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Jung F, Liu J, Yang S, Tseng H, Chou SP, Lin J, Jow G. FJU-C28 inhibits the endotoxin-induced pro-inflammatory cytokines expression via suppressing JNK, p38 MAPK and NF-κB signaling pathways. Pharmacol Res Perspect 2021; 9:e00876. [PMID: 34669271 PMCID: PMC8527890 DOI: 10.1002/prp2.876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 09/09/2021] [Accepted: 09/11/2021] [Indexed: 11/13/2022] Open
Abstract
Despite marked improvements in supportive care, the mortality rate of acute respiratory distress syndrome due to the excessive inflammatory response caused by direct or indirect lung injury induced by viral or bacterial infection is still high. In this study, we explored the anti-inflammatory effect of FJU-C28, a new 2-pyridone-based synthetic compound, on lipopolysaccharide (LPS)-induced inflammation in vitro and in vivo models. FJU-C28 suppressed the LPS-induced mRNA and protein expression of iNOS, COX2 and proinflammatory cytokines. The cytokine protein array results showed that LPS stimulation enhanced the secretion of IL-10, IL-6, GCSF, Eotaxin, TNFα, IL-17, IL-1β, Leptin, sTNF RII, and RANTES. Conversely, the LPS-induced secretion of RANTES, TIMP1, IL-6, and IL-10 was dramatically suppressed by FJU-C28. FJU-C28 suppressed the LPS-induced expression of RANTES, but its parental compound FJU-C4 was unable to diminish RANTES in cell culture media or cell lysates. FJU-C28 blocked the secretion of IL-6 and RANTES in LPS-activated macrophages by regulating the activation of JNK, p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB). FJU-C28 prevented the LPS-induced decreases in lung function including vital capacity (VC), lung compliance (C chord), forced expiratory volume at 100 ms (FEV100), and forced vital capacity (FVC) in mice with LPS-induced systemic inflammatory responses. FJU-C28 also reduced neutrophil infiltration in the interstitium, lung damage and circulating levels of IL-6 and RANTES in mice with systemic inflammation. In conclusion, these findings suggest that FJU-C28 possesses anti-inflammatory activities to prevent endotoxin-induced lung function decrease and lung damages by down-regulating proinflammatory cytokines including IL-6 and RANTES via suppressing the JNK, p38 MAPK and NF-κB signaling pathways.
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Affiliation(s)
- Fang Jung
- Department of Respiratory TherapyFu‐Jen Catholic UniversityNew Taipei CityTaiwan
- Deparment of ChemistryFu‐Jen Catholic UniversityNew Taipei CityTaiwan
| | - Jung‐Sen Liu
- Department of Respiratory TherapyFu‐Jen Catholic UniversityNew Taipei CityTaiwan
- Department of SurgeryCathay General HospitalTaipeiTaiwan
| | - Shih‐Hsing Yang
- Department of Respiratory TherapyFu‐Jen Catholic UniversityNew Taipei CityTaiwan
| | - Hui‐Yun Tseng
- Department of Respiratory TherapyFu‐Jen Catholic UniversityNew Taipei CityTaiwan
- Deparment of ChemistryFu‐Jen Catholic UniversityNew Taipei CityTaiwan
- Graduate Institute of Biomedical and Pharmaceutical ScienceFu‐Jen Catholic UniversityNew Taipei CityTaiwan
| | | | - Jau‐Chen Lin
- Department of Respiratory TherapyFu‐Jen Catholic UniversityNew Taipei CityTaiwan
| | - Guey‐Mei Jow
- School of MedicineFu‐Jen Catholic UniversityNew Taipei CityTaiwan
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Sundar V, Senthil Kumar KA, Manickam V, Ramasamy T. Current trends in pharmacological approaches for treatment and management of acute pancreatitis – a review. J Pharm Pharmacol 2020; 72:761-775. [DOI: 10.1111/jphp.13229] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 12/06/2019] [Indexed: 12/12/2022]
Abstract
Abstract
Objectives
Acute pancreatitis (AP) is an inimical disorder associated with overall mortality rates between 10-15%. It is a disorder of the exocrine pancreas which is characterized by local and systemic inflammatory responses primarily driven by oxidative stress and death of pancreatic acinar cells. The severity of AP ranges from mild pancreatic edema with complete recuperative possibilities to serious systemic inflammatory response resulting in peripancreatic/pancreatic necrosis, multiple organ failure, and death.
Key findings
We have retrieved the potential alternative approaches that are developed lately for efficacious treatment of AP from the currently available literature and recently reported experimental studies. This review summarizes the need for alternative approaches and combinatorial treatment strategies to deal with AP based on literature search using specific key words in PubMed and ScienceDirect databases.
Summary
Since AP results from perturbations of multiple signaling pathways, the so called “monotargeted smart drugs” of the past decade is highly unlikely to be effective. Also, the conventional treatment approaches were mainly involved in providing palliative care instead of curing the disease. Hence, many researchers are beginning to focus on developing alternate therapies to treat AP effectively. This review also summarizes the recent trends in the combinatorial approaches available for AP treatment.
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Affiliation(s)
- Vaishnavi Sundar
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
| | | | - Venkatraman Manickam
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
| | - Tamizhselvi Ramasamy
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
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Hydrostatin-SN10 Ameliorates Pancreatitis-Induced Lung Injury by Affecting IL-6-Induced JAK2/STAT3-Associated Inflammation and Oxidative Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:9659757. [PMID: 31827715 PMCID: PMC6885838 DOI: 10.1155/2019/9659757] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 10/15/2019] [Indexed: 02/06/2023]
Abstract
Hydrostatin-SN1 (peptide sequence, DEQHLETELHTLTSVLTANGFQ), a kind of peptides extracted from snake venom, has been reported to have anti-inflammatory effect, but its truncated mutant hydrostatin-SN10 (peptide sequence, DEQHLETELH) on pancreatitis-induced acute lung injury has not been well documented. Interleukin- (IL-) 6-induced Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) pathway is involved with inflammatory and oxidative stress activities and may be associated with the pathogenesis of lung injury, and related molecules were measured. Taurocholate-induced pancreatitis associated with acute lung injury was established and treated with hydrostatin-SN10. Pancreatitis was confirmed by measuring the serum levels of amylase, lipase, and trypsinogen and urinary amylase. Lung injury was determined by histologically assessing acinar cell changes. The related molecules of IL-6-induced JAK2/STAT3-associated inflammation and oxidative stress were quantitated by real time-PCR, Western blot, and/or immunochemical assay. Hydrostatin-SN10 reduced the levels of serum amylase, lipase, and trypsinogen and urinary amylase when compared with the model group (p < 0.05). Hydrostatin-SN10 significantly inhibited the IL-6-stimulated JAK2/STAT3 pathway and reduced the number of apoptotic cells via the downregulation of caspase 3 and BAX (proapoptotic) and upregulation of Bcl2 (antiapoptotic) (p < 0.05). IL-6 induced the increase in the levels of JAK2 and STAT3, which was reversed by hydrostatin-SN10 treatment (p < 0.05). In addition, hydrostatin-SN10 reduced the expression of IL-6 and TNF- (tumor necrosis factor-) α and increased the level of IL-10 (p < 0.05). On the other hand, hydrostatin-SN10 treatment increased the levels of superoxide dismutase (SOD) and reduced glutathione (GSH) and the levels of malondialdehyde (MDA) and alanine aminotransferase (ALT) (p < 0.05). These results suggest that hydrostatin-SN10 may inhibit pancreatitis-induced acute lung injury by affecting IL-6-mediated JAK2/STAT3 pathway-associated inflammation and oxidative stress.
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Pan Y, Fang H, Lu F, Pan M, Chen F, Xiong P, Yao Y, Huang H. Ulinastatin ameliorates tissue damage of severe acute pancreatitis through modulating regulatory T cells. J Inflamm (Lond) 2017; 14:7. [PMID: 28344516 PMCID: PMC5360080 DOI: 10.1186/s12950-017-0154-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 03/14/2017] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Ulinastatin or urinary trypsin inhibitor (UTI) has been shown to ameliorate the inflammatory response induced by experimental severe acute pancreatitis (SAP) and hence reduce the mortality, however the mechanism of its action remains incompletely understood. We have investigated the effect of ulinastatin on regulatory T-cells (Tregs) in an established rat model of SAP. METHODS We established a rat SAP model by injecting 5% Na-taurocholate into the pancreatic duct and treated the SAP rats with ulinastatin with different dose level (5000, 10000, 30000 U/kg) through intraperitoneal injection at 0, 6 and 12 h. RESULTS We showed that the tissue damage of pancreas and the mortality of the SAP rats were significantly reduced by ulinastatin. We also showed that in the SAP rats the frequencies of CD4+ T cells and Tregs, as well as the expressions of TGF-β1, CTLA-4, and Foxp3 were decreased in the SAP animals while IL-1β, IL-10 and TNF-α were significantly increased. Treatment with ulinastatin up-regulated the proportion of Tregs in CD4+ T cells and the expression of IL-10, Foxp3 and CTLA-4 in the SAP rats in a dose dependence fashion, while down-regulating the levels of L-1β and TNF-α, myeloperoxidase (MPO) activity. CONCLUSIONS Our findings suggest that ulinastatin alleviates inflammatory response and tissue damage in SAP rats by increasing the proportion of Tregs. Our study provides a new mechanism for the beneficial effect of ulinastatin in SAP rat model.
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Affiliation(s)
- Yu Pan
- General Surgery Department, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001 People’s Republic of China
| | - Haizong Fang
- General Surgery Department, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001 People’s Republic of China
| | - Fengchun Lu
- General Surgery Department, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001 People’s Republic of China
| | - Minggui Pan
- Department of Oncology and Hematology, Kaiser Permanente Medical Center, 710 Lawrence Expressway, Santa Clara, CA 95051 USA
| | - Fei Chen
- General Surgery Department, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001 People’s Republic of China
| | | | - Yi Yao
- General Surgery Department, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001 People’s Republic of China
| | - Heguang Huang
- General Surgery Department, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001 People’s Republic of China
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Tomankova T, Kriegova E, Liu M. Chemokine receptors and their therapeutic opportunities in diseased lung: far beyond leukocyte trafficking. Am J Physiol Lung Cell Mol Physiol 2015; 308:L603-18. [PMID: 25637606 DOI: 10.1152/ajplung.00203.2014] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Accepted: 01/28/2015] [Indexed: 12/13/2022] Open
Abstract
Chemokine receptors and their chemokine ligands, key mediators of inflammatory and immune cell trafficking, are involved in the regulation of both physiological and pathological processes in the lung. The discovery that chemokine receptors/chemokines, typically expressed by inflammatory and immune cells, are also expressed in structural lung tissue cells suggests their role in mediating the restoration of lung tissue structure and functions. Thus, chemokine receptors/chemokines contribute not only to inflammatory and immune responses in the lung but also play a critical role in the regulation of lung tissue repair, regeneration, and remodeling. This review aims to summarize current state-of-the-art on chemokine receptors and their ligands in lung diseases such as chronic obstructive pulmonary disease, asthma/allergy, pulmonary fibrosis, acute lung injury, and lung infection. Furthermore, the therapeutic opportunities of chemokine receptors in aforementioned lung diseases are discussed. The review also aims to delineate the potential contribution of chemokine receptors to the processes leading to repair/regeneration of the lung tissue.
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Affiliation(s)
- Tereza Tomankova
- Faculty of Medicine and Dentistry, Department of Immunology, Palacky University Olomouc, Czech Republic; Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; and
| | - Eva Kriegova
- Faculty of Medicine and Dentistry, Department of Immunology, Palacky University Olomouc, Czech Republic
| | - Mingyao Liu
- Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; and Faculty of Medicine, Departments of Physiology, Surgery, and Medicine, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
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Akinosoglou K, Gogos C. Immune-modulating therapy in acute pancreatitis: Fact or fiction. World J Gastroenterol 2014; 20:15200-15215. [PMID: 25386069 PMCID: PMC4223254 DOI: 10.3748/wjg.v20.i41.15200] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2014] [Revised: 05/21/2014] [Accepted: 06/17/2014] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis (AP) is one of the most common diseases of the gastrointestinal tract, bearing significant morbidity and mortality worldwide. Current treatment of AP remains unspecific and supportive and is mainly targeted to aggressively prevent systemic complications and organ failure by intensive care. As acute pancreatitis shares an indistinguishable profile of inflammation with sepsis, therapeutic approaches have turned towards modulating the systemic inflammatory response. Targets, among others, have included pro- and anti-inflammatory modulators, cytokines, chemokines, immune cells, adhesive molecules and platelets. Even though, initial results in experimental models have been encouraging, clinical implementation of immune-regulating therapies in acute pancreatitis has had a slow progress. Main reasons include difficulty in clinical translation of experimental data, poor understanding of inflammatory response time-course, flaws in experimental designs, need for multimodal approaches and commercial drawbacks. Whether immune-modulation in acute pancreatitis remains a fact or just fiction remains to be seen in the future.
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Abstract
OBJECTIVE Infection of pancreatic necrosis in necrotizing pancreatitis increases the lethality of patients with acute pancreatitis. To examine mechanisms underlying this clinical observation, we developed and tested a model, in which primary infection of necrosis is achieved in taurocholate-induced pancreatitis in mice. METHODS Sterile necrosis of acute necrotizing pancreatitis was induced by retrograde injection of 4% taurocholate into the common bile duct of Balb/c mice. Primary infection of pancreatic necrosis was induced by coinjecting 10 colony-forming units of Escherichia coli. Animals were killed after 6, 12, 24, 48, and 120 hours, and pancreatic damage and pancreatitis-associated systemic inflammatory response were assessed. RESULTS Mice with pancreatic acinar cell necrosis had an increased bacterial concentration in all tissues and showed sustained bacteremia. Acute pancreatitis was induced only by coinjection of taurocholate and not by bacterial infection alone. Infection of pancreatic necrosis increased pancreatic damage and the pulmonary vascular leak. Serum glucose concentrations serving as a parameter of hepatic function were reduced in mice with infected pancreatic necrosis. CONCLUSIONS Primary infection of pancreatic necrosis with E. coli increases both pancreatic damage and pulmonary and hepatic complications in acute necrotizing pancreatitis in mice.
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Shen J, Gao J, Chen C, Lu H, Hu G, Shen J, Zhu S, Wu M, Wang X, Qian L, Yu Y, Han W, Wan R, Wang X. Antifibrotic role of chemokine CXCL9 in experimental chronic pancreatitis induced by trinitrobenzene sulfonic acid in rats. Cytokine 2013; 64:382-94. [PMID: 23819906 DOI: 10.1016/j.cyto.2013.05.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2012] [Revised: 05/09/2013] [Accepted: 05/17/2013] [Indexed: 02/07/2023]
Abstract
Chemokines have been shown to play an important role in the pathogenesis of pancreatitis, but the role of chemokine CXCL9 in pancreatitis is poorly understood. The aim of this study was to investigate whether CXCL9 was a modulating factor in chronic pancreatitis. Chronic pancreatitis was induced in Sprague-Dawley rats by intraductal infusion of trinitrobenzene sulfonic acid (TNBS) and CXCL9 expression was assessed by immunohistochemistry, Western blot analysis and enzyme linked immunosorbent assay (ELISA). Recombinant human CXCL9 protein (rCXCL9), neutralizing antibody and normal saline (NS) were administered to rats with chronic pancreatitis by subcutaneous injection. The severity of fibrosis was determined by measuring hydroxyproline in pancreatic tissues and histological grading. The effect of rCXCL9 on activated pancreatic stellate cells (PSCs) in vitro was examined and collagen 1α1, TGF-β1 and CXCR3 expression was assessed by Western blot analysis in isolated rat PSCs. Chronic pancreatic injury in rats was induced after TNBS treatment and CXCL9 protein was markedly upregulated during TNBS-induced chronic pancreatitis. Although parenchymal injury in the pancreas was not obviously affected after rCXCL9 and neutralizing antibody administration, rCXCL9 could attenuate fibrogenesis in TNBS-induced chronic pancreatitis in vivo and exerted antifibrotic effects in vitro, suppressing collagen production in activated PSCs. In conclusion, CXCL9 is involved in the modulation of pancreatic fibrogenesis in TNBS-induced chronic pancreatitis in rats, and may be a therapeutic target in pancreatic fibrosis.
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Affiliation(s)
- Jiaqing Shen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Jiangsu, China
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Abstract
OBJECTIVES This study aimed to search for protein kinases that play a role in acute pancreatitis and analyze their potential connection with each other. METHODS Information of human protein kinases were collected in protein kinase database, and then a systematic search was performed using PubMed for studies addressing the association between these kinases and acute pancreatitis. Gene Ontology Annotations were used to build interactions network for acute pancreatitis-associated protein kinases. RESULTS A total of 570 human protein kinases were found, in which 28 kinases play a role in acute pancreatitis. Among the 28 kinases, RIPK1, JAK2, SRC, EGFR, FYN, MET, JAK1, TYK2, and MTOR were annotated in Gene Ontology database. A gene ontology interactions network was built to visualize the common biological process these kinases participated in. CONCLUSIONS This study provides observations that protein kinases participate in all the sequential events in the exocrine pancreas in acute pancreatitis and that protein kinases are potential therapeutical target for acute pancreatitis.
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Lung microenvironment contributes to the resistance of alveolar macrophages to develop tolerance to endotoxin*. Crit Care Med 2013; 40:2987-96. [PMID: 22878679 DOI: 10.1097/ccm.0b013e31825b8d57] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Endotoxin tolerance corresponds to reprogramming of mononuclear phagocytes after iterative encounters with toll-like receptor agonists aimed to dampen the inflammatory response. We investigated why this phenomenon cannot be observed with murine alveolar macrophages. DESIGN Animal study. SETTING Research institution laboratory. SUBJECTS rag2-/-, rag2γc-/-, cd3ε-/-, µ-/-, il-15-/-, Jα18-/-, ifnγr-/-, il-18r-/-, and wild-type mice. INTERVENTIONS Alveolar macrophages were harvested from untreated mice or after injection of endotoxin. Alveolar macrophages were activated in vitro with endotoxin (lipopolysaccharide), and tumor necrosis factor production was monitored. MEASUREMENTS AND MAIN RESULTS In contrast to monocytes or peritoneal macrophages, alveolar macrophages did not display endotoxin tolerance in an ex vivo model after injection of endotoxin. An in vivo systemic inhibition of granulocyte-macrophage colony-stimulating factor or interferon-γ allowed the induction of alveolar macrophage endotoxin tolerance, which was also observed in interferon-γ receptor-deficient mice. Using mice missing different leukocyte subsets and adoptive cell transfers, we demonstrated the involvement of B lymphocytes in interferon-γ production within the lung microenvironment and in the prevention of alveolar macrophage endotoxin tolerance. Furthermore, we demonstrated the importance of interleukin-18 in preventing alveolar macrophage endotoxin tolerance through studies of interleukin-18 messenger RNA expression in il-18r-/- mice and injection of interleukin-18 in rag2-/- and µ-/- mice. CONCLUSIONS Our results support the conclusion that at homeostasis in the lungs, constitutive expression of granulocyte-macrophage colony-stimulating factor, interleukin-18, interferon-γ and possibly interleukin-15, and a cross-talk between B lymphocytes and alveolar macrophages create a microenvironment specific to the lungs that prevents alveolar macrophages from becoming tolerant to endotoxin.
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Bhatia M, Zemans RL, Jeyaseelan S. Role of chemokines in the pathogenesis of acute lung injury. Am J Respir Cell Mol Biol 2012; 46:566-572. [PMID: 22323365 PMCID: PMC3361356 DOI: 10.1165/rcmb.2011-0392tr] [Citation(s) in RCA: 193] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2011] [Accepted: 02/02/2012] [Indexed: 12/11/2022] Open
Abstract
Acute lung injury (ALI) is due to an uncontrolled systemic inflammatory response resulting from direct injury to the lung or indirect injury in the setting of a systemic process. Such insults lead to the systemic inflammatory response syndrome (SIRS), which includes activation of leukocytes-alveolar macrophages and sequestered neutrophils-in the lung. Although systemic inflammatory response syndrome is a physiologic response to an insult, systemic leukocyte activation, if excessive, can lead to end organ injury, such as ALI. Excessive recruitment of leukocytes is critical to the pathogenesis of ALI, and the magnitude and duration of the inflammatory process may ultimately determine the outcome in patients with ALI. Leukocyte recruitment is a well orchestrated process that depends on the function of chemokines and their receptors. Understanding the mechanisms that contribute to leukocyte recruitment in ALI may ultimately lead to the development of effective therapeutic strategies.
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Affiliation(s)
- Madhav Bhatia
- Department of Pathology, University of Otago, 2 Riccarton Avenue, Christchurch, New Zealand.
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Grommes J, Alard JE, Drechsler M, Wantha S, Mörgelin M, Kuebler WM, Jacobs M, von Hundelshausen P, Markart P, Wygrecka M, Preissner KT, Hackeng TM, Koenen RR, Weber C, Soehnlein O. Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury. Am J Respir Crit Care Med 2012; 185:628-36. [PMID: 22246174 DOI: 10.1164/rccm.201108-1533oc] [Citation(s) in RCA: 182] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
RATIONALE Acute lung injury (ALI) causes high mortality, but its molecular mechanisms and therapeutic options remain ill-defined. Gram-negative bacterial infections are the main cause of ALI, leading to lung neutrophil infiltration, permeability increases, deterioration of gas exchange, and lung damage. Platelets are activated during ALI, but insights into their mechanistic contribution to neutrophil accumulation in the lung are elusive. OBJECTIVES To determine mechanisms of platelet-mediated neutrophil recruitment in ALI. METHODS Interference with platelet-neutrophil interactions using antagonists to P-selectin and glycoprotein IIb/IIIa or a small peptide antagonist disrupting platelet chemokine heteromer formation in mouse models of ALI. MEASUREMENTS AND MAIN RESULTS In a murine model of LPS-induced ALI, we uncover important roles for neutrophils and platelets in permeability changes and subsequent lung damage. Furthermore, platelet depletion abrogated lung neutrophil infiltration, suggesting a sequential participation of platelets and neutrophils. Whereas antagonists to P-selectin and glycoprotein IIb/IIIa had no effects on LPS-mediated ALI, antibodies to the platelet-derived chemokines CCL5 and CXCL4 strongly diminished neutrophil eflux and permeability changes. The two chemokines were found to form heteromers in human and murine ALI samples, positively correlating with leukocyte influx into the lung. Disruption of CCL5-CXCL4 heteromers in LPS-, acid-, and sepsis-induced ALI abolished lung edema, neutrophil infiltration, and tissue damage, thereby revealing a causal contribution. CONCLUSIONS Taken together, our data identify a novel function of platelet-derived chemokine heteromers during ALI and demonstrate means for therapeutic interference.
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Affiliation(s)
- Jochen Grommes
- Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany
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Chevigné A, Fievez V, Schmit JC, Deroo S. Engineering and screening the N-terminus of chemokines for drug discovery. Biochem Pharmacol 2011; 82:1438-56. [DOI: 10.1016/j.bcp.2011.07.091] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2011] [Revised: 07/21/2011] [Accepted: 07/22/2011] [Indexed: 01/21/2023]
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Zhang HF, Zhong WE, Zhou GX, Ding XL, Huang H. Met-RANTES down-regulates the expression of MIP-3α and CCR6 in the colon of mice with experimental ulcerative colitis. Shijie Huaren Xiaohua Zazhi 2010; 18:657-663. [DOI: 10.11569/wcjd.v18.i7.657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of macrophage inflammatory protein-3α (MIP-3α) and chemokine receptor 6 (CCR6) in the pathogenesis of ulcerative colitis (UC) and to explore the mechanism of therapeutic effect of Met-RANTES against UC.
METHODS: Forty mice were randomly and equally divided into four groups: blank control group, model control group, normal saline group, and Met-RANTES treatment group. Ulcerative colitis was induced in mice by giving dextran sodium sulfate (DSS). The impact of Met-RANTES on disease activity index (DAI), gross morphological score (GMS) and histopathological score (HPS) in UC was then evaluated. The expression of MIP-3α and CCR6 mRNAs was measured by reverse transcription-polymerase chain reaction (RT-PCR). The expression of MIP-3α and CCR6 proteins was examined by Western blot and immunohistochemistry.
RESULTS: The DAI, GMS and HPS were higher in the model control group and the normal saline group than in the blank control group. The expression levels of MIP-3α and CCR6 mRNAs and proteins in UC were significantly higher in the model control group and the normal saline group than in the blank control group (all P < 0.01). The DAI, GMS and HPS as well as the expression levels of MIP-3α and CCR6 mRNAs and proteins in the Met-RANTES treatment group were significantly lower than those in the model control group and the normal saline group (mRNA: 0.21 ± 0.08 vs 1.09 ± 0.08 and 1.08 ± 0.07, and 0.25 ± 0.08 vs 1.11 ± 0.07 and 1.05 ± 0.08; protein: 0.28 ± 0.08 vs 0.98 ± 0.07 and 1.05 ± 0.06, and 0.25 ± 0.07 vs 1.19 ± 0.07 and 1.15 ± 0.06; all P < 0.01). In contrast, no statistical differences were noted in DAI, GMS and HPS as well as the expression levels of MIP-3α and CCR6 mRNAs and proteins between the model control group and the normal saline group (all P > 0.05).
CONCLUSION: The expression of MIP-3α and its receptor CCR6 is up-regulated in UC, which is closely related with the development and progression of UC. Met-RANTES can down-regulate the expression of MIP-3α and CCR6 and ameliorate inflammatory damage in mice with UC. MIP-3α and CCR6 may represent novel pharmacological targets for treatment of UC.
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Zyromski NJ, Mathur A, Pitt HA, Lu D, Gripe JT, Walker JJ, Yancey K, Wade TE, Swartz-Basile DA. A murine model of obesity implicates the adipokine milieu in the pathogenesis of severe acute pancreatitis. Am J Physiol Gastrointest Liver Physiol 2008; 295:G552-8. [PMID: 18583460 DOI: 10.1152/ajpgi.90278.2008] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Obesity is clearly an independent risk factor for increased severity of acute pancreatitis (AP), although the mechanisms underlying this association are unknown. Adipokines (including leptin and adiponectin) are pleiotropic molecules produced by adipocytes that are important regulators of the inflammatory response. We hypothesized that the altered adipokine milieu observed in obesity contributes to the increased severity of pancreatitis. Lean (C57BL/6J), obese leptin-deficient (LepOb), and obese hyperleptinemic (LepDb) mice were subjected to AP by six hourly intraperitoneal injections of cerulein (50 microg/kg). Severity of AP was assessed by histology and by measuring pancreatic concentration of the proinflammatory cytokines IL-1beta and IL-6, the chemokine MCP-1, and the marker of neutrophil activation MPO. Both congenitally obese strains of mice developed significantly more severe AP than wild-type lean animals. Severity of AP was not solely related to adipose tissue volume: LepOb mice were heaviest; however, LepDb mice developed the most severe AP both histologically and biochemically. Circulating adiponectin concentrations inversely mirrored the severity of pancreatitis. These data demonstrate that congenitally obese mice develop more severe AP than lean animals when challenged by cerulein hyperstimulation and suggest that alteration of the adipokine milieu exacerbates the severity of AP in obesity.
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Affiliation(s)
- Nicholas J Zyromski
- Department of Surgery, Indiana University School of Medicine, 535 Barnhill Dr., RT 130, Indianapolis, IN 46202, USA.
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Akyildiz H, Akcan A, Sozuer E, Kucuk C, Yilmaz N, Deniz K. The preventive effect of Met-RANTES on postoperative intraperitoneal adhesion formation in the rat model. Surgery 2008; 144:404-9. [PMID: 18707039 DOI: 10.1016/j.surg.2008.04.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2007] [Accepted: 04/16/2008] [Indexed: 11/27/2022]
Abstract
BACKGROUND Chemokines are proinflammatory proteins that participate in immune and inflammatory responses through chemoattraction and leukocyte activation. The chemokine antagonist Met-RANTES (Regulated upon Activation Normal T cell Expressed and Secreted) has been shown to be efficacious in decreasing inflammation in several animal disease models. The purpose of this study was to investigate the effects of administration of Met-RANTES on intra-abdominal adhesion formation after abdominal operation. MATERIALS AND METHODS A 42 and 4-month-old female Wistar-Albino rats were subjected to standardized lesions by cauterization of the cecum and uterine horn. They were divided randomly into 3 groups containing 14 rats each: group 1 (control), operative procedure without further treatment; group 2 (Seprafilm), operative procedure with an antiadhesive membrane; 2 x 1 cm of Seprafilm was interposed beneath the peritoneal incision, and group 3 (Met-RANTES), operative procedure with the chemokine antagonist Met-RANTES. The extent and severity of adhesions at the operative site were evaluated. Light microscopic examination was performed to determine semiquantitative scores of VEGF expression. RESULTS Rats in the control group formed extensive adhesions. In comparison with the control group, the adhesion scores were significantly lower in the 2 other groups. The immunohistochemical grading scores of vascular endothelial growth factor correlated closely with the total adhesion scores and were less in groups 2 and 3 (P < .005). CONCLUSIONS Selective chemokine suppression with Met-RANTES seems to decrease rates, extent, and severity of postoperative intraperitoneal adhesions.
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Affiliation(s)
- Hizir Akyildiz
- Department of General Surgery, School of Medicine, Erciyes University, Kayseri, Turkey.
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Ramnath RD, Ng SW, Guglielmotti A, Bhatia M. Role of MCP-1 in endotoxemia and sepsis. Int Immunopharmacol 2008; 8:810-818. [PMID: 18442784 DOI: 10.1016/j.intimp.2008.01.033] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2007] [Revised: 01/30/2008] [Accepted: 01/30/2008] [Indexed: 11/22/2022]
Abstract
Sepsis is a complex clinical syndrome resulting from a harmful host inflammatory response to infection. Similarly, lipopolysaccharide (LPS) induced endotoxemia is marked by the activation of inflammatory responses, which can lead to shock, multiple organ damage and even death. Inflammatory mediator, chemokines are known to play an important role in the pathogenesis of sepsis and endotoxemia. Monocyte chemoattractant protein (MCP)-1, a prototype of CC chemokines, is a potent chemoattractant and a regulatory mediator involved in a variety of inflammatory diseases. The objective of this study is to investigate the role of MCP-1, by using bindarit, a blocker of MCP-1 synthesis, in murine models of sepsis and endotoxemia. Treatment with bindarit both prophylactically and therapeutically significantly (P<0.05) reduced MCP-1 levels in the lungs and liver in both sepsis and endotoxemia. In addition, prophylactic and therapeutic treatment with bindarit significantly (P<0.05) protected mice against sepsis and endotoxemia, as evidenced by the attenuation in lung and liver myeloperoxidase (MPO) activity, an indicator of neutrophil recruitment. The protective effect of bindarit was further confirmed by histological examination of lung and liver sections. Treatment with bindarit reduced lung and liver injury as indicated by decreased thickening of alveolar and neutrophil infiltration in CLP-induced sepsis and LPS-induced endotoxemia. Considering these results, we propose that anti-MCP-1 strategies may be of potential therapeutic value in the treatment of sepsis and endotoxemia.
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Blocking of monocyte chemoattractant protein-1 (MCP-1) activity attenuates the severity of acute pancreatitis in rats. J Gastroenterol 2008; 43:79-85. [PMID: 18297440 DOI: 10.1007/s00535-007-2126-9] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2007] [Accepted: 10/08/2007] [Indexed: 02/04/2023]
Abstract
BACKGROUND Monocyte chemoattractant protein-1 (MCP-1) has been shown to affect the progression of various inflammatory disorders, including pancreatitis. To investigate the role of MCP-1 in acute pancreatitis and to seek possible therapeutic means, we evaluated the effect of a plasmid expression vector containing a dominant-negative mutant MCP-1 gene (mMCP-1). METHODS Two rat models of acute pancreatitis were employed that used either cerulein (for mild pancreatitis) or a mixture of 5% taurocholic acid and trypsin (for severe pancreatitis). At 6 h after induction of acute pancreatitis with or without injection of mMCP-1, serum amylase levels and cytokine levels, as well as morphological evaluation of the pancreas, were determined. Survival rates were also evaluated. RESULTS Severe pancreatitis was significantly reduced by mMCP-1 injection. mMCP-1 decreased serum levels of amylase, IL-6, IL-10, and LDH, and improved the survival rate 48 h after disease onset. Histopathological changes of pancreas and lungs were also improved by mMCP-1. CONCLUSIONS MCP-1 appears to be involved in the progression of severe forms of acute pancreatitis. Our data suggested that MCP-1 is a candidate as a therapeutic target to treat acute pancreatitis.
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Ramnath RD, Sun J, Adhikari S, Zhi L, Bhatia M. Role of PKC-delta on substance P-induced chemokine synthesis in pancreatic acinar cells. Am J Physiol Cell Physiol 2008; 294:C683-C692. [PMID: 18160487 DOI: 10.1152/ajpcell.00360.2007] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Interaction of the neuropeptide substance P (SP) with its high-affinity neurokinin-1 receptor (NK1R) plays an important role in the pathophysiology of acute pancreatitis. SP is known to stimulate the production of chemokines monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1 alpha, and MIP-2 in pancreatic acinar cells via the activation of NF-kappaB. However, the signaling mechanisms by which the SP-NK1R interaction induces NF-kappaB activation and chemokine production remain unclear. To that end, in the present study, we investigated the participation of PKC in SP-induced chemokine production in pancreatic acinar cells. In this study, we showed that SP stimulated an early phosphorylation of PKC isoform PKC-delta followed by increased activation of MAPKKK MEKK1 and MAPK ERK and JNK as well as transcription factor NF-kappaB and activator protein-1 driven chemokine production. Depletion of PKC-delta with its inhibitor rottlerin or the specific PKC-delta translocation inhibitor peptide dose dependently decreased SP-induced PKC-delta, MEKK1, ERK, JNK, NF-kappaB, and AP-1 activation. Moreover, rottlerin as well as PKC-delta translocation inhibitor inhibited SP-induced chemokine production in a concentration-dependent manner. We also demonstrated that PKC-delta activation was attenuated by CP96345, a selective NK1R antagonist, thus showing that PKC-delta activation was indeed mediated by SP in pancreatic acinar cells. These results show that PKC-delta is an important proinflammatory signal transducer for SP-NK1R-induced chemokine production in pancreatic acinar cells.
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Affiliation(s)
- Raina Devi Ramnath
- Dept. of Pharmacology, National Univ. of Singapore, Yong Loo Lin School of Medicine, Centre for life Sciences, 28 Medical Drive, Singapore 117456
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Abstract
OBJECTIVES The outcome from acute pancreatitis depends on the severity of systemic complications. To be able to investigate mechanisms underlying the development of these systemic complications in acute pancreatitis in both wild-type and genetically engineered animal models, a mouse model of severe necrotizing pancreatitis was developed and characterized. METHODS Pancreatitis was induced by retrograde infusion of sodium taurocholate into the common bile duct in mice. After determining the optimum volume and concentration of taurocholate, the pancreatic damage and systemic inflammatory response were compared with those in cerulein-induced pancreatitis. RESULTS Pancreatic damage was higher in taurocholate pancreatitis than hyperstimulation-induced pancreatitis (24 hours: cerulein, 5.8 +/- 0.2 points; taurocholate, 14.8 +/- 0.8 points; P < 0.001) and mortality reached up to 60% within the first 24 hours after taurocholate administration. Pulmonary damage was detected, as measured by an increase in albumin in bronchoalveolar lavage fluid only in taurocholate-induced pancreatitis (12 hours: cerulein, 97.1 +/- 22.83 mg/g of protein; taurocholate, 234.0 +/- 32.7 mg/g of protein; P < 0.001). Furthermore, plasma interleukin 6 concentration was significantly elevated in mice with taurocholate-induced pancreatitis (12 hours: cerulein, 2.6 +/- 6.1 pg/mL; taurocholate, 2168.8 +/- 941.7 microg/mL; P < 0.001) as compared with all other groups. CONCLUSIONS Taurocholate pancreatitis is a reliable model for severe necrotizing pancreatitis in mice with significantly greater pancreatic damage and systemic inflammatory response in comparison with cerulein-induced pancreatitis.
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Leem JW, Lee HJ, Nam TS, Yoon DM. The Role of the Peripheral Chemokine, CCL3, in Hyperalgesia following Peripheral Nerve Injury in the Rat. Korean J Pain 2008. [DOI: 10.3344/kjp.2008.21.3.187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Affiliation(s)
- Joong Woo Leem
- Department of Physiology, Yonsei University Medical College, Seoul, Korea
| | - Hyun Joo Lee
- Department of Physiology, Yonsei University Medical College, Seoul, Korea
| | - Taick Sang Nam
- Department of Physiology, Yonsei University Medical College, Seoul, Korea
| | - Duck Mi Yoon
- Department of Anesthesiology and Pain Medicine and Anesthesia & Pain Research Institute, Yonsei University Medical College, Seoul, Korea
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Gultekin FA, Kerem M, Tatlicioglu E, Aricioglu A, Unsal C, Bukan N. Leptin treatment ameliorates acute lung injury in rats with cerulein-induced acute pancreatitis. World J Gastroenterol 2007; 13:2932-8. [PMID: 17589942 PMCID: PMC4171144 DOI: 10.3748/wjg.v13.i21.2932] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the effect of exogenous leptin on acute lung injury (ALI) in cerulein-induced acute pancreatitis (AP).
METHODS: Forty-eight rats were randomly divided into 3 groups. AP was induced by intraperitoneal (i.p.) injection of cerulein (50 μg/kg) four times, at 1 h intervals. The rats received a single i.p. injection of 10 μg/kg leptin (leptin group) or 2 mL saline (AP group) after cerulein injections. In the sham group, animals were given a single i.p. injection of 2 mL saline. Experimental samples were collected for biochemical and histological evaluations at 24 h and 48 h after the induction of AP or saline administration. Blood samples were obtained for the determination of amylase, lipase, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, macrophage inflammatory peptide (MIP)-2 and soluble intercellular adhesion molecule (sICAM)-1 levels, while pancreatic and lung tissues were removed for myeloperoxidase (MPO) activity, nitric oxide (NOx) level, CD40 expression and histological evaluation.
RESULTS: Cerulein injection caused severe AP, confirmed by an increase in serum amylase and lipase levels, histopathological findings of severe AP, and pancreatic MPO activity, compared to the values obtained in the sham group. In the leptin group, serum levels of MIP-2, sICMA-1, TNF-α, and IL-1β, pancreatic MPO activity, CD40 expression in pancreas and lung tissues, and NOx level in the lung tissue were lower compared to those in the AP group. Histologically, pancreatic and lung damage was less severe following leptin administration.
CONCLUSION: Exogenous leptin attenuates inflamma-tory changes, and reduces pro-inflammatory cytokines, nitric oxide levels, and CD40 expression in cerulein-induced AP and may be protective in AP associated ALI.
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Affiliation(s)
- Fatma Ayca Gultekin
- Gazi University, School of Medicine, Department of General Surgery, Besevler 06510 Ankara, Turkey.
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He M, Horuk R, Bhatia M. Treatment with BX471, a nonpeptide CCR1 antagonist, protects mice against acute pancreatitis-associated lung injury by modulating neutrophil recruitment. Pancreas 2007; 34:233-241. [PMID: 17312463 DOI: 10.1097/mpa.0b013e31802e7598] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Chemokines and their receptors play a key role in the pathogenesis of acute pancreatitis. BX471 is a potent nonpeptide CC chemokine receptor 1 antagonist in both human and mouse. The aim of the present study was to evaluate the effect of prophylactic and therapeutic treatment with BX471 on experimental acute pancreatitis in the mouse and to investigate the underlying mechanisms. METHODS Acute pancreatitis was induced in mice by hourly intraperitoneal injection of cerulein. BX471 was administered either prophylactically or therapeutically, and pancreatic inflammation and lung injury were assessed. The expression of intercellular adhesion molecule 1, P-selectin, and E-selectin was studied by reverse transcriptase-polymerase chain reaction and immunohistochemistry. RESULTS In cerulein-induced acute pancreatitis, treatment with BX471 significantly protected mice against lung injury associated with cerulein-induced pancreatitis by attenuating myeloperoxidase activity, an indicator of neutrophil recruitment, and lung morphological changes in histological sections. Treatment with BX471 had little effect on pancreatic damage. Blocking CC chemokine receptor 1 by BX471 also down-regulated intercellular adhesion molecule 1, P-selectin, and E-selectin expression at mRNA and protein levels in both lungs and pancreas compared with vehicle-treated groups. CONCLUSIONS These findings suggest that interfering with neutrophil migration and activation by targeting CC chemokine receptor 1 may represent a promising strategy to prevent disease progression in acute pancreatitis.
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Affiliation(s)
- Min He
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Bldg MD2, 18 Medical Drive, Singapore
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24
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Moreno C, Nicaise C, Gustot T, Quertinmont E, Nagy N, Parmentier M, Louis H, Devière J. Chemokine receptor CCR5 deficiency exacerbates cerulein-induced acute pancreatitis in mice. Am J Physiol Gastrointest Liver Physiol 2006; 291:G1089-99. [PMID: 16891300 DOI: 10.1152/ajpgi.00571.2005] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Acute pancreatitis (AP) is an inflammatory disease involving the production of different cytokines and chemokines and is characterized by leukocyte infiltration. Because the chemokine receptor CCR5 and its ligands [the CC chemokines CCL3/MIP-1alpha, CCL4/MIP-1beta, and CCL5/regulated upon activation, normal T cell expressed and secreted (RANTES)] regulate leukocyte chemotaxis and activation, we investigated the expression of CCR5 ligands and the role of CCR5 and its ligands in experimental AP in mice. AP was induced by hourly intraperitoneal injections of cerulein in CCR5-deficient (CCR5(-/-)) or wild-type (WT) mice. Induction of AP by cerulein resulted in an early increase of pancreatic CCL2, CCL3, and CCL4 mRNA expression, whereas CCL5 mRNA expression occurred later. CCR5(-/-) mice developed a more severe pancreatic injury than WT mice during cerulein-induced AP, as assessed by a more pronounced increase in serum amylase and lipase levels and by more severe pancreatic edema, inflammatory infiltrates (mainly neutrophils), and necrosis. CCR5(-/-) mice also exhibited increased production of CCL2/MCP-1, CCL3/MIP-1alpha, and CCL4/MIP-1beta during the course of cerulein-induced AP. In vivo simultaneous neutralization of CC chemokines with monoclonal antibodies in CCR5(-/-) mice reduced the severity of cerulein-induced AP, indicating a role of CC chemokines in exacerbating the course of AP in the absence of CCR5. Moreover, simultaneous neutralization of CCR5 ligands in WT mice also reduced the severity of cerulein-induced AP. In conclusion, lack of the chemokine receptor CCR5 exacerbates experimental cerulein-induced AP and leads to increased levels of CC chemokines and a more pronounced pancreatic inflammatory infiltrate, suggesting that CCR5 expression can modulate severity of AP.
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Affiliation(s)
- Christophe Moreno
- Division of Gastroenterology and Hepatopancreatology, Erasme Hospital, Brussels B 1070, Belgium.
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25
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Ness TL, Kunkel SL, Hogaboam CM. CCR5 antagonists: the answer to inflammatory disease? Expert Opin Ther Pat 2006; 16:1051-65. [DOI: 10.1517/13543776.16.8.1051] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Kucuk C, Sozuer E, Gursoy S, Canoz O, Artis T, Akcan A, Akyildiz H, Muhtaroglu S. Treatment with Met-RANTES decreases bacterial translocation in experimental colitis. Am J Surg 2006; 191:77-83. [PMID: 16399111 DOI: 10.1016/j.amjsurg.2005.10.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2005] [Revised: 04/28/2005] [Indexed: 12/13/2022]
Abstract
BACKGROUND During colitis, epithelial function is impaired, leading to increased bacterial translocation. Recent studies have shown the important role of proinflammatory cytokines and chemokines, including RANTES (regulated on activation, normal T-cell expressed and secreted), in inflammatory bowel diseases (IBDs). In this study, we evaluated the role of Met-RANTES, an antagonist of the RANTES receptor, on the impairment of bacterial translocation in a rat model of colitis. METHODS Rats were randomly assigned to 3 groups. Group 1 = control, group 2 = experimental colitis, and group 3 = colitis plus Met-RANTES treatment. On day 7 after colitis was induced, plasma tumor necrosis factor-alpha colon tissue myeloperoxidase and portal blood endotoxin levels were measured. Lymph node, liver, and spleen culture quantified bacterial translocation. RESULTS Met-RANTES treatment resulted in significant decreases in colonic damage as well as bacterial translocation in experimental colitis. CONCLUSIONS These results suggest that chemokine receptor antagonists may potentially be useful in the treatment of IBDs.
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Affiliation(s)
- Can Kucuk
- Department of General Surgery, Erciyes University School of Medicine, 38039, Kayseri, Turkey.
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Abstract
Chemokines (chemotactic cytokines) are a family of low-molecular-weight proteins that direct the cellular migration of leukocytes by binding to and activating the G protein-coupled receptors displayed on the leukocyte cell surface. The inadvertent or excessive generation of chemokines has been associated with the inflammatory component of several disease processes, and consequently, considerable efforts have been made to characterise chemokine/chemokine receptor interactions with the ultimate aim of therapeutic intervention. This review focuses on the biology of CC chemokine receptor 1, which together with its ligands is thought to recruit leukocytes during the progression of rheumatoid arthritis, multiple sclerosis and organ transplant rejection. The developments made in antagonising this receptor and efficacies of these compounds in the clinical setting are also highlighted.
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MESH Headings
- Animals
- Arthritis, Rheumatoid/drug therapy
- Arthritis, Rheumatoid/immunology
- Arthritis, Rheumatoid/metabolism
- Drug Evaluation, Preclinical/trends
- Drugs, Investigational/chemistry
- Drugs, Investigational/pharmacology
- Drugs, Investigational/therapeutic use
- Graft Rejection/immunology
- Graft Rejection/prevention & control
- Humans
- Multiple Sclerosis/drug therapy
- Multiple Sclerosis/immunology
- Multiple Sclerosis/metabolism
- Receptors, CCR1
- Receptors, Chemokine/antagonists & inhibitors
- Receptors, Chemokine/metabolism
- Technology, Pharmaceutical/trends
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Affiliation(s)
- James E Pease
- Biomedical Sciences Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, South Kensington Campus, London SW7 2AZ, UK.
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Bhatia M, Ramnath RD, Chevali L, Guglielmotti A. Treatment with bindarit, a blocker of MCP-1 synthesis, protects mice against acute pancreatitis. Am J Physiol Gastrointest Liver Physiol 2005; 288:G1259-G1265. [PMID: 15691869 DOI: 10.1152/ajpgi.00435.2004] [Citation(s) in RCA: 104] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Chemokines are believed to play a key role in the pathogenesis of acute pancreatitis. We have earlier shown that pancreatic acinar cells produce the chemokine monocyte chemotactic protein (MCP)-1 in response to caerulein hyperstimulation, demonstrating that acinar-derived MCP-1 is an early mediator of inflammation in acute pancreatitis. Blocking chemokine production or action is a major target for pharmacological intervention in a variety of inflammatory diseases, such as acute pancreatitis. 2-Methyl-2-[[1-(phenylmethyl)-1H-indazol-3yl]methoxy]propanoic acid (bindarit) has been shown to preferentially inhibit MCP-1 production in vitro in monocytes and in vivo without affecting the production of the cytokines IL-1, IL-6, or the chemokines IL-8, protein macrophage inflammatory-1alpha, and RANTES. The present study aimed to define the role of MCP-1 in acute pancreatitis with the use of bindarit. In a model of acute pancreatitis induced by caerulein hyperstimulation, prophylactic as well as therapeutic treatment with bindarit significantly reduced MCP-1 levels in the pancreas. Also, this treatment significantly protected mice against acute pancreatitis as evident by attenuated hyperamylasemia neutrophil sequestration in the pancreas (pancreatic MPO activity), and pancreatic acinar cell injury/necrosis on histological examination of pancreas sections.
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Affiliation(s)
- Madhav Bhatia
- Dept. of Pharmacology, National Univ. of Singapore, Faculty of Medicine, Bldg. MD2, 18 Medical Dr., Singapore 117597.
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29
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Abstract
Acute pancreatitis is a common clinical condition. It is a disease of variable severity in which some patients experience mild, self-limited attacks while others manifest a severe, highly morbid, and frequently lethal attack. The exact mechanisms by which diverse etiological factors induce an attack are still unclear. It is generally believed that the earliest events in acute pancreatitis occur within acinar cells. Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction. If this inflammatory reaction is marked, it leads to a systemic inflammatory response syndrome (SIRS). An excessive SIRS leads to distant organ damage and multiple organ dysfunction syndrome (MODS). MODS associated with acute pancreatitis is the primary cause of morbidity and mortality in this condition. Recent studies have established the role played by inflammatory mediators in the pathogenesis of acute pancreatitis and the resultant MODS. At the same time, recent research has demonstrated the importance of acinar cell death in the form of apoptosis and necrosis as a determinant of pancreatitis severity. In this review, we will discuss about our current understanding of the pathophysiology of acute pancreatitis.
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Affiliation(s)
- Madhav Bhatia
- Department of Pharmacology, National University of Singapore, Singapore.
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30
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Lau HY, Wong FL, Bhatia M. A key role of neurokinin 1 receptors in acute pancreatitis and associated lung injury. Biochem Biophys Res Commun 2005; 327:509-515. [PMID: 15629143 DOI: 10.1016/j.bbrc.2004.12.030] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2004] [Indexed: 10/26/2022]
Abstract
Earlier studies have shown that mice deficient in NK1 receptors or its ligand, substance P, are protected against acute pancreatitis and associated lung injury. In the current study, the protective effect of NK1 receptor blockage against acute pancreatitis and associated lung injury was investigated, using a specific receptor antagonist, CP-96345. Acute pancreatitis was induced in mice by intraperitoneal (i.p.) injections of caerulein. Substance P levels in plasma, pancreas, and lungs were found to be elevated in a caerulein dose-dependent manner. Mice treated with CP-96345, either prophylactically, or therapeutically, were protected against acute pancreatitis and associated lung injury as evident by attenuation in plasma amylase, pancreatic and pulmonary myeloperoxidase activities, and histological evidence of pancreatic and pulmonary injuries. Pulmonary microvascular permeability was also reduced as a result of CP-96345 treatment. These results point to a key role of NK1 receptors in acute pancreatitis and associated lung injury.
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Affiliation(s)
- Hon Yen Lau
- Department of Pharmacology, National University of Singapore, Singapore
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31
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Abstract
A characteristic feature of all inflammatory disorders is the excessive recruitment of leukocytes to the site of inflammation. The loss of control in trafficking these cells contributes to inflammatory diseases. Leukocyte recruitment is a well-orchestrated process that includes several protein families including the large cytokine subfamily of chemotactic cytokines, the chemokines. Chemokines and their receptors are involved in the pathogenesis of several diseases. Acute lung injury that clinically manifests as acute respiratory distress syndrome (ARDS) is caused by an uncontrolled systemic inflammatory response resulting from clinical events including major surgery, trauma, multiple transfusions, severe burns, pancreatitis, and sepsis. Systemic inflammatory response syndrome involves activation of alveolar macrophages and sequestered neutrophils in the lung. The clinical hallmarks of ARDS are severe hypoxemia, diffuse bilateral pulmonary infiltrates, and normal intracardiac filling pressures. The magnitude and duration of the inflammatory process may ultimately determine the outcome in patients with ARDS. Recent evidence shows that activated leukocytes and chemokines play a key role in the pathogenesis of ARDS. The expanding number of antagonists of chemokine receptors for inflammatory disorders may hold promise for new medicines to combat ARDS.
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Affiliation(s)
- Padmam Puneet
- Dept. of Pharmacology, National University of Singapore, Singapore 117597
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32
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Abstract
Acute pancreatitis is an inflammatory disorder, and inflammation not only affects the pathogenesis but also the course of the disease. Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction; if marked this leads to a systemic inflammatory response syndrome (SIRS). An excessive SIRS leads to distant organ damage and multiple organ dysfunction syndrome (MODS). MODS associated with acute pancreatitis is the primary cause of morbidity and mortality in this condition. Recent studies by us and other investigators have established the critical role played by inflammatory mediators such as TNF-alpha, IL-1beta, IL-6, IL-8, CINC/GRO-alpha, MCP-1, PAF, IL-10, CD40L, C5a, ICAM-1, MIP1-alpha, RANTES, substance P, and hydrogen sulfide in acute pancreatitis and the resultant MODS. This review intends to present an overview of the inflammatory response that takes place following pancreatic acinar cell injury.
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Affiliation(s)
- M Bhatia
- Department of Pharmacology, National University of Singapore, Faculty of Medicine, Singapore.
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Abstract
PURPOSE OF REVIEW Acute pancreatitis is associated with a significant morbidity and a mortality as high as 10%. This review summarizes the most relevant articles in the past year that have contributed to understanding and management of this disease. RECENT FINDINGS Pathologic activation of both digestive zymogens and the transcription factor nuclear factor kappaB are early events in acute pancreatitis; these pathologic processes are inhibited in experimental pancreatitis by curcumin and the pH modulator chloroquine. Primary sensory neurons may constitute a final common pathway for pancreatic inflammation. Experimental acute pancreatitis and associated lung injury are attenuated by inhibiting the prostanoid mediators cyclo-oxygenase-2 and 5-lipoxygenase and CC chemokine receptor antagonist Met-RANTES. Endoscopic retrograde cholangiopancreatography-induced acute pancreatitis can be reduced experimentally by intraductal neurokinin-1 receptor antagonist and clinically by use of diclofenac and pancreatic duct stenting. MRI in the setting of acute pancreatitis is a reliable method of staging disease severity. Distinct patterns of cytokine response are observed in acute pancreatitis. SUMMARY Early events within the acinar cell and the regulation of inflammation by transcription factors continue to be elucidated. Although experimental acute pancreatitis can be successfully ameliorated by use of cytokine and inflammatory inhibitors, this has not been demonstrated in clinical disease. The finding of a compartmentalization of the inflammatory response in acute pancreatitis may be important for planning therapeutic interventions. Pancreatic duct stenting reduces the risk of developing postendoscopic retrograde cholangiopancreatography pancreatitis in high-risk people.
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Affiliation(s)
- Anil B Nagar
- Internal Medicine and Gastroenterology, West Haven VA and Yale University, West Haven, Connecticut 06516, USA.
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Bonville CA, Lau VK, DeLeon JM, Gao JL, Easton AJ, Rosenberg HF, Domachowske JB. Functional antagonism of chemokine receptor CCR1 reduces mortality in acute pneumovirus infection in vivo. J Virol 2004; 78:7984-9. [PMID: 15254170 PMCID: PMC446089 DOI: 10.1128/jvi.78.15.7984-7989.2004] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
We present an antiviral-immunomodulatory therapeutic strategy involving the chemokine receptor antagonist Met-RANTES, which yields significant survival in the setting of an otherwise fatal respiratory virus infection. In previous work, we demonstrated that infection with the natural rodent pathogen pneumonia virus of mice involves robust virus replication accompanied by cellular inflammation modulated by the CC chemokine macrophage inflammatory protein 1alpha (MIP-1alpha). We found that the antiviral agent ribavirin limited virus replication in vivo but had no impact on morbidity and mortality associated with this disease in the absence of immunomodulatory control. We show here that ribavirin reduces mortality, from 100% to 10 and 30%, respectively, in gene-deleted CCR1(-/-) mice and in wild-type mice treated with the small-molecule chemokine receptor antagonist, Met-RANTES. As MIP-1alpha-mediated inflammation is a common response to several distantly related respiratory virus pathogens, specific antiviral therapy in conjunction with blockade of the MIP-1alpha/CCR1 inflammatory cascade may ultimately prove to be a useful, generalized approach to severe respiratory virus infection and its pathological sequelae in human subjects.
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Affiliation(s)
- Cynthia A Bonville
- Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY 13210, USA
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Abstract
Acute pancreatitis is a disease of variable severity in which some patients experience mild, self-limited attacks while others manifest a severe, highly morbid, and frequently lethal attack. The events that regulate the severity of acute pancreatitis are, for the most part, unknown. Several recent studies have suggested that the acinar cell response to injury may be an important determinant of disease severity. In these studies, mild acute pancreatitis was found to be associated with extensive apoptotic acinar cell death while severe acute pancreatitis was found to involve extensive acinar cell necrosis but very little acinar cell apoptosis. These observations have led to the hypothesis that apoptosis might be a favorable response to acinar cell and that interventions which favor induction of apoptotic, as opposed to necrotic, acinar cell death might reduce the severity of an attack of acute pancreatitis. This review aims to discuss our current understanding of the contribution of acinar cell apoptosis to the severity of acute pancreatitis.
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Affiliation(s)
- M Bhatia
- Department of Pharmacology, National University of Singapore, Singapore 117597, Singapore.
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Raraty MGT, Connor S, Criddle DN, Sutton R, Neoptolemos JP. Acute pancreatitis and organ failure: pathophysiology, natural history, and management strategies. Curr Gastroenterol Rep 2004; 6:99-103. [PMID: 15191686 DOI: 10.1007/s11894-004-0035-0] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2023]
Abstract
Acute pancreatitis is a common condition that carries a significant risk of morbidity and mortality. It is characterized by intra-acinar cell activation of digestive enzymes and a subsequent systemic inflammatory response governed by the release of proinflammatory cytokines. In 80% of patients the disease runs a self-limiting course, but in the rest, pancreatic necrosis and systemic organ failure carry a mortality rate of up to 40%. The key to management is early identification of the patients liable to have a severe attack and require treatment in a high-dependency or critical-care setting by a specialist team. In gallstone-induced pancreatitis, early removal of ductal calculi by endoscopic sphincterotomy is indicated. The use of prophylactic antibiotics to prevent the infection of pancreatic necrosis remains controversial, but once established, infected necrosis must be removed. Although a number of techniques to accomplish this end have been described, minimally invasive techniques are gaining in popularity.
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Affiliation(s)
- Michael G T Raraty
- Department of Surgery, University of Liverpool, 5th Floor, UCD Building, Royal Liverpool University Hospital, Daulby Street, Liverpool L69 3GA, UK
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Bhatia M, Moochhala S. Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J Pathol 2004; 202:145-156. [PMID: 14743496 DOI: 10.1002/path.1491] [Citation(s) in RCA: 868] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2003] [Accepted: 09/29/2003] [Indexed: 12/17/2022]
Abstract
Inflammatory response leading to organ dysfunction and failure continues to be the major problem after injury in many clinical conditions such as sepsis, severe burns, acute pancreatitis, haemorrhagic shock, and trauma. In general terms, systemic inflammatory response syndrome (SIRS) is an entirely normal response to injury. Systemic leukocyte activation, however, is a direct consequence of a SIRS and if excessive, can lead to distant organ damage and multiple organ dysfunction syndrome (MODS). When SIRS leads to MODS and organ failure, the mortality becomes high and can be more than 50%. Acute lung injury that clinically manifests as acute respiratory distress syndrome (ARDS) is a major component of MODS of various aetiologies. Inflammatory mediators play a key role in the pathogenesis of ARDS, which is the primary cause of death in these conditions. This review summarizes recent studies that demonstrate the critical role played by inflammatory mediators such as tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, platelet activating factor (PAF), IL-10, granulocyte macrophage-colony stimulating factor (GM-CSF), C5a, intercellular adhesion molecule (ICAM)-1, substance P, chemokines, VEGF, IGF-I, KGF, reactive oxygen species (ROS), and reactive nitrogen species (RNS) in the pathogenesis of ARDS. It is reasonable to speculate that elucidation of the key mediators in ARDS coupled with the discovery of specific inhibitors would make it possible to develop clinically effective anti-inflammatory therapy.
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Affiliation(s)
- Madhav Bhatia
- Department of Pharmacology, National University of Singapore, Singapore.
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