title: Ventilator-induced lung injury is reduced in transgenic mice that overexpress endothelial nitric oxide synthase.
abstract: Although mechanical ventilation (MV) is an important supportive strategy for patients with acute respiratory distress syndrome, MV itself can cause a type of acute lung damage termed ventilator-induced lung injury (VILI). Because nitric oxide (NO) has been reported to play roles in the pathogenesis of acute lung injury, the present study explores the effects on VILI of NO derived from chronically overexpressed endothelial nitric oxide synthase (eNOS). Anesthetized eNOS-transgenic (Tg) and wild-type (WT) C57BL/6 mice were ventilated at high or low tidal volume (Vt; 20 or 7 ml/kg, respectively) for 4 h. After MV, lung damage, including neutrophil infiltration, water leakage, and cytokine concentration in bronchoalveolar lavage fluid (BALF) and plasma, was evaluated. Some mice were given N(omega)-nitro-L-arginine methyl ester (L-NAME), a potent NOS inhibitor, via drinking water (1 mg/ml) for 1 wk before MV. Histological analysis revealed that high Vt ventilation caused severe VILI, whereas low Vt ventilation caused minimal VILI. Under high Vt conditions, neutrophil infiltration and lung water content were significantly attenuated in eNOS-Tg mice compared with WT animals. The concentrations of macrophage inflammatory protein-2 in BALF and plasma, as well as plasma tumor necrosis factor-alpha and monocyte chemoattractant protein-1, also were decreased in eNOS-Tg mice. L-NAME abrogated the beneficial effect of eNOS overexpression. In conclusion, chronic eNOS overexpression may protect the lung from VILI by inhibiting the production of inflammatory chemokines and cytokines that are associated with neutrophil infiltration into the air space.
authors.affiliation: Division of Cardiovascular and Respiratory Medicine, Kobe Univ. Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Takenaka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Teruaki
authors.initials: T
authors.lastname: Nishiuma
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sakashita
authors.forename: Tomoya
authors.initials: T
authors.lastname: Yamashita
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Miyako
authors.initials: M
authors.lastname: Satouchi
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Ishida
authors.forename: Seinosuke
authors.initials: S
authors.lastname: Kawashima
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D008171:Lung Diseases / Q000139:chemically induced*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D012122:Ventilators, Mechanical / Q000009:adverse effects*
chemical_list: D052250:Nitric Oxide Synthase Type III; D019331:NG-Nitroarginine Methyl Ester