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: Zachary T Kelleher, Erin N Potts, Mulugu V Brahmajothi, Matthew W Foster, Richard L Auten, W Michael Foster, Harvey E Marshall
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 301 Issue 3 Pg. L327-33 (Sep 2011) ISSN: 1522-1504 [Electronic] United States
• PMID: 21724860 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Lipopolysaccharides
• Transcription Factor RelA
• Nitric Oxide
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse

Topics

• Animals
• Bronchoalveolar Lavage Fluid (chemistry)
• Inflammation (chemically induced)
• Lipopolysaccharides
• Mice
• Mice, Inbred C57BL
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (biosynthesis, physiology)
• Respiratory Mucosa (metabolism)
• Transcription Factor RelA (metabolism)