Increased hyperoxia-induced lung injury in nitric oxide synthase 2 null mice is mediated via angiopoietin 2.
Supplemental oxygen is frequently prescribed. However, prolonged exposure to high concentrations of oxygen causes hyperoxic acute lung injury (HALI), which manifests as acute respiratory distress syndrome in adults and leads to bronchopulmonary dysplasia in newborns (NBs). Nitric oxide (NO), NO synthases (NOSs), and angiopoietin (Ang) 2 have been implicated in the pathogenesis of HALI. However, the mechanisms of the contributions of NOS/NO and the relationship(s) between NOS/NO and Ang2 have not been addressed. In addition, the relevance of these moieties in adults and NBs has not been evaluated. To address these issues, we compared the responses in hyperoxia of wild-type (NOS [+/+]) and NOS null (-/-) young adult and NB mice. When compared with NOS2(+/+) adult controls, NOS2(-/-) animals manifest exaggerated alveolar-capillary protein leak and premature death. These responses were associated with enhanced levels of structural cell death, enhanced expression of proapoptotic regulatory proteins, and Ang2. Importantly, silencing RNA knockdown of Ang2 decreased the levels of cell death and the expression of proapoptotic mediators. These effects were at least partially NOS2 specific, and were development dependent, because survival was similar in adult NOS3(+/+) and NOS3(-/-) mice and NB NOS2(+/+) and NOS2(-/-) mice, respectively. These studies demonstrate that NOS2 plays an important protective role in HALI in adult animals. They also demonstrate that this response is mediated, at least in part, by the ability of NOS2 to inhibit hyperoxia-induced Ang2 production and thereby decrease Ang2-induced tissue injury.
Division of Perinatal Medicine, Yale University School of Medicine, Department of Pediatrics, Children's Hospital, 20 York Street, New Haven, CT 06520-8057, USA. vineet.bhandari@yale.edu
Vineet
V
Bhandari
Rayman
R
Choo-Wing
Anantha
A
Harijith
Huanxing
H
Sun
Mansoor Ali
MA
Syed
Robert J
RJ
Homer
Jack A
JA
Elias
D042702:Angiopoietin-2 / Q000502:physiology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D015971:Gene Expression Regulation, Enzymologic; D018496:Hyperoxia / Q000150:complications*; D055370:Lung Injury / Q000201:enzymology / Q000209:etiology*; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering
D042702:Angiopoietin-2; D034741:RNA, Small Interfering; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse