammatory compensatory response initiated to dampen the inflammatory process. Unfortunately, this regulatory response leads to an altered immune status of leukocytes that can increase the susceptibility to further infection. Again, the nature of the insult, the nature of the leukocytes, the presence of circulating microbial components, and the nature of the triggering agent employed to trigger cells, greatly influence the immune status of the leukocytes that may differ from one compartment to another. While anti-inflammatory mediators predominate within the blood stream to avoid igniting new inflammatory foci, their presence within tissues may not always be sufficient to prevent the initiation of a deleterious inflammatory response in the different compartments.
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Affiliation(s)
| | - Djillali Annane
- Service de Réanimation, Hôpital Raymond Poincaré, Assistance Publique - Hôpitaux de Paris, Faculté de Médecine Paris Ile de France Ouest, Université de Versailles Saint-Quentin-en-Yvelines, Garches, France
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28
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Dekker ABE, Krijnen P, Schipper IB. Predictive value of cytokines for developing complications after polytrauma. World J Crit Care Med 2016; 5:187-200. [PMID: 27652210 PMCID: PMC4986547 DOI: 10.5492/wjccm.v5.i3.187] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 04/07/2016] [Accepted: 04/22/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate posttraumatic cytokine alterations and their value for predicting complications and mortality in polytraumatized patients.
METHODS: Studies on the use of specific cytokines to predict the development of complications and mortality were identified in MEDLINE, EMBASE, Web of Science and the Cochrane Library. Of included studies, relevant data were extracted and study quality was scored.
RESULTS: Forty-two studies published between 1988 and 2015 were identified, including 28 cohort studies and 14 “nested” case-control studies. Most studies investigated the cytokines interleukin (IL)-6, IL-8, IL-10 and tumor necrosis factor (TNF-α). IL-6 seems related to muliorgan dysfunction syndrome, multiorgan failure (MOF) and mortality; IL-8 appears altered in acute respiratory distress syndrome, MOF and mortality; IL-10 alterations seem to precede sepsis and MOF; and TNF-α seems related to MOF.
CONCLUSION: Cytokine secretion patterns appear to be different for patients developing complications when compared to patients with uneventful posttraumatic course. More research is needed to strengthen the evidence for clinical relevance of these cytokines.
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29
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Dickson RP, Singer BH, Newstead MW, Falkowski NR, Erb-Downward JR, Standiford TJ, Huffnagle GB. Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome. Nat Microbiol 2016; 1:16113. [PMID: 27670109 DOI: 10.1038/nmicrobiol.2016.113] [Citation(s) in RCA: 450] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 06/03/2016] [Indexed: 12/15/2022]
Abstract
Sepsis and the acute respiratory distress syndrome (ARDS) are major causes of mortality without targeted therapies. Although many experimental and clinical observations have implicated gut microbiota in the pathogenesis of these diseases, culture-based studies have failed to demonstrate translocation of bacteria to the lungs in critically ill patients. Here, we report culture-independent evidence that the lung microbiome is enriched with gut bacteria both in a murine model of sepsis and in humans with established ARDS. Following experimental sepsis, lung communities were dominated by viable gut-associated bacteria. Ecological analysis identified the lower gastrointestinal tract, rather than the upper respiratory tract, as the likely source community of post-sepsis lung bacteria. In bronchoalveolar lavage fluid from humans with ARDS, gut-specific bacteria (Bacteroides spp.) were common and abundant, undetected by culture and correlated with the intensity of systemic inflammation. Alveolar TNF-α, a key mediator of alveolar inflammation in ARDS, was significantly correlated with altered lung microbiota. Our results demonstrate that the lung microbiome is enriched with gut-associated bacteria in sepsis and ARDS, potentially representing a shared mechanism of pathogenesis in these common and lethal diseases.
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Affiliation(s)
- Robert P Dickson
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
| | - Benjamin H Singer
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
| | - Michael W Newstead
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
| | - Nicole R Falkowski
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
| | - John R Erb-Downward
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
| | - Theodore J Standiford
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
| | - Gary B Huffnagle
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.,Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
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Serum Amyloid P Contained in Alveolar Fluid From Patients With Acute Respiratory Distress Syndrome Mediates the Inhibition of Monocyte Differentiation into Fibrocyte. Crit Care Med 2016; 44:e563-73. [DOI: 10.1097/ccm.0000000000001612] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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31
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Taysse L, Daulon S, Calvet J, Delamanche S, Hilaire D, Bellier B, Breton P. Induction of Acute Lung Injury after Intranasal Administration of Toxin Botulinum A Complex. Toxicol Pathol 2016; 33:336-42. [PMID: 15814363 DOI: 10.1080/01926230590922884] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
The inhalation of aerozolized botulinum toxin may represent a potential significant hazard to both military and civilian personnel. Since the lung is the primary target organ for inhaled toxin, the investigation reported herein was conducted to examine lung function in mice exposed to botulinum toxin A complex by intranasal route. Data includes lethality, symptomatology, measurement of respiratory function (minute ventilation, respiratory frequency, and tidal volume), and histopathology of the lungs. The clinical signs of intoxication are similar to those observed in foodborne botulism. Plethysmography revealed severe impairment of all respiratory parameters tested from 7 hours postexposure. Severe lung lesions, possibly secondary to the intoxication, were observed in mice who survived 14 days after the toxin challenge. These included intra-alveolar hemorrhage and interstitial edema. Mice immunized by the pentavalent (ABCDE) toxoid were protected against the neurotoxin (4 LD50) as revealed by the decrease of lethality and severity of nervous signs of intoxication, but not against histopathological changes in the lungs. These effects are nonspecific and require further experiments in order to specify the relationships between the pathology and the inflammatory process in the lung due to mediators such as cytokines, and possibly permanent physiological sequelae.
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Affiliation(s)
- L Taysse
- Centre d'Etudes du Bouchet (Defense Research Center) BP No. 3, 91710 Vert le Petit France.
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Scheraga RG, Abraham S, Niese KA, Southern BD, Grove LM, Hite RD, McDonald C, Hamilton TA, Olman MA. TRPV4 Mechanosensitive Ion Channel Regulates Lipopolysaccharide-Stimulated Macrophage Phagocytosis. THE JOURNAL OF IMMUNOLOGY 2015; 196:428-36. [PMID: 26597012 DOI: 10.4049/jimmunol.1501688] [Citation(s) in RCA: 144] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 11/01/2015] [Indexed: 12/31/2022]
Abstract
Macrophage phagocytosis of particles and pathogens is an essential aspect of innate host defense. Phagocytic function requires cytoskeletal rearrangements that depend on the interaction between macrophage surface receptors, particulates/pathogens, and the extracellular matrix. In the present study we determine the role of a mechanosensitive ion channel, transient receptor potential vanilloid 4 (TRPV4), in integrating the LPS and matrix stiffness signals to control macrophage phenotypic change for host defense and resolution from lung injury. We demonstrate that active TRPV4 mediates LPS-stimulated murine macrophage phagocytosis of nonopsonized particles (Escherichia coli) in vitro and opsonized particles (IgG-coated latex beads) in vitro and in vivo in intact mice. Intriguingly, matrix stiffness in the range seen in inflamed or fibrotic lung is required to sensitize the TRPV4 channel to mediate the LPS-induced increment in macrophage phagocytosis. Furthermore, TRPV4 is required for the LPS induction of anti-inflammatory/proresolution cytokines. These findings suggest that signaling through TRPV4, triggered by changes in extracellular matrix stiffness, cooperates with LPS-induced signals to mediate macrophage phagocytic function and lung injury resolution. These mechanisms are likely to be important in regulating macrophage function in the context of pulmonary infection and fibrosis.
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Affiliation(s)
- Rachel G Scheraga
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195; and
| | - Susamma Abraham
- Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195; and
| | - Kathryn A Niese
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195
| | - Brian D Southern
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195; and
| | - Lisa M Grove
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195
| | - R Duncan Hite
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195; and
| | - Christine McDonald
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195
| | | | - Mitchell A Olman
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195; and
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Bhan U, Podsiad AB, Kovach MA, Ballinger MN, Keshamouni V, Standiford TJ. Linezolid has unique immunomodulatory effects in post-influenza community acquired MRSA pneumonia. PLoS One 2015; 10:e0114574. [PMID: 25635685 PMCID: PMC4312022 DOI: 10.1371/journal.pone.0114574] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Accepted: 11/11/2014] [Indexed: 12/17/2022] Open
Abstract
Introduction Post influenza pneumonia is a leading cause of mortality and morbidity, with mortality rates approaching 60% when bacterial infections are secondary to multi-drug resistant (MDR) pathogens. Staphylococcus aureus, in particular community acquired MRSA (cMRSA), has emerged as a leading cause of post influenza pneumonia. Hypothesis Linezolid (LZD) prevents acute lung injury in murine model of post influenza bacterial pneumonia Methods Mice were infected with HINI strain of influenza and then challenged with cMRSA at day 7, treated with antibiotics (LZD or Vanco) or vehicle 6 hours post bacterial challenge and lungs and bronchoalveolar lavage fluid (BAL) harvested at 24 hours for bacterial clearance, inflammatory cell influx, cytokine/chemokine analysis and assessment of lung injury. Results Mice treated with LZD or Vanco had lower bacterial burden in the lung and no systemic dissemination, as compared to the control (no antibiotic) group at 24 hours post bacterial challenge. As compared to animals receiving Vanco, LZD group had significantly lower numbers of neutrophils in the BAL (9×103 vs. 2.3×104, p < 0.01), which was associated with reduced levels of chemotactic chemokines and inflammatory cytokines KC, MIP-2, IFN-γ, TNF-α and IL-1β in the BAL. Interestingly, LZD treatment also protected mice from lung injury, as assessed by albumin concentration in the BAL post treatment with H1N1 and cMRSA when compared to vanco treatment. Moreover, treatment with LZD was associated with significantly lower levels of PVL toxin in lungs. Conclusion Linezolid has unique immunomodulatory effects on host inflammatory response and lung injury in a murine model of post-viral cMRSA pneumonia.
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Affiliation(s)
- Urvashi Bhan
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America
- * E-mail:
| | - Amy B. Podsiad
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America
| | - Melissa A. Kovach
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America
| | - Megan N. Ballinger
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Ohio State University, Columbus, Ohio, United States of America
| | - Venkateshwar Keshamouni
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America
| | - Theodore J. Standiford
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America
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Shukla P, Verma AK, Dwivedi P, Yadav A, Gupta PK, Rath SK, Mishra PR. Moxifloxacin-loaded nanoemulsions having tocopheryl succinate as the integral component improves pharmacokinetics and enhances survival in E. coli-induced complicated intra-abdominal infection. Mol Pharm 2014; 11:4314-26. [PMID: 25317848 DOI: 10.1021/mp5003762] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
In the present work, a novel nanoemulsion laden with moxifloxacin has been developed for effective management of complicated intra-abdominal infections. Moxifloxacin nanoemulsion fabricated using high pressure homogenization was evaluated for various pharmaceutical parameters, pharmacokinetics (PK) and pharmacodynamics (PD) in rats with E. coli-induced peritonitis and sepsis. The developed nanoemulsion MONe6 (size 168 ± 28 nm and zeta potential (ZP) 24.78 ± 0.45 mV, respectively) was effective for intracellular delivery and sustaining the release of MOX. MONe6 demonstrated improved plasma (AUC(MONe6/MOX) = 2.38-fold) and tissue pharmacokinetics of MOX (AUC(MONe6/MOX) = 2.63 and 1.47 times in lung and liver, respectively). Calculated PK/PD index correlated well with a reduction in bacterial burden in plasma as well as tissues. Enhanced survival on treatment with MONe6 (65.44%) and as compared to the control group (8.22%) was a result of reduction in lipid peroxidation, neutrophil migration, and cytokine levels (TNF-α and IL6) as compared to untreated groups in the rat model of E. coli-induced sepsis. Parenteral nanoemulsions of MOX hold a promising advantage in the therapy of E. coli-induced complicated intra-abdominal infections and is helpful in the prevention of further complications like septic shock and death.
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Affiliation(s)
- Prashant Shukla
- Pharmaceutics Division and ‡Toxicology Division, CSIR-Central Drug Research Institute (Council of Scientific and Industrial Research) , B 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, UP 226031, India
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Abstract
PURPOSE OF REVIEW The article provides an overview of efforts to identify and validate biomarkers in acute respiratory distress syndrome (ARDS) and a discussion of the challenges confronting researchers in this area. RECENT FINDINGS Although various putative biomarkers have been investigated in ARDS, the data have been largely disappointing and the 'troponin' of ARDS remains elusive. Establishing a relationship between measurable biological processes and clinical outcomes is vital to advancing clinical trials in ARDS and expanding our arsenal of treatments for this complex syndrome. SUMMARY This article summarizes the current status of ARDS biomarker research and provides a framework for future investigation.
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Dai WP, Li G, Li X, Hu QP, Liu JX, Zhang FX, Su ZR, Lai XP. The roots of Ilex asprella extract lessens acute respiratory distress syndrome in mice induced by influenza virus. JOURNAL OF ETHNOPHARMACOLOGY 2014; 155:1575-1582. [PMID: 25102242 DOI: 10.1016/j.jep.2014.07.051] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 06/07/2014] [Accepted: 07/25/2014] [Indexed: 06/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE In traditional Chinese medicine, the root of Ilex asprella (Hook. & Arn.) Champ. ex Benth. (IA) has been widely used to treat influenza, lung abscess and other diseases in South China for many years. The present study is aimed at investigating the treatment effect of IA on acute respiratory distress syndrome (ARDS) induced by the H1N1 virus in mice. MATERIALS AND METHODS After being inoculated with several viral doses of influenza A/FM/1/47 H1N1 virus, mice were given oral administration of IA extract (500 mg/kg or 12 5mg/kg per day) for five or 10 consecutive days, respectively. Mice survival rate and clinical condition were observed for 15 days after inoculation. Lung weight, pathological analysis and arterial blood gas analysis were assessed. Lung viral load was quantified by RT-PCR. Moreover, immunological analysis was measured by leukocyte counts and the levels of inflammatory cytokines, including IL-6, IL-10, TNF-α, IFN-γ, MCP-1 and IL-12p 70 in serum of mice. RESULTS We found that the extract of Ilex asprella at dosages of 500 mg/kg could effectively diminish mortality rate, and ameliorate lung edema and inflammation. Administration of IA extract significantly depressed the expression of IL-6, TNF-α and MCP-1, and significantly increased the expression of IL-10 and IFN-γ in serum. Simultaneously, the extract was also found to reduce the lung viral load and improve pulmonary ventilation. CONCLUSION The present study shows that the extract of IA has the potential to treat ARDS, due to its abilities of attenuation of systemic and pulmonary inflammatory responses and inhibition of viral replication.
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Affiliation(s)
- Wei-Ping Dai
- Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Geng Li
- Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Xiong Li
- Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Qiu-Ping Hu
- Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Jian-Xing Liu
- Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Feng-Xue Zhang
- Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
| | - Zi-Ren Su
- Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Xiao-Ping Lai
- Dongguan Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Traditional Chinese Medicine, Dongguan 523808, China.
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CHEN YUQING, RONG LING, QIAO JIANOU. Anti-inflammatory effects of Panax notoginseng saponins ameliorate acute lung injury induced by oleic acid and lipopolysaccharide in rats. Mol Med Rep 2014; 10:1400-8. [DOI: 10.3892/mmr.2014.2328] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Accepted: 01/22/2014] [Indexed: 11/05/2022] Open
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Weiterer S, Schulte D, Müller S, Kohlen T, Uhle F, Weigand MA, Henrich M. Tumor necrosis factor alpha induces a serotonin dependent early increase in ciliary beat frequency and epithelial transport velocity in murine tracheae. PLoS One 2014; 9:e91705. [PMID: 24626175 PMCID: PMC3953516 DOI: 10.1371/journal.pone.0091705] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 02/14/2014] [Indexed: 12/21/2022] Open
Abstract
The tracheal epithelium prevents via its highly effective clearance mechanism the contamination of the lower airways by pathogens. This mechanism is driven by ciliary bearing cells which are not only in contact with the gas phase; in addition they are also influenced by inflammatory mediators. These mediators can alter the protective function of the epithelium. Since the pro-inflammatoric cytokine tumor necrosis factor-α (TNF-α) plays a pivotal role within the inflammatory cascade, we investigated its effect onto the tracheal epithelium measured by its ciliary beat frequency and the particle transport velocity. In organ explant experiments the ciliary beat frequency and the particle transport velocity were measured under the application of TNF-α using tracheae from male C57BL6J mice. We observed a dose dependent TNF-α induced increase of both particle transport velocity and ciliary beat frequency. Knock out mice experiments made evident that the increase was depended on the expression of tumor necrosis factor receptor 1 (TNF-R1). The increases in ciliary beat frequency as well as the accelerated particle transport velocity were either inhibited by the unspecific serotonin antagonist methysergide or by cyproheptadine a specific 5-HT2 receptor antagonist. Thus, acetylcholine antagonists or nitric oxide synthase (NOS) inhibitors failed to inhibit the TNF-α induced activation. In conclusion, TNF-α may play a pivotal role in the protection of lower airways by inducing ciliary activity and increase in particle transport velocity via TNF-R1 and 5-HT2 receptor.
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Affiliation(s)
- Sebastian Weiterer
- Department of Anaesthesiology, Intensive Care Medicine, Pain Therapy, Justus-Liebig-University Giessen, Giessen, Germany
| | - Dagmar Schulte
- Department of Anaesthesiology, Intensive Care Medicine, Pain Therapy, Justus-Liebig-University Giessen, Giessen, Germany
| | - Sabrina Müller
- Department of Anaesthesiology, Intensive Care Medicine, Pain Therapy, Justus-Liebig-University Giessen, Giessen, Germany
| | - Thomas Kohlen
- Department of Anaesthesiology, Intensive Care Medicine, Pain Therapy, Justus-Liebig-University Giessen, Giessen, Germany
| | - Florian Uhle
- Department of Anaesthesiology, Intensive Care Medicine, Pain Therapy, Justus-Liebig-University Giessen, Giessen, Germany
| | - Markus A. Weigand
- Department of Anaesthesiology, Intensive Care Medicine, Pain Therapy, Justus-Liebig-University Giessen, Giessen, Germany
| | - Michael Henrich
- Department of Anaesthesiology, Intensive Care Medicine, Pain Therapy, Justus-Liebig-University Giessen, Giessen, Germany
- * E-mail:
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Wilkinson TS, Conway Morris A, Kefala K, O'Kane CM, Moore NR, Booth NA, McAuley DF, Dhaliwal K, Walsh TS, Haslett C, Sallenave JM, Simpson AJ. Ventilator-associated pneumonia is characterized by excessive release of neutrophil proteases in the lung. Chest 2013; 142:1425-1432. [PMID: 22911225 DOI: 10.1378/chest.11-3273] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Ventilator-associated pneumonia (VAP) is characterized by neutrophils infiltrating the alveolar space. VAP is associated with high mortality, and accurate diagnosis remains difficult. We hypothesized that proteolytic enzymes from neutrophils would be significantly increased and locally produced inhibitors of human neutrophil elastase (HNE) would be decreased in BAL fluid (BALF) from patients with confirmed VAP. We postulated that in suspected VAP, neutrophil proteases in BALF may help identify "true" VAP. METHODS BAL was performed in 55 patients with suspected VAP and in 18 control subjects. Isolation of a pathogen(s) at > 10⁴ colony-forming units/mL of BALF dichotomized patients into VAP (n = 12) and non-VAP (n = 43) groups. Matrix metalloproteinases (MMPs), HNE, inhibitors of HNE, and tissue inhibitors of matrix metalloproteinases (TIMPs) were quantified. Plasminogen activator (PA) activity was estimated by sodium dodecyl sulfate polyacrylamide gel electrophoresis and zymography. RESULTS Neutrophil-derived proteases HNE, MMP-8, and MMP-9 were significantly increased in cell-free BALF from patients with VAP as compared with those without VAP (median values: HNE, 2,708 ng/mL vs 294 ng/mL, P < .01; MMP-8, 184 ng/mL vs 5 ng/mL, P < .01; MMP-9, 310 ng/mL vs 11 ng/mL, P < .01). HNE activity was also significantly increased in VAP (0.45 vs 0.01 arbitrary units; P < .05). In contrast, no significant differences were observed for protease inhibitors, TIMPs, or PAs. HNE in BALF, at a cutoff of 670 ng/mL, identified VAP with a sensitivity of 93% and specificity of 79%. CONCLUSIONS Neutrophil proteases are significantly elevated in the alveolar space in VAP and may contribute to pathogenesis. Neutrophil proteases appear to have potential in suspected VAP for distinguishing true cases from "non-VAP" cases.
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Affiliation(s)
- Thomas S Wilkinson
- Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland; Institute of Life Science, Medical Microbiology and Infectious Disease, Swansea University, Swansea, Wales
| | - Andrew Conway Morris
- Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland
| | - Kallirroi Kefala
- Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland
| | - Cecilia M O'Kane
- Centre for Infection and Immunity, Queen's University of Belfast, Belfast, Northern Ireland
| | - Norma R Moore
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland
| | - Nuala A Booth
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland
| | - Daniel F McAuley
- Centre for Infection and Immunity, Queen's University of Belfast, Belfast, Northern Ireland
| | - Kevin Dhaliwal
- Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland
| | - Timothy S Walsh
- Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland
| | - Christopher Haslett
- Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland
| | | | - A John Simpson
- Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland; Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, England.
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Patel BV, Wilson MR, O'Dea KP, Takata M. TNF-induced death signaling triggers alveolar epithelial dysfunction in acute lung injury. THE JOURNAL OF IMMUNOLOGY 2013; 190:4274-82. [PMID: 23487422 DOI: 10.4049/jimmunol.1202437] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The ability of the alveolar epithelium to prevent and resolve pulmonary edema is a crucial determinant of morbidity and mortality in acute lung injury (ALI). TNF has been implicated in ALI pathogenesis, but the precise mechanisms remain undetermined. We evaluated the role of TNF signaling in pulmonary edema formation in a clinically relevant mouse model of ALI induced by acid aspiration and investigated the effects of TNF p55 receptor deletion, caspase-8 inhibition, and alveolar macrophage depletion on alveolar epithelial function. We found that TNF plays a central role in the development of pulmonary edema in ALI through activation of p55-mediated death signaling, rather than through previously well-characterized p55-mediated proinflammatory signaling. Acid aspiration produced pulmonary edema with significant alveolar epithelial dysfunction, as determined by alveolar fluid clearance (AFC) and intra-alveolar levels of the receptor for advanced glycation end-products. The impairment of AFC was strongly correlated with lung caspase-8 activation, which was localized to type 1 alveolar epithelial cells by flow cytometric analysis. p55-deficient mice displayed markedly attenuated injury, with improved AFC and reduced caspase-8 activity but no differences in downstream cytokine/chemokine production and neutrophil recruitment. Caspase-8 inhibition significantly improved AFC and oxygenation, whereas depletion of alveolar macrophages attenuated epithelial dysfunction with reduced TNF production and caspase-8 activity. These results provide in vivo evidence for a novel role for TNF p55 receptor-mediated caspase-8 signaling, without substantial apoptotic cell death, in triggering alveolar epithelial dysfunction and determining the early pathophysiology of ALI. Blockade of TNF-induced death signaling may provide an effective early-phase strategy for ALI.
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Affiliation(s)
- Brijesh V Patel
- Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London SW10 9NH, United Kingdom.
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Sato H, Tanaka T, Kasai K. Ethanol consumption impairs the hemodynamic response to hemorrhagic shock in rats. Alcohol 2013; 47:47-52. [PMID: 23084028 DOI: 10.1016/j.alcohol.2012.10.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Revised: 10/02/2012] [Accepted: 10/02/2012] [Indexed: 11/29/2022]
Abstract
Alcohol intoxication can exacerbate hemodynamic instability following hemorrhagic shock. Impairment of hormonal, neurohumoral, and immune responses can contribute to such instability; however, the relationship between blood alcohol levels and the progression of hemorrhagic shock accompanied with these responses has not been clearly demonstrated. Herein, we examined this relationship in rats treated with various dose of alcohol. After oral administration of alcohol and then hemorrhage, the recovery of mean blood pressure (MBP); increase in plasma level of norepinephrine, epinephrine, and vasopressin; and survival interval decreased in a dose-dependent manner as the blood alcohol level increased. There were no significant differences in the production of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β among the groups. The present results demonstrated alcohol aggravates hemorrhagic shock in a dose-dependent manner not by alerting the immune response, but by suppressing hormonal and neurohumoral responses, thereby inhibiting hemodynamic autoregulation and shortening the survival interval.
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Affiliation(s)
- Hiroaki Sato
- Department of Forensic Medicine, School of Medicine, University of Occupational and Environmental Health, Iseigaoka1-1, Yahata-Nishi, Kitakyushu 807-8555, Japan.
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Abstract
Proteases are enzymes that have the capacity to hydrolyze peptide bonds and degrade other proteins. Proteases can promote inflammation by regulating expression and activity of different pro-inflammatory cytokines, chemokines and other immune components in the lung compartment. They are categorized in three major subcategories: serine proteases, metalloproteases and cysteine proteases especially in case of lung diseases. Neutrophil-derived serine proteases (NSPs), metalloproteases and some mast cell-derived proteases are mainly focused here. Their modes of actions are different in different diseases for e.g. NE induces the release of IL-8 from lung epithelial cells through a MyD88/IRAK/TRAF-6-dependent pathway and also through EGFR MAPK pathway. NSPs contribute to immune regulation during inflammation through the cleavage and activation of specific cellular receptors. MMPs can also influence the progression of various inflammatory processes and there are many non-matrix substrates for MMPs, such as chemokines, growth factors and receptors. During lung inflammation interplay between NE and MMP is an important significant phenomenon. They have been evaluated as therapeutic targets in several inflammatory lung diseases. Here we review the role of proteases in various lung inflammatory diseases with emphasis on their mode of action and contribution to immune regulation during inflammation.
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Affiliation(s)
- Sajal Chakraborti
- Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal India
| | - Naranjan S. Dhalla
- Institute of Cardiovascular Sciences, University of Manitoba, St. Boniface Hospital Research Centre, Winnipeg, Manitoba Canada
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de Oliveira-Santos J, Abreu Nunes V, Cruz-Silva I, Praxedes-Garcia P, Gozzo AJ, Rydlewski M, González YG, Nader HB, Araújo MDS. Glycosaminoglycans Modify Elastase Action In Vitro and Enhance Elastase-Induced Cell Death in Cultured Fibroblasts. ACTA ACUST UNITED AC 2012. [DOI: 10.5402/2012/973983] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Human neutrophil elastase (HNE) has been shown to be involved on death of different cell types, including epithelial lung cells, which is related to several pulmonary diseases. Since HNE activity may be influenced by extracellular matrix (ECM) molecules such as glycosaminoglycans (GAGs), and fibroblasts are the most common ECM-producing cells of lung connective tissue, the aim of this work was to verify if HNE can induce fibroblast death and to study the enzyme modulation by GAGs. HNE-like activity was mimicked by using human neutrophils conditioned medium (NCM). Heparan sulfate and chondroitin 6-sulfate reduce the enzyme activity and modify its secondary structure. NCM reduced cell viability, and this effect was higher in the presence of those GAGs. NCM also increased DNA fragmentation, suggesting the occurrence of apoptosis, but without influence of GAGs. These results can contribute to the understanding of HNE modulation in physio- and pathological processes where this enzyme is involved.
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Affiliation(s)
- José de Oliveira-Santos
- Departamento de Bioquímica, Universidade Federal de São Paulo, 04044-020 São Paulo, SP, Brazil
| | - Viviane Abreu Nunes
- Escola de Artes, Ciências e Humanidades, Universidade de São Paulo, 03828-000 São Paulo, SP, Brazil
| | - Ilana Cruz-Silva
- Departamento de Bioquímica, Universidade Federal de São Paulo, 04044-020 São Paulo, SP, Brazil
| | | | - Andrezza Justino Gozzo
- Departamento de Bioquímica, Universidade Federal de São Paulo, 04044-020 São Paulo, SP, Brazil
| | - Mariana Rydlewski
- Departamento de Bioquímica, Universidade Federal de São Paulo, 04044-020 São Paulo, SP, Brazil
| | - Yamile González González
- Centro de Estúdio de Proteínas, Facultad de Biología, Universidad de la Habana, Calle 25 No. 455 Vedado, Ciudad de La Habana, Cuba
| | - Helena Bonciani Nader
- Departamento de Bioquímica, Universidade Federal de São Paulo, 04044-020 São Paulo, SP, Brazil
| | - Mariana da Silva Araújo
- Departamento de Bioquímica, Universidade Federal de São Paulo, 04044-020 São Paulo, SP, Brazil
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Bai GZ, Yu HT, Ni YF, Li XF, Zhang ZP, Su K, Lei J, Liu BY, Ke CK, Zhong DX, Wang YJ, Zhao JB. Shikonin attenuates lipopolysaccharide-induced acute lung injury in mice. J Surg Res 2012; 182:303-11. [PMID: 23158409 DOI: 10.1016/j.jss.2012.10.039] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2012] [Revised: 10/15/2012] [Accepted: 10/18/2012] [Indexed: 12/21/2022]
Abstract
BACKGROUND Shikonin, a natural naphthoquinone pigment extracted from the root of Lithospermum erythrorhizon, has shown a variety of pharmacologic properties including anti-inflammatory effect. In the present study, we analyzed the role of shikonin in acute lung injury induced by lipopolysaccharide (LPS) in mice. MATERIALS AND METHODS Sixty male BALB/C mice were randomly allocated into six groups (n = 10, each): control group, shikonin group (50 mg/kg), LPS group, and three different doses (12.5, 25, and 50 mg/kg) for shikonin-treated groups. Shikonin or vehicle was given with an intragastric administration 1 h before an intratracheal instillation of LPS (5 mg/kg). The severity of pulmonary injury was evaluated 6 h after LPS challenge. RESULTS Shikonin pretreatment significantly attenuated LPS-induced pulmonary histopathologic changes, alveolar hemorrhage, and neutrophil infiltration. The lung wet-to-dry weight ratios, as the index of pulmonary edema, were markedly decreased by shikonin pretreatment. Moreover, shikonin decreased the productions of the proinflammatory cytokines including tumor necrosis factor alpha and interleukin 1β and the concentration of total proteins in the bronchoalveolar lavage fluid. Shikonin pretreatment also reduced the concentrations of myeloperoxidase and nitric oxide in lung tissues. In addition, shikonin pretreatment significantly suppressed LPS-induced activation of cyclooxygenase 2 and inducible nitric oxide synthase and the nuclear factor κB DNA-binding activity in lung tissues. CONCLUSIONS This study indicates that shikonin may have a protective effect against LPS-induced acute lung injury, and the potential mechanism of this action may attribute partly to the inhibition of inducible nitric oxide synthase and cyclooxygenase 2 expression by downregulating nuclear factor κB activation.
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Affiliation(s)
- Guang-Zhen Bai
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, PR China
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Alveolar fluid in acute respiratory distress syndrome promotes fibroblast migration: role of platelet-derived growth factor pathway*. Crit Care Med 2012; 40:2041-9. [PMID: 22713216 DOI: 10.1097/ccm.0b013e31824e65ba] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVES Fibroblast migration is an initiating step in fibroproliferation; its involvement during acute lung injury and acute respiratory distress syndrome remains poorly understood. The aims of this study were: 1) to determine whether bronchoalveolar lavage fluids from patients with acute lung injury/acute respiratory distress syndrome modulate lung fibroblast migration; 2) to assess lung fibroblast migration's clinical relevance; and 3) to evaluate the role of the platelet-derived growth factor pathway in this effect. DESIGN Prospective cohort study. SETTING Three intensive care units of a large tertiary referral center. PATIENTS Ninety-three ventilated patients requiring bronchoalveolar lavage fluids were enrolled (48 with acute respiratory distress syndrome, 33 with acute lung injury, and 12 ventilated patients without acute lung injury/acute respiratory distress syndrome). INTERVENTIONS After bronchoalveolar lavage fluids collection during standard care, the patients were followed up for 28 days and clinical outcomes were recorded. Migration assays were performed by using a Transwell model; bronchoalveolar lavage fluids platelet-derived growth factor and soluble platelet-derived growth factor receptor-α were characterized by Western blot and measured by ELISA. MEASUREMENTS AND MAIN RESULTS Most of the bronchoalveolar lavage fluids inhibited basal fibroblast migration. Bronchoalveolar lavage fluids chemotactic index increased with severity of lung injury (28% in patients without acute lung injury/acute respiratory distress syndrome and with acute lung injury vs. 91% in acute respiratory distress syndrome patients; p = .016). In acute lung injury/acute respiratory distress syndrome patients, inhibition of basal fibroblast migration by bronchoalveolar lavage fluids below 52% was independently associated with a lower 28-day mortality (odds ratio [95% confidence interval] 0.313 [0.10-0.98], p = .046). Platelet-derived growth factor-related peptides and soluble platelet-derived growth factor-Rα were detected in all bronchoalveolar lavage fluids from acute lung injury/acute respiratory distress syndrome patients. The effect of bronchoalveolar lavage fluids stimulating migration was inhibited by a specific platelet-derived growth factor receptor inhibitor (AG1296). Bronchoalveolar lavage fluids inhibiting migration reversed the effect of rh-platelet-derived growth factor-BB and reduced by 40% the binding of 125I-platelet-derived growth factor-BB to fibroblast cell surface in favor of a role for platelet-derived growth factor-sRα. CONCLUSIONS : Together, our results suggest that during acute lung injury, fibroblast migration is modulated by bronchoalveolar lavage fluids through a platelet-derived growth factor/platelet-derived growth factor-sRα balance. Migration is associated with clinical severity and patient 28-day mortality.
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Impact of mechanical ventilation and fluid load on pulmonary glycosaminoglycans. Respir Physiol Neurobiol 2012; 181:308-20. [DOI: 10.1016/j.resp.2012.03.013] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2011] [Revised: 02/14/2012] [Accepted: 03/17/2012] [Indexed: 11/22/2022]
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Repine JE, Elkins ND. Effect of ergothioneine on acute lung injury and inflammation in cytokine insufflated rats. Prev Med 2012; 54 Suppl:S79-82. [PMID: 22197759 PMCID: PMC3355229 DOI: 10.1016/j.ypmed.2011.12.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2011] [Revised: 12/05/2011] [Accepted: 12/06/2011] [Indexed: 12/29/2022]
Abstract
OBJECTIVE The Acute Respiratory Distress Syndrome (ARDS), the most severe form of Acute Lung Injury (ALI), is a highly-fatal, diffuse non-cardiogenic edematous lung disorder. The pathogenesis of ARDS is unknown but lung inflammation and lung oxidative stress are likely contributing factors. Since no specific pharmacologic intervention exists for ARDS, our objective was to determine the effect of treatment with ergothioneine-a safe agent with multiple anti-inflammatory and antioxidant properties on the development of lung injury and inflammation in rats insufflated with cytokines found in lung lavages of ARDS patients. METHOD Sprague-Dawley rats (3-10/group) were given 15 mg/kg or 150 mg/kg l-ergothioneine intravenously 1h before or 18 h after cytokine (IL-1 and IFNγ) insufflation. Lung injury (lavage LDH levels) and lung inflammation (lavage neutrophil numbers) were measured 24h after cytokine insufflation. RESULTS Ergothioneine pre- and post-treatment generally decreased lung injury and lung inflammation in cytokine insufflated rats. CONCLUSION Ergothioneine should be considered for additional testing as a potential therapy for treating and preventing ARDS.
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Affiliation(s)
- John E. Repine
- Webb-Waring Center, University of Colorado Denver V20, Mail Stop C322 12850 East Montview Blvd. Aurora, CO 80045 USA ,
| | - Nancy D. Elkins
- Webb-Waring Center, University of Colorado Denver V20, Mail Stop C322 12850 East Montview Blvd. Aurora, CO 80045 USA ,
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Bhargava M, Wendt CH. Biomarkers in acute lung injury. Transl Res 2012; 159:205-17. [PMID: 22424425 PMCID: PMC4537856 DOI: 10.1016/j.trsl.2012.01.007] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Revised: 01/06/2012] [Accepted: 01/08/2012] [Indexed: 01/11/2023]
Abstract
Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) result in high permeability pulmonary edema causing hypoxic respiratory failure with high morbidity and mortality. As the population ages, the incidence of ALI is expected to rise. Over the last decade, several studies have identified biomarkers in plasma and bronchoalveolar lavage fluid providing important insights into the mechanisms involved in the pathophysiology of ALI. Several biomarkers have been validated in subjects from the large, multicenter ARDS clinical trials network. Despite these studies, no single or group of biomarkers has made it into routine clinical practice. New high throughput "omics" techniques promise improved understanding of the biologic processes in the pathogenesis in ALI and possibly new biomarkers that predict disease and outcomes. In this article, we review the current knowledge on biomarkers in ALI.
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Affiliation(s)
- Maneesh Bhargava
- Pulmonary and Critical Care Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN 55417, USA
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Raymondos K, Martin MU, Schmudlach T, Baus S, Weilbach C, Welte T, Krettek C, Frink M, Hildebrand F. Early alveolar and systemic mediator release in patients at different risks for ARDS after multiple trauma. Injury 2012; 43:189-95. [PMID: 21703617 DOI: 10.1016/j.injury.2011.05.034] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2010] [Accepted: 05/25/2011] [Indexed: 02/02/2023]
Abstract
Alveolar IL-8 has been reported to early identify patients at-risk to develop ARDS. However, it remains unknown how alveolar IL-8 is related to pulmonary and systemic inflammation in patients predisposed for ARDS. We studied 24 patients 2-6h after multiple trauma. Patients with IL-8 >200 pg/ml in bronchoalveolar lavage (BAL) were assigned to the group at high risk for ARDS (H, n = 8) and patients with BAL IL-8 <200 pg/ml to the group at low risk for ARDS (L, n = 16). ARDS developed within 24h after trauma in 5 patients at high and at least after 1 week in 2 patients at low risk for ARDS (p = 0.003). High-risk patients had also increased BAL IL-6, TNF-α, IL-1β, IL-10 and IL-1ra levels (p<0.05). BAL neutrophil counts did not differ between patient groups (H vs. L, 12% (3-73%) vs. 6% (2-32%), p = 0.1) but correlated significantly with BAL IL-8, IL-6 and IL-1ra. High-risk patients had increased plasma levels of pro- but not anti-inflammatory mediators. The enhanced alveolar and systemic inflammation associated with alveolar IL-8 release should be considered to identify high-risk patients for pulmonary complications after multiple trauma to adjust surgical and other treatment strategies to the individual risk profile.
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Distinct proteasome subpopulations in the alveolar space of patients with the acute respiratory distress syndrome. Mediators Inflamm 2012; 2012:204250. [PMID: 22363101 PMCID: PMC3272875 DOI: 10.1155/2012/204250] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2011] [Accepted: 10/12/2011] [Indexed: 12/03/2022] Open
Abstract
There is increasing evidence that proteasomes have a biological role in the extracellular alveolar space, but inflammation could change their composition. We tested whether immunoproteasome protein-containing subpopulations are present in the alveolar space of patients with lung inflammation evoking the acute respiratory distress syndrome (ARDS). Bronchoalveolar lavage (BAL) supernatants and cell pellet lysate from ARDS patients (n = 28) and healthy subjects (n = 10) were analyzed for the presence of immunoproteasome proteins (LMP2 and LMP7) and proteasome subtypes by western blot, chromatographic purification, and 2D-dimensional gelelectrophoresis. In all ARDS patients but not in healthy subjects LMP7 and LMP2 were observed in BAL supernatants. Proteasomes purified from pooled ARDS BAL supernatant showed an altered enzyme activity ratio. Chromatography revealed a distinct pattern with 7 proteasome subtype peaks in BAL supernatant of ARDS patients that differed from healthy subjects. Total proteasome concentration in BAL supernatant was increased in ARDS (971 ng/mL ± 1116 versus 59 ± 25; P < 0.001), and all fluorogenic substrates were hydrolyzed, albeit to a lesser extent, with inhibition by epoxomicin (P = 0.0001). Thus, we identified for the first time immunoproteasome proteins and a distinct proteasomal subtype pattern in the alveolar space of ARDS patients, presumably in response to inflammation.
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