title: Modulating the Biologic Activity of Mesenteric Lymph after Traumatic Shock Decreases Systemic Inflammation and End Organ Injury.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Simone
authors.identifier: http://orcid.org/0000-0001-7206-5186
authors.initials: S
authors.lastname: Langness
authors.affiliation: 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.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Costantini
authors.affiliation: Division of Acute Critical Care and Disaster Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Morishita
authors.affiliation: 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.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Eliceiri
authors.affiliation: 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.
authors.forename: Raul
authors.initials: R
authors.lastname: Coimbra
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D004195:Disease Models, Animal; D006835:Hydrazones / Q000627:therapeutic use*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D008196:Lymph / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D042601:Lymphatic Vessels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008643:Mesentery / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D012774:Shock, Traumatic / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism
chemical_list: C571838:CPSI-121; D006835:Hydrazones; D018836:Inflammation Mediators