Neuronal nitric oxide synthase deficiency decreases survival in bacterial peritonitis and sepsis

Objective: To investigate the role of neuronal nitric oxide synthase (NOS1) in murine polymicrobial peritonitis and sepsis. Design: Randomized experimental trial. Setting: Animal research facility. Subjects: B6129S NOS1(+/+) and B6; 129S4 NOS-/- mice. Interventions: NOS1(+/+) and NOS1(-/-) animals underwent cecal ligation and puncture (CLP) or sham surgery and received the NOS1 inhibitor 7-nitroindazole (7-NI) or vehicle. Measurements and main results: After CLP, genetic deficiency and pharmacologic inhibition of NOS1 significantly increased risk of mortality [8.69 (3.27, 23.1), p < 0.0001 and 1.71 (1.00, 2.92) p = 0.05, hazard ratio of death (95% confidence interval) for NOS1(-/-) and 7-NI-treated NOS1(+/+) respectively] compared with NOS1(+/+) animals. In 7-NI-treated NOS1(+/+) animals, there were increases (6 h) and then decreases (24 h), whereas in NOS-/- animals persistent increases in blood bacteria counts (p = 0.04 for differing effects of 7-NI and NOS1(-/-)) were seen compared with NOS1+/+ animals. After CLP, NOS1(-/-) had upregulation of inducible NOS and proinflammatory cytokines and greater increases in serum tumor necrosis factor-alpha and interleukin-6 levels compared with NOS1+/+ mice (all p < 0.05). Following CLP, there were similar significant decreases in circulating leukocytes and lung lavage cells (p = 0.0008) and significant increases in peritoneal lavage cells (p = 0.0045) in all groups. Over 6 h and 24 h following CLP, compared with NOS1(+/+), NOS-/- mice had significantly higher peritoneal cell concentrations {respectively 0.40 +/- 0.09 vs 0.79 +/- 0.15 [ log(x 10(4)cells/ml)] averaged over both times p = 0.038}. Conclusions: Deficiency and inhibition of NOS1 increases mortality, possibly by increasing proinflammatory cytokine response and impairing bacterial clearance after CLP. These data suggest that NOS1 is important for survival, bacterial clearance, and regulation of cytokine response during infection and sepsis.