title: 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: *Environmental Respiratory Health and Chemistry and Inhalation Exposure Programs, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108 and Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115 *Environmental Respiratory Health and Chemistry and Inhalation Exposure Programs, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108 and Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors: Piotr T
authors: PT
authors: Filipczak
authors: *Environmental Respiratory Health and Chemistry and Inhalation Exposure Programs, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108 and Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors: Albert P
authors: AP
authors: Senft
authors: *Environmental Respiratory Health and Chemistry and Inhalation Exposure Programs, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108 and Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors: JeanClare
authors: J
authors: Seagrave
authors: *Environmental Respiratory Health and Chemistry and Inhalation Exposure Programs, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108 and Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors: Waylon
authors: W
authors: Weber
authors: *Environmental Respiratory Health and Chemistry and Inhalation Exposure Programs, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108 and Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors: Philip J
authors: PJ
authors: Kuehl
authors: *Environmental Respiratory Health and Chemistry and Inhalation Exposure Programs, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108 and Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors: Laura E
authors: LE
authors: Fredenburgh
authors: *Environmental Respiratory Health and Chemistry and Inhalation Exposure Programs, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108 and Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors: Jacob D
authors: JD
authors: McDonald
authors: *Environmental Respiratory Health and Chemistry and Inhalation Exposure Programs, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108 and Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115 rbaron@partners.org.
authors: Rebecca M
authors: RM
authors: Baron
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced*; D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D010705:Phosgene / Q000633:toxicity*
chemical_list: D002619:Chemical Warfare Agents; D010705:Phosgene; D052247:Nitric Oxide Synthase Type II
keywords: acute lung injury; lung epithelium; nitric oxide synthase 2; phosgene; surfactant protein B; tight junction protein 1