NOS-2 Inhibition in Phosgene-Induced Acute Lung Injury.

Abstract

Phosgene exposure via an industrial or warfare release produces severe acute lung injury (ALI) with high mortality, characterized by massive pulmonary edema, disruption of epithelial tight junctions, surfactant dysfunction, and oxidative stress. There are no targeted treatments for phosgene-induced ALI. Previous studies demonstrated that nitric oxide synthase 2 (NOS-2) is upregulated in the lungs after phosgene exposure; however, the role of NOS-2 in the pathogenesis of phosgene-induced ALI remains unknown. We previously demonstrated that NOS-2 expression in lung epithelium exacerbates inhaled endotoxin-induced ALI in mice, mediated partially through downregulation of surfactant protein B (SP-B) expression. Therefore, we hypothesized that a selective NOS-2 inhibitor delivered to the lung epithelium by inhalation would mitigate phosgene-induced ALI. Inhaled phosgene produced increases in bronchoalveolar lavage fluid protein, histologic lung injury, and lung NOS-2 expression at 24 h. Administration of the selective NOS-2 inhibitor 1400 W via inhalation, but not via systemic delivery, significantly attenuated phosgene-induced ALI and preserved epithelial barrier integrity. Furthermore, aerosolized 1400 W augmented expression of SP-B and prevented downregulation of tight junction protein zonula occludens 1 (ZO-1), both critical for maintenance of normal lung physiology and barrier integrity. We also demonstrate for the first time that NOS-2-derived nitric oxide downregulates the ZO-1 expression at the transcriptional level in human lung epithelial cells, providing a novel target for ameliorating vascular leak in ALI. Our data demonstrate that lung NOS-2 plays a critical role in the development of phosgene-induced ALI and suggest that aerosolized NOS-2 inhibitors offer a novel therapeutic strategy for its treatment.

• Authors: Piotr T Filipczak, Albert P Senft, JeanClare Seagrave, Waylon Weber, Philip J Kuehl, Laura E Fredenburgh, Jacob D McDonald, Rebecca M Baron
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 146 Issue 1 Pg. 89-100 (Jul 2015) ISSN: 1096-0929 [Electronic] United States
• PMID: 25870319 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Chemical Warfare Agents
• Phosgene
• Nitric Oxide Synthase Type II

Topics

• Acute Lung Injury (chemically induced)
• Animals
• Chemical Warfare Agents (toxicity)
• Mice
• Mice, Inbred C57BL
• Nitric Oxide Synthase Type II (antagonists & inhibitors)
• Phosgene (toxicity)