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1 Division of Cardiovascular and Respiratory Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
* To whom correspondence should be addressed. E-mail: nishiy{at}med.kobe-u.ac.jp.
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). Since nitric oxide (NO) has been reported to play roles in the pathogenesis of acute lung injury, the present study explores the effects of NO derived from chronically overexpressed endothelial nitric oxide synthase (eNOS), on VILI. 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 hours. After MV, lung damage including neutrophil infiltration, water leakage and cytokine concentration in bronchoalveolar lavage fluid (BALF) and plasma were evaluated. Some mice were given N
-nitro-L-arginine methyl ester (L-NAME), a potent NOS inhibitor, via drinking water (1 mg/mL) for one week 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 wild type animals. The concentrations of macrophage inflammatory protein-2 in BALF and plasma as well as plasma tumor necrosis factor-
and monocyte chemoattractant protein-1 were also decreased in eNOS-Tg mice. L-NAME abrogated the beneficial effect of eNOS-overexpression. In conclusion, chronic eNOS-overexpression might protect the lung from VILI by inhibiting the production of inflammatory chemokines and cytokines that are associated with neutrophil infiltration into the airspace.
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