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Am J Physiol Lung Cell Mol Physiol 296: L462-L469, 2009. First published December 12, 2008; doi:10.1152/ajplung.90377.2008
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Novel soluble guanylyl cyclase stimulator BAY 41-2272 attenuates ischemia-reperfusion-induced lung injury

Bakytbek Egemnazarov,1,4 Akylbek Sydykov,1,4 Ralph T. Schermuly,1,5 Norbert Weissmann,1 Johannes-Peter Stasch,3 Akpai S. Sarybaev,4 Werner Seeger,1 Friedrich Grimminger,2 and Hossein A. Ghofrani1

Departments of 1Internal Medicine II and 2Internal Medicine V, University Hospital Giessen and Marburg, Giessen; 3Pharma Research Center, Bayer HealthCare, Wuppertal, Germany; 4National Center of Cardiology and Internal Medicine, Bishkek, Kyrgyz Republic; and 5Max-Plank-Institute for Heart and Lung Research, Bad Nauheim, Germany

Submitted 9 July 2008 ; accepted in final form 8 December 2008

The protective effects of nitric oxide (NO), a physiological activator of soluble guanylyl cyclase (sGC), have been reported in ischemia-reperfusion (I/R) syndrome of the lung. Therefore, we studied the effects of BAY 41-2272, a novel sGC stimulator, on I/R injury of the lung in an isolated intact organ model. Lung injury was assessed by measuring 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. Rabbit lungs were treated with BAY 41-2272, NG-monomethyl-L-arginine (L-NMMA), or NO to evaluate the effects on I/R-induced lung injury. In untreated lungs, a dramatic rise in Kfc values and weight gain during reperfusion were observed, and these results were associated with increased ROS production. Both, BAY 41-2272 and L-NMMA significantly attenuated vascular leakage and suppressed ROS release. Additional experiments showed that BAY 41-2272 diminished PMA-induced ROS production by NADPH oxidase. A pharmacological inhibition of the enzyme with consequent reduction in ROS levels decreased I/R injury. NO had only marginal effect on I/R injury. Thus BAY 41-2272 protects against I/R-induced lung injury by interfering with the activation of NADPH oxidases.

acute lung injury; nitric oxide; oxidative stress; reactive oxygen species; guanosine 3',5'-cyclic monophosphate


Address for reprint requests and other correspondence: H. A. Ghofrani, Dept. of Internal Medicine II, University Hospital Giessen and Marburg, Klinikstrasse 36, D-35392 Giessen, Germany (e-mail: ardeschir.ghofrani{at}innere.med.uni-giessen.de)






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