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  • Given the involvement of dysregulated S nitrosylation in mul


    Given the involvement of dysregulated S-nitrosylation in multiple pathological conditions, a number of approaches to regulate S-nitrosylation therapeutically are being tried in multiple indications [18]. In the lung, GSNO releasing compounds and GSNOR inhibitors are being considered as potential therapeutic approaches for hydroxycarboxylic acid receptors [19] and cystic fibrosis [17]. However, since GSNOR−/− mice appear to be more susceptible to experimental peritoneal sepsis [3] as well as lung inflammation [4], we hypothesize that GSNOR deficiency may increase sensitivity to lung infection. Klebsiella pneumoniae is a common cause of nosocomial pneumonia. Recent increase in nosocomial infection by carbapenem-resistant enterobacteriaceae, which is associated with high mortality, is mostly observed in K. pneumoniae[20]. K. pneumoniae infection induces NOS activity and NO production in mouse and human alveolar macrophages [21], [22]. NO or related reactive nitrogen species (RNS) produced by the macrophages is indispensible for effective phagocytosis and killing of K. pneumoniae[21], [22]. Therefore, we have investigated whether GSNOR−/− mice are more susceptible to pulmonary infection by K. pneumoniae.
    Materials and methods
    Discussion In this study, we demonstrated that GSNOR−/− mice exhibited increased bacterial load and mortality in a pulmonary K. pneumoniae infection model. Bacterial loads 48h after infection were increased over 4-folds in lung and spleen and strikingly, over 1000-folds in blood of GSNOR−/− mice. Thus, GSNOR appears to play a crucial role in controlling pulmonary and systemic infection by K. pneumoniae. The important contribution to host defense against K. pneumoniae by GSNOR may result from its protection of immune cells from nitrosative stress. K. pneumoniae infection induces NOS activity and NO production in macrophages [21], [22], which is indispensible for effective phagocytosis and killing of K. pneumoniae[21], [22]. NO production by immune cells can cause nitrosative stress, which in absence of GSNOR can cause extensive cell death [2], [4]. Thus during immune response to K. pneumoniae infection, GSNOR may be essential for protection against NO-induced damage and death of immune cells in lung and spleen. Splenic macrophages, responsible for recycling of hemoglobin-derived iron [26], might sustain increased formation of S-nitrosothiols from NO [27] and thus critically depend on disposal of S-nitrosothiols by GSNOR. Lack of this protection in GSNOR−/− mice may account for increased damage and inflammation in spleen. Injury of the spleens, including particularly splenic macrophages, may disrupt their important function in the trapping and clearance of blood-borne pathogens [26], resulting in the marked failure of systemic control of the bacterial infection in GSNOR−/− mice. In addition, GSNOR−/− mice suffer increased apoptosis from nitrosative stress in thymic development that results in decreased CD4 T cells. While mice lacking αβ-T cells showed no increased susceptibility to K. pneumoniae in a pneumonia model, mice lacking γδ-T cells displayed unimpaired clearance of pulmonary bacterial but mildly increased peripheral blood dissemination and mortality [28]. It remains to be determined whether GSNOR−/− mice exhibit a loss or deficiency of γδ-T cells. GSNOR may contribute to the control of K. pneumoniae infection by preventing S-nitrosylation and inactivation of surfactant protein D (SP-D) or other proteins important for host defense. SP-D is secreted by lung epithelial cells and binds pathogen-associated molecular patterns as part of innate immune response [29]. SP-D can bind K. pneumoniae LPS [30] and improve phagocytosis and killing [31]. The binding to K. pneumoniae LPS requires higher-order multimerization of SP-D [30], which is inhibited by S-nitrosylation [32]. Whether GSNOR deficiency increases S-nitrosylation of SP-D or other antibacterial proteins during K. pneumoniae infection remains to be determined.