Inhibition of amiodarone-induced lung fibrosis but not alveolitis by angiotensin system antagonists.
Earlier work in this laboratory showed that amiodarone induces apoptosis in alveolar epithelial cells by a mechanism inhibitable by angiotensin system antagonists. A variety of recent studies suggests a critical role for alveolar epithelial cell apoptosis in the pathogenesis of lung fibrosis. On this basis we hypothesized that amiodarone-induced alveolar epithelial cell apoptosis and lung fibrosis in vivo might be inhibitable by the angiotensin converting enzyme inhibitor captopril or the angiotensin receptor antagonist losartan. Amiodarone-induced lung fibrosis was induced in male Wistar rats by oral administration over six months. Replicate groups of rats received captopril or losartan in addition to amiodarone. Apoptosis was detected by increased total lung activity of caspase 3 and in situ end labeling (ISEL) of fragmented DNA. Collagen was localized and quantitated by the picrosirius red technique. Alveolar epithelial cell apoptosis was detected in amiodarone-treated animals as early as three weeks after the start of amiodarone administration; by six months exposure, the incidence of alveolar epithelial cell apoptosis was significantly reduced by coadministration of captopril or losartan. Alveolar wall collagen accumulation also was significantly attenuated by captopril (100%) or losartan (74%), but neither agent blunted the accumulation of alveolar macrophages evoked by amiodarone (5.3-fold at 6 months). Lung neutrophil content was unchanged by amiodarone treatment for three weeks or six months. These results indicate that amiodarone induces alveolar epithelial cell apoptosis in vivo that is inhibitable by angiotensin antagonists. They also support the hypothesis that blockade of angiotensin formation or function attenuates amiodarone-induced lung fibrosis irrespective of the severity of alveolitis.
Department of Physiology, Michigan State University, East Lansing, Michigan 48824, USA. uhal@msu.edu
Bruce D
BD
Uhal
Rongqi
R
Wang
Jeremy
J
Laukka
Jiaju
J
Zhuang
Valerie
V
Soledad-Conrad
Gerasimos
G
Filippatos
D000638:Amiodarone / Q000009:adverse effects*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology*; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D019808:Losartan / Q000494:pharmacology; D008168:Lung / Q000473:pathology*; D008297:Male; D011650:Pulmonary Alveoli / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000889:Anti-Arrhythmia Agents; D002216:Captopril; D019808:Losartan; D000638:Amiodarone