Influence of cyclooxygenase and lipoxygenase inhibitors on oxidative stress-induced lung injury.

OBJECTIVE

Hypochlorous acid (HOCl) is the main oxidant of activated neutrophil granulocytes. It is generated by their myeloperoxidase during respiratory burst. This study investigates the effects of HOCl on vascular permeability and pulmonary artery pressure (PAP) and characterizes the influence of the cyclooxygenase inhibitor acetylsalicylic acid (ASA) and the 5-lipoxygenase inhibitor caffeic acid (CaA) on the observed alterations.

DESIGN

Prospective experimental study using isolated perfused rabbit lungs.

SETTING

Experimental laboratory in a university teaching hospital.

INTERVENTIONS

HOCl was infused into the perfusate containing either no inhibitors, ASA (500 micromol/L), or CaA (1 micromol/L).

MEASUREMENTS AND MAIN RESULTS

PAP, pulmonary venous pressure, and ventilation pressure as well as lung weight gain were continuously recorded. Capillary filtration coefficient [Kf,c (10(-4) cm3 x sec(-1) x cm H2O(-1) x g(-1)]) was calculated before and 30, 60, and 90 mins after start of HOCl application. Continuous HOCl application (500, 1000, and 2000 nmol/min) resulted in a time- and dose-dependent increase in Kf,c and PAP with a threshold dose at 500 nmol/min. The onset of these changes was inversely related to the HOCl dose used. Both inhibitors, CaA and ASA, exhibited protective effects on the HOCl-induced alterations in pulmonary microcirculation. ASA predominantly reduced the HOCl-induced pressure response and had a minor but also significant inhibitory effect on edema formation as measured by Kf,c and fluid retention. CaA reduced significantly the rise in Kf,c and subsequent edema formation without effects on pulmonary pressure response.

CONCLUSIONS

Cyclooxygenase and 5-lipoxygenase are involved in oxidative stress induced acute lung injury, suggesting a link between neutrophil-derived oxidative stress and endothelial eicosanoid metabolism.