Journal Article

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

Raul Coimbra, Simone Langness, Brian P. Eliceiri, Todd W. Costantini, Koji Morishita

2016

Overview

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. 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. 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. 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.

• Publisher: Public Library of Science (PLoS),Public Library of Science
• Subject: 2.1 Biological and endogenous factors / Acute Lung Injury / Acute Lung Injury - metabolism / Acute Lung Injury - pathology / Acute Lung Injury - prevention & control / Acute Respiratory Distress Syndrome / Adult respiratory distress syndrome / Aetiology / Agonists (Biochemistry) / Animal / Animals / Arthritis / Attenuation / Biology and Life Sciences / Biomedical and Clinical Sciences / Blood / Clinical Sciences / Complications and side effects / Critical care / Disease Models / Disease Models, Animal / Feasibility studies / General Science & Technology / Genetically modified mice / Health sciences / Hemodynamics / Hemorrhage / Hemorrhagic / Hemorrhagic shock / Histology / Hydrazones / Hydrazones - therapeutic use / Hypotension / Inbred C57BL / Inflammation / Inflammation - metabolism / Inflammation - pathology / Inflammation - prevention & control / Inflammation Mediators / Inflammation Mediators - metabolism / Inflammatory response / Injury analysis / Injury prevention / Leukocytes (neutrophilic) / Lung / Lungs / Lymph / Lymph - drug effects / Lymph - immunology / Lymph - metabolism / Lymphatic Vessels / Lymphatic Vessels - drug effects / Lymphatic Vessels - metabolism / Macrophages / Male / Medicine / Medicine and Health Sciences / Mesentery / Mesentery - drug effects / Mesentery - immunology / Mesentery - metabolism / Mesentery - pathology / Mice / Mice, Inbred C57BL / Monocytes / Multiple organ dysfunction syndrome / Parenchyma / Pathogenesis / Permeability / Pharmacology / Phosphorylation / Physical Injury - Accidents and Adverse Effects / Physical Sciences / Polyethylene / Prevention / Q / R / Rare Diseases / Rats / Rats, Sprague-Dawley / Recruitment / Research and Analysis Methods / Research Article / Respiratory / Respiratory distress syndrome / Risk factors / Rodents / Science / Sepsis / Shock / Shock, Hemorrhagic / Shock, Hemorrhagic - complications / Shock, Hemorrhagic - drug therapy / Shock, Hemorrhagic - immunology / Shock, Hemorrhagic - metabolism / Shock, Traumatic / Shock, Traumatic - complications / Shock, Traumatic - drug therapy / Shock, Traumatic - immunology / Shock, Traumatic - metabolism / Sprague-Dawley / Stat3 protein / Stimulation / Surgery / Therapeutic applications / Trauma / Traumatic / Vagus nerve / Vagus nerve stimulation / Veins & arteries