Cyclooxygenase inhibition in ventilator-induced lung injury.
BACKGROUND
We tested the hypothesis that inhibition of cyclooxygenase (COX) attenuates in vivo ventilator-induced lung injury (VILI) in a prospective, randomized laboratory investigation in a university-affiliated laboratory. Adult male rats were anesthetized and randomized with or without nonselective COX inhibition (ibuprofen) and were subjected to injurious mechanical ventilation (positive end-expiratory pressure = 0; peak inspiratory pressure = 21 mm Hg).


METHODS
We investigated the profile of VILI (respiratory mechanics, cytokines, eicosanoids), expression of COX enzymes, and activation of nuclear factor (NF)-κB in ibuprofen- versus vehicle-treated animals. Injurious ventilation caused lung injury (i.e., decrement in compliance, tissue edema, and elevated inflammatory cytokines, eicosanoids, and COX-2).


RESULTS
Pretreatment with ibuprofen that effectively inhibited eicosanoid synthesis and COX-2 activity increased survival and attenuated lung edema and decrement in respiratory mechanics. Ibuprofen had no modulatory effect on ventilator-induced activation of NF-κB or inflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1β, IL-6, GRO/KC [growth-related oncogene/keratinocyte chemoattractant]). COX activity seems important in the pathogenesis of VILI in the in vivo rat. Inhibition of COX provides significant protection (i.e., survival, pulmonary function) in VILI, but without affecting levels of important mediators (tumor necrosis factor-α, IL-1β, IL-6, GRO/KC) or activation of NF-κB.


CONCLUSIONS
These data confirm that nonselective COX inhibition provides partial protection against VILI and that the NF-κB signaling pathway is not exclusively eicosanoid dependent. Studies of COX inhibition in ventilator-associated lung injury might benefit from multimodal targeting that includes a comprehensive focus on inflammatory cytokines and NF-κB.
Program in Physiology & Experimental Medicine, Hospital for Sick Children, Toronto, Canada.
Takehiro
T
Niitsu
Shinya
S
Tsuchida
Vanya
V
Peltekova
Doreen
D
Engelberts
Ian
I
Copland
Gail
G
Otulakowski
Martin
M
Post
Brian P
BP
Kavanagh
D000818:Animals; D001784:Blood Gas Analysis / Q000379:methods; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D008297:Male; D011446:Prospective Studies; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D055397:Ventilator-Induced Lung Injury / Q000188:drug therapy* / Q000201:enzymology*
D016861:Cyclooxygenase Inhibitors