Role of NO-cGMP signalling pathway in mediation of ischemia-reperfusion lung injury
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Ischemia reperfusion (I/R) lung injury is a complex pathological process, which occurs in many clinical situations. Previous studies reported equivocal results about the role of nitric oxide (NO) synthase isoforms in the mediation of the injury and their possible mechanisms of action. Therefore, the aim of our study was to evaluate the role of NO synthase isoforms and NO-cGMP signaling pathway on I/R injury of the lung in an isolated perfused organ model employing rabbits as well as wild type and iNOS and eNOS knock out (KO) mice. Lung injury was assessed by measurements of weight gain and microvascular permeability (capillary filtration coefficient (Kfc)). Release of reactive oxygen species (ROS) into the perfusate was measured during early reperfusion by electron spin resonance (ESR) spectroscopy. Unselective NOS inhibitor (L NMMA), selective iNOS inhibitor (1400W, BYK 191023), selective nNOS inhibitor (VNIO), sGC stimulator (BAY 41-2272), or NADPH oxidase inhibitor (apocynin) were applied 5 min before ischemia according to the protocol. In untreated lungs dramatic rise in Kfc values and weight gain during reperfusion were observed. This was associated with increased reactive oxygen species (ROS) production. In rabbit and wild type mouse lungs, unselective NOS and selective iNOS or nNOS inhibition protected against I/R injury and was accompanied by reduced intravascular ROS release. iNOS and nNOS were upregulated on protein and transcript level in the course of I/R. In eNOS and iNOS KO mice the contribution of nNOS and iNOS to I/R injury was confirmed. Direct stimulation of sGC using BAY 41-2272 significantly attenuated vascular leakage and suppressed ROS release. In an additional set of experiments BAY 41-2272 diminished phorbol-myristrate-acetate (PMA) induced ROS production by NADPH-oxidases. Involvement of ROS generated by NADPH-oxidases in I/R was demonstrated by favorable effects of enzyme inhibition by apocynin. Thus, we conclude that iNOS and nNOS contribute to mediation of I/R induced lung injury by ROS production. On the other hand, NO-cGMP signalling pathway protects against I/R induced lung injury by interfering with NAPDH oxidase activation.Verknüpfung zu Publikationen oder weiteren Datensätzen
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Am J Physiol Lung Cell Mol Physiol. 2009; 296(3):L462-9.