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Articles in PresS, published online ahead of print November 15, 2002
Am J Physiol Lung Cell Mol Physiol, 10.1152/ajplung.00273.2002
Submitted on August 8, 2002
Accepted on November 5, 2002
1 Department of Physiology, Michigan State University, East Lansing, Michigan, USA
* To whom correspondence should be addressed. E-mail: uhal{at}msu.edu.
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, fragmented of DNA, activated 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 and (<p0.01 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 ACE inhibitor captopril or by 82%, respectively, by neutralizing antibodies specific for ANGII (both p<0.01). Antagonists of ANG receptor AT1 (losartan, L158809 or saralasin), but not an AT2-selective blocker (PD123319), 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.
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