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

Departments of ¹Surgery, University of Colorado Denver; ²Denver Health Medical Center; and ³Bonfils 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 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 LTB₄ 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 LTB₄ and PMNs in the lung. Lymph diversion decreased lung LTB₄ by 75% and PMNs by 40%. PSML stimulated PMN priming (11.56 ± 1.25 vs. 3.95 ± 0.29 nmol O₂^–/min; 3.75 x 10⁵ cells/ml; P < 0.01) that was attenuated by LTB₄ receptor blockade (2.64 ± 0.58; P < 0.01). AA stimulated PMNs to produce LTB₄, and AA-induced PMN priming was attenuated by LTB₄ receptor 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 LTB₄ production and subsequent PMN-mediated lung injury.

acute lung injury; multiple organ failure; intestinal hypoperfusion; hemorrhagic shock; neutrophils

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