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Department of Physiology, Michigan State University, East Lansing, Michigan 48824
Primary cultures of rat
type II alveolar epithelial cells (AECs) or human AEC-derived A549
cells, when exposed to bleomycin (Bleo), exhibited
concentration-dependent apoptosis detected by altered nuclear
morphology, fragmentation of DNA, activation of caspase-3, and net cell
loss over time. In both cell culture models, exposure to Bleo caused
time-dependent increases in angiotensinogen (ANGEN) mRNA.
Antisense oligonucleotides against ANGEN mRNA inhibited Bleo-induced
apoptosis of rat AEC or A549 cells by 83 and 84%, respectively
(P < 0.01 and P < 0.05), and
prevented Bleo-induced net cell loss. Apoptosis of rat AECs or
A549 cells in response to Bleo was inhibited 91% by the ANG-converting
enzyme inhibitor captopril or 82%, respectively, by neutralizing
antibodies specific for ANG II (both P < 0.01).
Antagonists of ANG receptor AT1 (losartan, L-158809, or
saralasin), but not an AT2-selective blocker (PD-123319), inhibited Bleo-induced apoptosis of either rat AECs (79%,
P < 0.01) or A549 cells (83%, P < 0.01) and also reduced the activity of caspase-3 by 52%
(P < 0.05). These data indicate that Bleo, like
FasL or TNF-
, induces transactivation of ANG synthesis
de novo that is required for AEC apoptosis. They also support
the theory that ANG system antagonists have potential for the blockade of AEC apoptosis in situ.
renin-angiotensin system; type II pneumocyte; lung fibrosis; programmed cell death; angiotensinogen
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