Enalapril protects mice from pulmonary hypertension by inhibiting TNF-mediated activation of NF- B and AP-1

Ortiz, Luis A., Hunter C. Champion, Joseph A. Lasky, Federica Gambelli, Evelyn Gozal, Gary W. Hoyle, Mary B. Beasley, Albert L. Hyman, Mitchell Friedman, and Philip J. Kadowitz. Enalapril protects mice from pulmonary hypertension by inhibiting TNF-mediated activation of NFB and AP-1. Am J Physiol Lung Cell Mol Physiol 282: L1209–L1221, 2002. First published January 12, 2002; 10.1152/ajplung.00144.2001.—The present study was undertaken to investigate the effects of treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril in a mouse model of pulmonary hypertension induced by bleomycin. Bleomycin-induced lung injury in mice is mediated by enhanced tumor necrosis factor(TNF) expression in the lung, which determines the murine strain sensitivity to bleomycin, and murine strains are sensitive (C57BL/6) or resistant (BALB/c). Bleomycin induced significant pulmonary hypertension in C57BL/6, but not in BALB/c, mice; average pulmonary arterial pressure (PAP) was 26.4 2.5 mmHg (P 0.05) vs. 15.2 3 mmHg, respectively. Bleomycin treatment induced activation of nuclear factor (NF)B and activator protein (AP)-1 and enhanced collagen and TNF mRNA expression in the lung of C57BL/6 but not in BALB/c mice. Double TNF receptor-deficient mice (in a C57BL/6 background) that do not activate NFB or AP-1 in response to bleomycin did not develop bleomycin-induced pulmonary hypertension (PAP 14 3 mmHg). Treatment of C57BL/6 mice with enalapril significantly (P 0.05) inhibited the development of pulmonary hypertension after bleomycin exposure. Enalapril treatment inhibited NFB and AP-1 activation, the enhanced TNF and collagen mRNA expression, and the deposition of collagen in bleomycin-exposed C57BL/6 mice. These results suggest that ACE inhibitor treatment decreases lung injury and the development of pulmonary hypertension in bleomycin-treated mice.