title: Arachidonic acid in postshock mesenteric lymph induces pulmonary synthesis of leukotriene B4.
abstract: 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.
authors.affiliation: Department of Surgery, University of Colorado Denver, Denver, CO, USA.
authors.forename: Janeen R
authors.initials: JR
authors.lastname: Jordan
authors.forename: Ernest E
authors.initials: EE
authors.lastname: Moore
authors.forename: Eric L
authors.initials: EL
authors.lastname: Sarin
authors.forename: Sagar S
authors.initials: SS
authors.lastname: Damle
authors.forename: Sara B
authors.initials: SB
authors.lastname: Kashuk
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Silliman
authors.forename: Anirban
authors.initials: A
authors.lastname: Banerjee
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008171:Lung Diseases / Q000378:metabolism / Q000473:pathology; D008196:Lymph / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008643:Mesentery / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009240:N-Formylmethionine Leucyl-Phenylalanine; D020556:Neutrophil Infiltration / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000378:metabolism / Q000473:pathology; D013481:Superoxides / Q000378:metabolism
chemical_list: D013481:Superoxides; D007975:Leukotriene B4; D016718:Arachidonic Acid; D009240:N-Formylmethionine Leucyl-Phenylalanine