Amiodarone induces apoptosis of human and rat alveolar epithelial cells in vitro
| Autor: | Gerasimos Filippatos, Aleksandar Jankov, Raed Bargout, Erhan Dincer, Themis Komodromos, Olivia Ibarra-Sunga, Bruce D. Uhal, Rongqi Wang |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Male
Pulmonary and Respiratory Medicine medicine.medical_specialty Programmed cell death Captopril Lung Neoplasms Physiology Pulmonary toxicity Metabolite Amiodarone Angiotensin-Converting Enzyme Inhibitors Apoptosis Adenocarcinoma Cysteine Proteinase Inhibitors In Vitro Techniques Pharmacology Biology Amino Acid Chloromethyl Ketones Renin-Angiotensin System chemistry.chemical_compound Physiology (medical) Internal medicine Tumor Cells Cultured medicine Animals Humans Enzyme Inhibitors Rats Wistar Lung Dose-Response Relationship Drug Cytotoxins Epithelial Cells Cell Biology respiratory system In vitro Rats Pulmonary Alveoli medicine.anatomical_structure Endocrinology chemistry Hypot medicine.drug |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 278:L1039-L1044 |
| ISSN: | 1522-1504 1040-0605 |
| DOI: | 10.1152/ajplung.2000.278.5.l1039 |
| Popis: | The antiarrhythmic amiodarone (AM) and its metabolite desethylamiodarone (Des) are known to cause AM-induced pulmonary toxicity, but the mechanisms underlying this disorder remain unclear. We hypothesized that AM might cause AM-induced pulmonary toxicity in part through the induction of apoptosis or necrosis in alveolar epithelial cells (AECs). Two models of type II pneumocytes, the human AEC-derived A549 cell line and primary AECs isolated from adult Wistar rats, were incubated with AM or Des for 20 h. Apoptotic cells were determined by morphological assessment of nuclear fragmentation with propidium iodide on ethanol-fixed cells. Necrotic cells were quantitated by loss of dye exclusion. Both AM and Des caused dose-dependent necrosis starting at 2.5 and 0.1 μg/ml, respectively, in primary rat AECs and at 10 and 5 μg/ml in subconfluent A549 cells ( P < 0.05 and P < 0.01, respectively). AM and Des also induced dose-dependent apoptosis beginning at 2.5 μg/ml in the primary AECs ( P < 0.05 for both compounds) and at 10 and 5 μg/ml, respectively, in the A549 cell line ( P < 0.01). The two compounds also caused significant net cell loss (up to 80% over 20 h of incubation) by either cell type at drug concentrations near or below the therapeutic serum concentration for AM. The cell loss was not due to detachment but was blocked by the broad-spectrum caspase inhibitor Z-Val-Ala-Asp-fluoromethylketone. Furthermore, the angiotensin-converting enzyme inhibitor captopril (500 ng/ml) and the angiotensin-receptor antagonist saralasin (50 μg/ml) significantly inhibited both the induction of apoptosis and net cell loss in response to AM. These results are consistent with recent work from this laboratory demonstrating potent inhibition of apoptosis in human AECs by captopril (Uhal BD, Gidea C, Bargout R, Bifero A, Ibarra-Sunga O, Papp M, Flynn K, and Filippatos G. Am J Physiol Lung Cell Mol Physiol 275: L1013–L1017, 1998). They also suggested that the accumulation of AM and/or its primary metabolite Des in lung tissue may induce cytotoxicity of AECs that might be inhibitable by angiotensin-converting enzyme inhibitors or other antagonists of the renin-angiotensin system. |
| Databáze: | OpenAIRE |
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