Arachidonic acid in postshock mesenteric lymph induces pulmonary synthesis of leukotriene B4

Departments of 1 Surgery, University of Colorado Denver; 2 Denver Health Medical Center; and 3 Bonfils Blood Center, Denver, Colorado Submitted 5 January 2007 ; accepted in final form 4 February 2008 Mesenteric lymph is the mechanistic link between splanchnic hypoperfusion and acute lung injury (ALI), but the culprit mediator(s) remains elusive. Previous work has shown that administration of a phospholipase A 2 (PLA 2 ) inhibitor attenuated postshock ALI and also identified a non-ionic lipid within the postshock mesenteric lymph (PSML) responsible for polymorphonuclear neutrophil (PMN) priming. Consequently, we hypothesized that gut-derived leukotriene B 4 (LTB 4 ) is a key mediator in the pathogenesis of ALI. Trauma/hemorrhagic shock (T/HS) was induced in male Sprague-Dawley rats and the mesenteric duct cannulated for lymph collection/diversion. PSML, arachidonic acid (AA), and a LTB 4 receptor antagonist were added to PMNs in vitro. LC/MS/MS was employed to identify bioactive lipids in PSML and the lungs. T/HS increased AA in PSML and increased LTB 4 and PMNs in the lung. Lymph diversion decreased lung LTB 4 by 75% and PMNs by 40%. PSML stimulated PMN priming (11.56 ± 1.25 vs. 3.95 ± 0.29 nmol O 2 – /min; 3.75 x 10 5 cells/ml; P < 0.01) that was attenuated by LTB 4 receptor blockade (2.64 ± 0.58; P < 0.01). AA stimulated PMNs to produce LTB 4 , and AA-induced PMN priming was attenuated by LTB 4 receptor antagonism. Collectively, these data indicate that splanchnic ischemia/reperfusion activates gut PLA 2 -mediated release of AA into the lymph where it is delivered to the lungs, provoking LTB 4 production and subsequent PMN-mediated lung injury. acute lung injury; multiple organ failure; intestinal hypoperfusion; hemorrhagic shock; neutrophils Address for reprint requests and other correspondence: E. E. Moore, Dept. of Surgery, Denver Health Medical Center, 777 Bannock St., Denver, CO 80204 (e-mail: ernest.moore{at}dhha.org )