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

Objective: Hypochlorous acid (HOCl) is the main oxidant of activated neutro phil granulocytes. It is generated by their myeloperoxidase during respirat ory burst. This study investigates the effects of HOCl on vascular permeabi lity and pulmonary artery pressure (PAP) and characterizes the influence of the cyclooxy-genase inhibitor acetylsalicylic acid (ASA) and the 5-lipoxyg enase 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 inh ibitors, ASA (500 mu mol/L), or CaA (1 mu mol/L). Measurements and Main Results: PAP, pulmonary venous pressure, and ventilat ion pressure as well as lung weight gain were continuously recorded, Capill ary filtration coefficient [K-f,K-c(10(-4.)cm(3.)sec(-1.)cm H2O-1 g(-1)) wa s 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 K-f,K-c and PAP with a threshold dose at 500 nmol/min, The onset of these changes was inversely related to the HO Cl dose used. Both inhibitors, CaA and ASA, exhibited protective effects on the HOCl-induced alterations in pulmonary microcirculation, ASA predominan tly reduced the HOCl-induced pressure response and had a minor but also sig nificant inhibitory effect on edema formation as measured by K-f,K-c and fl uid retention, CaA reduced significantly the rise in IC, and subsequent ede ma formation without effects on pulmonary pressure response. Conclusions: Cyclooxygenase and 5-lipoxygenase are involved in oxidative st ress induced acute lung injury, suggesting a link between neutrophil-derive d oxidative stress and endothelial eicosanoid metabolism.