Inhibition of PMN- and HOCl-induced vascular injury in isolated rabbit lungs by acetylsalicylic acid: a possible link between neutrophil-derived oxidative stress and eicosanoid metabolism?

Abstract

Neutrophils are involved in the pathogenesis of acute lung injury. The neutrophil-derived enzyme myeloperoxidase (MPO) catalyzes the formation of the oxidant hypochlorous acid (HOCl). This study characterizes the effects of (A) continuous HOCl infusion, and (B) stimulated neutrophils on pulmonary circulation in an isolated rabbit lung model. Furthermore, the effect of cyclooxygenase inhibition by acetylsalicylic acid (ASA, 0.5 mM) on these effects was investigated. (A) Infusion of HOCl (in nmol min −1, groups: 0, 0+ASA, 1000, 1000+ASA, 2000, and 2000+ASA) into the isolated organ was started after a 45-min steady-state period ( t=0). (B) Neutrophils (PMN group: 1480±323 and ASA group 1294±320 μl −1) were added into the perfusate between ( t=−45 min) and stimulated with FMLP (1 μM) after two 45-min steady-state periods ( t=0). Perfusate MPO activity was measured at t=−90, −45, 0, 1, 2, 3, 5, 10, 15, 30, 60, and 90 min. For both groups, pulmonary artery pressure (PAP) and lung weight were continuously recorded and the capillary filtration coefficient ( K f,c in 10 −4 cm 3 s −1 cm H 2O −1 g −1) was calculated from the slope of weight gain after a hydrostatic challenge at t=−45, −15, 30, 60 and 90 min. (A) Continuous HOCl infusion (1000/2000 nmol min −1) evoked a significant increase in ΔPAP and an up to 10-fold increase in K f,c reaching the maximum extent of the observed effects significant earlier in the 2000 nmol min −1 group. ASA reduced ΔPAP max significantly to about 50% in corresponding groups and the increase in PAP and K f,c occurred later in the ASA groups. (B) Neutrophil stimulation (PMN group/ASA group) evoked a rapid increase in ΔPAP and MPO activity, while the changes in vascular permeability were rather moderate, but still significant. The release of MPO activity was similar in both groups. ASA significantly reduced the increase in ΔPAP without affecting the release of MPO activity. Compared to baseline values, the preventive effects on vascular permeability increase reached level of significance as well. In summary, the described changes in pulmonary circulation caused by HOCl infusion or by neutrophil stimulation are significantly reduced by ASA. An involvement of cyclooxygenase products in the mediation of neutrophil-derived oxidative stress could be concluded.