S-nitrosoglutathione reductase (GSNOR) is a key denitrosylase and critically important for protecting immune and other cells from nitrosative stress. Pharmacological inhibition of GSNOR is being actively pursued as a therapeutic approach to increase S-nitrosoglutathione levels for the treatment of asthma and cystic fibrosis. In the present study, we employed GSNOR-deficient (GSNOR(-/-)) mice to investigate whether inactivation of GSNOR may increase susceptibility to pulmonary infection by Klebsiella pneumoniae, a common cause of nosocomial pneumonia. We found that compared to wild-type mice, bacterial colony forming units 48 h after intranasal infection with K. pneumoniae were increased over 4-folds in lung and spleen and strikingly, over a 1000-folds in blood of GSNOR(-/-) mice. Lung injury was comparable between infected wild-type and GSNOR(-/-) mice, but inflammation and injury was significantly elevated in spleen of GSNOR(-/-) mice. Whereas all wild-type mice survived 48 h after infection, 10 of 23 GSNOR(-/-) mice died. Thus, GSNOR appears to play a crucial role in controlling pulmonary and systemic infection by K. pneumoniae. Our results suggest that patients treated in clinical trials with inhibitors of GSNOR should be carefully monitored for signs of infection. (C) 2013 Elsevier Inc. All rights reserved.