NOS2 regulation of LPS-induced airway inflammation via S-nitrosylation of NF- B p65

Kelleher ZT, Potts EN, Brahmajothi MV, Foster MW, Auten RL, Foster WM, Marshall HE. NOS2 regulation of LPS-induced airway inflammation via S-nitrosylation of NFB p65. Am J Physiol Lung Cell Mol Physiol 301: L327–L333, 2011. First published July 1, 2011; doi:10.1152/ajplung.00463.2010.—Inducible nitric oxide synthase (NOS2) expression is increased in the airway epithelium in acute inflammatory disorders although the physiological impact remains unclear. We have previously shown that NOS2 inhibits NFB (p50-p65) activation in respiratory epithelial cells by inducing Snitrosylation of the p65 monomer (SNO-p65). In addition, we have demonstrated that mouse lung SNO-p65 levels are acutely depleted in a lipopolysaccharide (LPS) model of lung injury and that augmenting SNO-p65 levels before LPS treatment results in decreased airway epithelial NFB activation, airway inflammation, and lung injury. We now show that aerosolized LPS induces NOS2 expression in the respiratory epithelium concomitant with an increase in lung SNO-p65 levels and a decrease in airway NFB activity. Genetic deletion of NOS2 results in an absence of SNO-p65 formation, persistent NFB activity in the respiratory epithelium, and prolonged airway inflammation. These results indicate that a primary function of LPS-induced NOS2 expression in the respiratory epithelium is to modulate the inflammatory response through deactivation of NFB via S-nitrosylation of p65, thereby counteracting the initial stimulus-coupled denitrosylation.