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1 The Cardiovascular Institute
and 3 Division of Neonatology,
Michael Reese Hospital, Chicago, Illinois 60616;
2 Instituto Nacional de
Enfermedades Respiratorias,
Earlier work
from this laboratory found that fibroblasts isolated from fibrotic
human lung [human interstitial pulmonary fibrosis (HIPF)]
secrete a soluble inducer(s) of apoptosis in alveolar epithelial cells
(AECs) in vitro [B. D. Uhal, I. Joshi, A. True, S. Mundle, A. Raza, A. Pardo, and M. Selman. Am. J. Physiol. 269 (Lung Cell. Mol.
Physiol. 13): L819-L828, 1995]. The cultured human fibroblast strains most active in producing the apoptotic activity contained high numbers of stellate cells expressing 
-smooth muscle actin, a myofibroblast marker. The apoptotic activity eluted from gel-filtration columns only in fractions corresponding to proteins. Western blotting of the protein fraction identified immunoreactive angiotensinogen (ANGEN), and two-step RT-PCR revealed expression of ANGEN by HIPF fibroblasts but not by normal human lung
fibroblasts. Specific ELISA detected angiotensin II (ANG II) at
concentrations sixfold higher in HIPF-conditioned medium than in normal
fibroblast-conditioned medium. Pretreatment of the concentrated medium
with purified renin plus purified angiotensin-converting enzyme (ACE)
further increased the ELISA-detectable ANG II eightfold. Apoptosis of
AECs in response to HIPF-conditioned medium was completely abrogated by
the ANG II receptor antagonist saralasin (50 µg/ml) or anti-ANG II
antibodies. These results identify the protein inducers of AEC
apoptosis produced by HIPF fibroblasts as ANGEN and its derivative ANG
II. They also suggest a mechanism for AEC death adjacent to HIPF
myofibroblasts [B. D. Uhal,, I. Joshi, C. Ramos, A. Pardo, and M. Selman. Am. J. Physiol. 275 (Lung Cell. Mol. Physiol. 19):
L1192-L1199, 1998].
type II pneumocyte; pulmonary fibrosis; programmed cell death; converting enzyme; angiotensin-converting enzyme inhibitor
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