Nitric oxide synthase 2 augments the survival of mice upon Salmonella Typhimurium infection induced sepsis: impact on innate immune responses & organ damage

Abstract

Abstract Sepsis is defined as infection induced deregulation of host immune responses that may lead to multi organ dysfunction. Enhanced inflammation and persistent organ damage often leads to impaired recovery and death of sepsis patients. Thus molecules that attenuate inflammatory responses are potential therapeutic targets for sepsis. We have established intra-peritoneal S. Typhimurium infection induced peritonitis model of sepsis in mice characterized by: enhanced amounts of nitric oxide (NO), ROS, cytokines, neutrophil recruitment at the site of infection, organ damage and death of mice. Nitric oxide (NO), a highly reactive molecule has pleiotropic effects in host ranging from cell signaling and gene modulation to antimicrobial effects. Enhanced activity of Nos2 and NO is seen in sepsis patients. However, the roles of NO in pathogenesis of sepsis are controversial. Using Nos2−/− mice we attempted to elucidate the roles of Nos2 derived NO in sepsis. Upon infection Nos2−/− mice showed attenuated induction of ROS, pro-inflammatory cytokines and neutrophil recruitment. Importantly, dampened innate immune responses in Nos2−/− mice correlated with increased microbial burden, liver damage, cardiac dysfunction and reduced survival upon sepsis. Clearly Nos2 derived NO promotes protective innate immune responses during sepsis. The precise role of Nos2 derived NO was further evaluated by exogenous supplementation of Nos2−/− mice with a NO donor. Administration of exogenous NO in Nos2−/− mice beneficially restored host innate immune responses and increased survival. Our findings are crucial in the context of therapeutic interventions for sepsis and the implications for NO as a target molecule are discussed.