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      Modulating the Biologic Activity of Mesenteric Lymph after Traumatic Shock Decreases Systemic Inflammation and End Organ Injury

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          Abstract

          Introduction

          Trauma/hemorrhagic shock (T/HS) causes the release of pro-inflammatory mediators into the mesenteric lymph (ML), triggering a systemic inflammatory response and acute lung injury (ALI). Direct and pharmacologic vagal nerve stimulation prevents gut barrier failure and alters the biologic activity of ML after injury. We hypothesize that treatment with a pharmacologic vagal agonist after T/HS would attenuate the biologic activity of ML and prevent ALI.

          Methods

          ML was collected from male Sprague-Dawley rats after T/HS, trauma-sham shock (T/SS) or T/HS with administration of the pharmacologic vagal agonist CPSI-121. ML samples from each experimental group were injected into naïve mice to assess biologic activity. Blood samples were analyzed for changes in STAT3 phosphorylation (pSTAT3). Lung injury was characterized by histology, permeability and immune cell recruitment.

          Results

          T/HS lymph injected in naïve mice caused a systemic inflammatory response characterized by hypotension and increased circulating monocyte pSTAT3 activity. Injection of T/HS lymph also resulted in ALI, confirmed by histology, lung permeability and increased recruitment of pulmonary macrophages and neutrophils to lung parenchyma. CPSI-121 attenuated T/HS lymph-induced systemic inflammatory response and ALI with stable hemodynamics and similar monocyte pSTAT3 levels, lung histology, lung permeability and lung immune cell recruitment compared to animals injected with lymph from T/SS.

          Conclusion

          Treatment with CPSI-121 after T/HS attenuated the biologic activity of the ML and decreased ALI. Given the superior clinical feasibility of utilizing a pharmacologic approach to vagal nerve stimulation, CPSI-121 is a potential treatment strategy to limit end organ dysfunction after injury.

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          Most cited references 62

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          Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine.

           R Bone,  R Balk,  F Cerra (1992)
          An American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference was held in Northbrook in August 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic parameters by which a patient may be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods when dealing with septic patients was recommended as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended. The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.
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            The acute respiratory distress syndrome.

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              Animal models of acute lung injury.

              Acute lung injury in humans is characterized histopathologically by neutrophilic alveolitis, injury of the alveolar epithelium and endothelium, hyaline membrane formation, and microvascular thrombi. Different animal models of experimental lung injury have been used to investigate mechanisms of lung injury. Most are based on reproducing in animals known risk factors for ARDS, such as sepsis, lipid embolism secondary to bone fracture, acid aspiration, ischemia-reperfusion of pulmonary or distal vascular beds, and other clinical risks. However, none of these models fully reproduces the features of human lung injury. The goal of this review is to summarize the strengths and weaknesses of existing models of lung injury. We review the specific features of human ARDS that should be modeled in experimental lung injury and then discuss specific characteristics of animal species that may affect the pulmonary host response to noxious stimuli. We emphasize those models of lung injury that are based on reproducing risk factors for human ARDS in animals and discuss the advantages and disadvantages of each model and the extent to which each model reproduces human ARDS. The present review will help guide investigators in the design and interpretation of animal studies of acute lung injury.
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                Author and article information

                Affiliations
                [1 ]Division of Trauma, Surgical Critical Care, Burns and Acute Care Surgery, Department of Surgery, University of California, San Diego Health Sciences, San Diego, California, United States of America
                [2 ]Division of Acute Critical Care and Disaster Medicine, Tokyo Medical and Dental University, Tokyo, Japan
                USF Health Morsani College of Medicine, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: SL TC RC.

                • Data curation: SL KM.

                • Formal analysis: SL KM BE TC RC.

                • Investigation: SL KM.

                • Methodology: SL KM BE.

                • Project administration: BE TC RC.

                • Resources: BE.

                • Software: BE.

                • Supervision: BE TC RC.

                • Validation: SL KM.

                • Visualization: SL.

                • Writing – original draft: SL.

                • Writing – review & editing: SL BE TC RC.

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                15 December 2016
                2016
                : 11
                : 12
                PONE-D-16-12356
                10.1371/journal.pone.0168322
                5158049
                27977787
                © 2016 Langness et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Counts
                Figures: 4, Tables: 0, Pages: 14
                Product
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Lymph
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Lymph
                Biology and Life Sciences
                Physiology
                Body Fluids
                Lymph
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Lymph
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Sepsis
                Systemic Inflammatory Response Syndrome
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Sepsis
                Systemic Inflammatory Response Syndrome
                Biology and Life Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Immunology
                Immune Response
                Inflammation
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                Diagnostic Medicine
                Signs and Symptoms
                Inflammation
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                Pathology and Laboratory Medicine
                Signs and Symptoms
                Inflammation
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
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                White Blood Cells
                Macrophages
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                Cell Biology
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                Animal Cells
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                Immunology
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                Monocytes
                Biology and Life Sciences
                Anatomy
                Histology
                Medicine and Health Sciences
                Anatomy
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                Research and Analysis Methods
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                Spectrophotometry
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                Custom metadata
                All relevant data are within the paper and its Supporting Information files. The minimal dataset is available from the Figshare database ( http://dx.doi.org/10.6084/m9.figshare.3411826).

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