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 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.
Jordan
Janeen R
JR
Department of Surgery, University of Colorado Denver, Denver, CO, USA.
Moore
Ernest E
EE
Sarin
Eric L
EL
Damle
Sagar S
SS
Kashuk
Sara B
SB
Silliman
Christopher C
CC
Banerjee
Anirban
A
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
D013481:Superoxides; D007975:Leukotriene B4; D016718:Arachidonic Acid; D009240:N-Formylmethionine Leucyl-Phenylalanine