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Am J Physiol Lung Cell Mol Physiol (January 12, 2002). doi:10.1152/ajplung.00144.2001
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Articles in PresS, published online ahead of print January 11, 2002
Am J Physiol Lung Cell Mol Physiol, 10.1152/ajplung.00144.2001
Submitted on April 25, 2001
Accepted on December 24, 2001

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

Luis A Ortiz1*, Hunter C Champion2, Joseph A Lasky1, Federica Gambelli1, Evelyn Gozal1, Gary W Hoyle1, Mary B Beasley3, Albert L Hyman2, Mitchell Friedman1, and Philip J Kadowitz1

1 Medicine, Tulane Health Science Center, New Orleans, LA, USA
2 Pharmacology, Tulane health Science Center, New Orleans, LA, USA
3 Pathology, Tulane health Science Center, New Orleans, LA, USA

* To whom correspondence should be addressed. E-mail: lortiz{at}tulane.edu.

Pulmonary hypertension is a serious complication of pulmonary fibrosis. Little information is available regarding the development of pulmonary hypertension in animal models of lung fibrosis. A high level of activity of the angiotensin converting enzyme (ACE) can be found in patients with pulmonary fibrosis and in animal models of pulmonary hypertension. The present study was undertaken to investigate the effects of treatment with the ACE inhibitor enalapril in a mouse model of pulmonary hypertension induced by bleomycin. Bleomycin induction of lung injury in mice is mediated by enhanced TNF expression in the lung. This enhanced expression of TNF 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 PAP of 26.4 ± 2.5 mmHg (p< 0.05) Vs 15.2 ± 3 mmHg, respectively. Bleomycin treatment induced activation of NF-{kappa}B and 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) who do not activate NF-{kappa}B nor 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 following bleomycin exposure. Enalapril treatment inhibited NF-{kappa}B 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.




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