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B and AP-1
1 Section of Pulmonary Diseases, Critical Care, and Environmental Medicine, Departments of 2 Pharmacology and 3 Pathology and the Lung Biology Program, Tulane University Medical Center, New Orleans, Louisiana 70112
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 NF-B 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 NF-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.
pulmonary hypertension; tumor necrosis factor; nuclear factor-B; activator protein-1; angiotensin II
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