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      Induction of acute lung inflammation in mice with hemorrhagic shock and resuscitation: role of HMGB1

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          Abstract

          Background

          Hemorrhagic shock and resuscitation (HS/R) can induce multiple organ failure which is associated with high mortality. The lung is an organ commonly affected by the HS/R. Acute lung injury is a major cause of dysfunction in other organ systems. The objective of this study is to test the hypothesis that HS/R causes increased gut permeability which results in induction of high mobility group box1 protein (HMGB1) and further leads to the development of acute lung inflammation.

          Materials and methods

          A mouse model of HS/R was employed in this study. Gut permeability and bacterial translocation were assessed with circulating FD4 and lipopolysaccharide (LPS). Circulating HMGB1 was determined with ELISA. Acute lung inflammation (ALI) was determined with lung myeloperoxidase (MPO) activity and pulmonary protein leakage.

          Results

          HS/R induced intestinal barrier dysfunction as evidenced by increased circulating FD4 and LPS at 30 min and 2 hrs after resuscitation, respectively. In addition, circulating HMGB1 levels were increased in mice with HS/R as compared with sham animals (p < 0.05). HS/R resulted in ALI (increased lung MPO activity and pulmonary protein leakage in mice with HS/R compared with sham mice, p < 0.05). Inhibition of HMGB1 (A-box and TLR4 −/−) attenuated the ALI in mice with HS/R. However, inhibition of HMGB1 did not show protective effect on gut injury in early phase of HS/R in mice.

          Conclusions

          Our results suggest that induction of HMGB1 is important in hemorrhagic shock and resuscitation-induced acute lung inflammation.

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          Most cited references19

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          High-mobility group box-1 in ischemia-reperfusion injury of the heart.

          High-mobility group box-1 (HMGB1) is a nuclear factor released by necrotic cells and by activated immune cells. HMGB1 signals via members of the toll-like receptor family and the receptor for advanced glycation end products (RAGE). Although HMGB1 has been implicated in ischemia/reperfusion (I/R) injury of the liver and lung, its role in I/R injury of the heart remains unclear. Here, we demonstrate that HMGB1 acts as an early mediator of inflammation and organ damage in I/R injury of the heart. HMGB1 levels were already elevated 30 minutes after hypoxia in vitro and in ischemic injury of the heart in vivo. Treatment of mice with recombinant HMGB1 worsened I/R injury, whereas treatment with HMGB1 box A significantly reduced infarct size and markers of tissue damage. In addition, HMGB1 inhibition with recombinant HMGB1 box A suggested an involvement of the mitogen-activated protein kinases jun N-terminal kinase and extracellular signal-regulated kinase 1/2, as well as the nuclear transcription factor nuclear factor-kappaB in I/R injury. Interestingly, infarct size and markers of tissue damage were not affected by administration of recombinant HMGB1 or HMGB1 antagonists in RAGE(-/-) mice, which demonstrated significantly reduced damage in reperfused hearts compared with wild-type mice. Coincubation studies using recombinant HMGB1 in vitro induced an inflammatory response in isolated macrophages from wild-type mice but not in macrophages from RAGE(-/-) mice. HMGB1 plays a major role in the early event of I/R injury by binding to RAGE, resulting in the activation of proinflammatory pathways and enhanced myocardial injury. Therefore, blockage of HMGB1 might represent a novel therapeutic strategy in I/R injury.
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            HMGB1 loves company.

            HMGB1, outside of a cell, is a trigger of inflammation and a stimulus for tissue reconstruction; the balance may depend on the complexes it forms with other molecules. HMGB1 is the prime example of a danger signal that originates from the damaged self rather than from invading pathogens. HMGB1 is released by cells that die traumatically and is secreted by cells destined to die and by activated cells of the innate immunity system. As a danger signal, HMGB1 is expected to trigger inflammation, but recent reports indicate that pure recombinant HMGB1 has no proinflammatory activity and only acts as a chemoattractant and a mitogen. However, HMGB1 forms highly inflammatory complexes with ssDNA, LPS, IL-1beta, and nucleosomes, which interact with TLR9, TLR4, IL-1R, and TLR2 receptors, respectively. Thus, HMGB1 has dual activities, solo or in company; I speculate that this may serve our body's necessity to sacrifice or reconstruct tissues as required by the presence or absence of pathogens.
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              Multiple organ failure. Pathophysiology and potential future therapy.

              Multiple organ failure (MOF) has reached epidemic proportions in most intensive care units and is fast becoming the most common cause of death in the surgical intensive care unit. Furthermore, in spite of the development of successive generations of new and more powerful antibiotics and increasing sophisticated techniques of organ support, our ability to salvage patients once MOF has become established has not appreciably improved over the last two decades. Clearly, new therapeutic strategies aimed at preventing or limiting the development of the physiologic abnormalities that induce organ failure are needed to improve survival in these critically ill patients. Based on our rapidly increasing knowledge of the mechanisms of MOF and the fruits of molecular biology, a number of new therapeutic approaches are in various stages of development. To effectively use these new therapeutic options as they become available, it is necessary to have a clear understanding of the pathophysiology of MOF. Thus, the goals of this review are to integrate the vast amount of new information on the basic biology of MOF and to focus special attention on the potential therapeutic consequences of these recent advances in our understanding of this complex and perplexing syndrome.
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                Author and article information

                Contributors
                rkao3@uwo.ca
                Xuemei.Xu@lawsonresearch.com
                anagyros.xenocostas@lhsc.on.ca
                neil.parry@lhsc.on.ca
                tina.mele@lhsc.on.ca
                cmartin1@uwo.ca
                trui@uwo.ca
                Journal
                J Inflamm (Lond)
                J Inflamm (Lond)
                Journal of Inflammation (London, England)
                BioMed Central (London )
                1476-9255
                8 October 2014
                8 October 2014
                2014
                : 11
                : 1
                : 30
                Affiliations
                [ ]Department of National Defense, Canadian Forces Health Services, Ottawa, ON Canada
                [ ]Critical Care Western, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON Canada
                [ ]Division of Hematology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON Canada
                [ ]Center for Critical Illness Research, Lawson Health Research Institute, 800 Commissioner’s Rd E, N6A 5 W9 London, ON Canada
                Article
                30
                10.1186/s12950-014-0030-7
                4193406
                25309129
                056e5b3d-c586-4aa3-9db9-1172ad146c13
                © Kao et al.; licensee BioMed Central Ltd. 2014

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 12 March 2014
                : 29 September 2014
                Categories
                Research
                Custom metadata
                © The Author(s) 2014

                Immunology
                hemorrhagic shock,gut injury,acute lung inflammation,hmgb1
                Immunology
                hemorrhagic shock, gut injury, acute lung inflammation, hmgb1

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