title: NOS2 regulation of LPS-induced airway inflammation via S-nitrosylation of NF-{kappa}B p65.
abstract: 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 NF-κB (p50-p65) activation in respiratory epithelial cells by inducing S-nitrosylation 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 NF-κB 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 NF-κB activity. Genetic deletion of NOS2 results in an absence of SNO-p65 formation, persistent NF-κB 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 NF-κB via S-nitrosylation of p65, thereby counteracting the initial stimulus-coupled denitrosylation.
authors: Division of Pulmonary Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors: Zachary T
authors: ZT
authors: Kelleher
authors: Erin N
authors: EN
authors: Potts
authors: Mulugu V
authors: MV
authors: Brahmajothi
authors: Matthew W
authors: MW
authors: Foster
authors: Richard L
authors: RL
authors: Auten
authors: W Michael
authors: WM
authors: Foster
authors: Harvey E
authors: HE
authors: Marshall
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D007249:Inflammation / Q000139:chemically induced; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000502:physiology*; D020545:Respiratory Mucosa / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D051996:Transcription Factor RelA; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse