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Systemic Microvascular Leak in an In Vivo Rat Model of Ventilator-induced Lung Injury

Department of Medicine, Pulmonary/Critical Care Unit and Renal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Charles A. Hales, M.D., Massachusetts General Hospital, Pulmonary and Critical Care Medicine, 55 Fruit Street, Bullfinch 148, Boston, MA 02114. E-mail: chales{at}partners.org

Positive pressure mechanical ventilation has significant systemic effects, but the systemic effects associated with ventilator-induced lung injury (VILI) are unexplored. We hypothesized that VILI would cause systemic microvascular leak that is dependent on nitric oxide synthase (NOS) expression. Rats were ventilated with room air at 85 breaths/minute for 2 hours with either VT 7 or 20 ml/kg. Kidney microvascular leak, which was assessed by measuring 24-hour urine protein and Evans blue dye, was used as a marker of systemic microvascular leak. A significant microvascular leak occurred in both lung and kidney with large VT (20 ml/kg) ventilation. Injection of 0.9% NaCl corrected the hypotension and the decreased cardiac output related to large VT, but it did not attenuate microvascular leak of lung and kidney. Serum vascular endothelial growth factor was significantly elevated in large VT groups. Endothelial NOS expression significantly increased in the lung and kidney tissue with large VT ventilation but not inducible NOS. The NOS inhibitor, N-nitro-L-arginine methyl ester, attenuated the microvascular leak of lung and kidney and the proteinuria with large VT ventilation. Endothelial NOS may mediate the systemic microvascular leak of the present model of VILI.

Key Words: microvascular leak • permeability • proteinuria • endothelial nitric oxide synthase • N-nitro-L-arginine methyl ester

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