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

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 A2(PLA2) 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 B4(LTB4) 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 LTB4receptor 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 LTB4and PMNs in the lung. Lymph diversion decreased lung LTB4by 75% and PMNs by 40%. PSML stimulated PMN priming (11.56 ± 1.25 vs. 3.95 ± 0.29 nmol O2−/min; 3.75 × 105cells/ml; P < 0.01) that was attenuated by LTB4receptor blockade (2.64 ± 0.58; P < 0.01). AA stimulated PMNs to produce LTB4, and AA-induced PMN priming was attenuated by LTB4receptor antagonism. Collectively, these data indicate that splanchnic ischemia/reperfusion activates gut PLA2-mediated release of AA into the lymph where it is delivered to the lungs, provoking LTB4production and subsequent PMN-mediated lung injury.