Inhibition of COX-2 aggravates neutrophil migration and pneumocyte apoptosis in surfactant-depleted rat lungs.
Pulmonary inflammation and parenchymal apoptosis are implicated in the pathogenesis of the acute lung injury, but the mechanisms of these reactions are still unclear. Because inhibition of the proinflammatory cyclo-oxygenase (COX)-2 enzyme action is proposed to be useful in various inflammatory lung injuries, we decided to investigate the expression of COX-2 and the possible beneficial effects of its inhibition on pulmonary inflammation and apoptosis in surfactant-depleted lungs. The injury was induced in 2-mo-old rats by repeated lung lavage to remove alveolar surfactant. Eight of these rats were pretreated with a specific COX-2 inhibitor, NS-398. All rats, including control rats without lung lavage, were ventilated with 60% oxygen for 5 h, and the lungs were then studied histologically for tissue injury and with DNA nick-end labeling, cleaved caspase-3 immunohistochemistry, and electron microscopy for apoptotic cell death. Lung tissue myeloperoxidase activity and the expression of COX-2 protein and concentration of prostaglandin E2 were additionally analyzed. Lung lavage increased pulmonary neutrophil migration, histologic injury, and the occurrence of epithelial apoptosis. In contrast, expression of COX-2 and amount of PGE2 were significantly lower in surfactant-depleted lungs than controls. Pretreatment with the COX-2 inhibitor further increased the migration of neutrophils and occurrence of epithelial apoptosis in the surfactant-depleted lungs, compared with nontreated insulted lungs. These results suggest that specific inhibitors of COX-2 should be used cautiously in association with surfactant-deficient lung injuries.
Lukkarinen
Heikki
H
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, FIN-20520 Turku, Finland. heikki.lukkarinen@utu.fi
Laine
Jukka
J
Aho
Heikki
H
Asikainen
Eeva
E
Penttinen
Pauliina
P
Kääpä
Pekka
P
D000818:Animals; D017209:Apoptosis; D002634:Chemotaxis, Leukocyte; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000276:immunology / Q000473:pathology*; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000502:physiology*; D009578:Nitrobenzenes / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology*; D011663:Pulmonary Surfactants / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; D009578:Nitrobenzenes; D011663:Pulmonary Surfactants; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D009195:Peroxidase; D051546:Cyclooxygenase 2