Leukotrienes are indicated as mediators of hyperoxia-inhibited alveolarization in newborn rats.
We investigated the role of leukotrienes (LT) in hyperoxia-induced changes in lung parenchyma in neonatal rat pups. Rat pups were exposed to 21% O(2) (air) or >95% O(2) from days 4 to 14 after birth and were administered the 5-lipoxygenase (5-LO) inhibitor and LTD4 receptor antagonist Wy-50295, 5-LO-activating protein inhibitor MK-0591, or vehicle from days 3 to 14. All measurements were done on days 12-14. There was a significant (P < 0.05) increase in peptido-LT output from lung slices of animals exposed to O(2) compared with air-exposed animals. Both Wy-50295 and MK-0591 significantly lowered (P < 0.05) peptido-LT output in O(2)-exposed animals. The 6-ketoprostaglandin F(1alpha) output was increased similarly in both vehicle- and drug-treated O(2)-exposed animals. O(2) exposure also caused a significant increase in bronchoalveolar lavage fluid protein and extravascular lung water that could not be ameliorated by Wy-50295 or MK-0591. Hyperoxia-induced inhibition of alveolarization, indicated by a significantly (P < 0.05) lower parenchymal tissue density, specific internal surface area, and airspace perimeter-to-area ratio, and a significantly (P < 0.05) higher mean linear intercept and airspace unit volume than air-exposed animals, was prevented by both Wy-50295 and MK-0591. Although hyperoxia had no effect on septal thickness, Wy-50295 caused significant thickening in both air- and O(2)-exposed pups. Our studies provide evidence that hyperoxia-induced peptido-LT may mediate O(2)-induced inhibition of alveolarization and that this is not caused by an arachidonic acid shunt to cyclooxygenase.
Boros
V
V
Department of Pediatrics, The University of Alberta, Edmonton, Canada.
Burghardt
J S
JS
Morgan
C J
CJ
Olson
D M
DM
D000208:Acute Disease; D000818:Animals; D000831:Animals, Newborn; D001094:Arachidonate 5-Lipoxygenase; D001835:Body Weight / Q000187:drug effects; D005260:Female; D018496:Hyperoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D015289:Leukotrienes / Q000502:physiology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008168:Lung / Q000254:growth & development; D055370:Lung Injury; D008297:Male; D009280:Naphthaleneacetic Acids / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D007211:Indoles; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D009280:Naphthaleneacetic Acids; D011804:Quinolines; C067525:S(alpha)-methyl-6-(2-quinolinylmethoxy)-2-naphthaleneacetic acid; C078266:MK 0591; D001094:Arachidonate 5-Lipoxygenase