Indomethacin can induce cell death in rat gastric parietal cells through alteration of some apoptosis- and autophagy-associated molecules
| Autor: | Usama M. Abdelaal, Hoda M. Elsayed, Masa-Aki Shibata, Sahar M. Gebril, Mahmoud R. Hussein, Kazuhide Higuchi, Eman E. Abu-Dief, Yuko Ito, Kentaro Maemura, Yoshinori Otsuki |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Male
Programmed cell death Indomethacin Apoptosis Caspase 8 Cathepsin B Pathology and Forensic Medicine Rats Sprague-Dawley Parietal Cells Gastric Gastric mucosa medicine Autophagy Animals Molecular Biology Caspase TUNEL assay biology Cell Death Chemistry Anti-Inflammatory Agents Non-Steroidal Cell Biology Original Articles Rats medicine.anatomical_structure Gastric Mucosa Caspases Cancer research biology.protein DNA Damage Signal Transduction |
| Zdroj: | Int J Exp Pathol |
| ISSN: | 1365-2613 |
| Popis: | In clinical medicine, indomethacin (IND, a non‐steroidal anti‐inflammatory drug) is used variously in the treatment of severe osteoarthritis, rheumatoid arthritis, gouty arthritis or ankylosing spondylitis. A common complication found alongside the therapeutic characteristics is gastric mucosal damage. This complication is mediated through apoptosis and autophagy of the gastrointestinal mucosal epithelium. Apoptosis and autophagy are critical homeostatic pathways catalysed by caspases downstream of the gastrointestinal mucosal epithelial injury. Both act through molecular signalling pathways characterized by the initiation, mediation, execution and regulation of the cell regulatory cycle. In this study we hypothesized that dysregulated apoptosis and autophagy are associated with IND‐induced gastric damage. We examined the spectra of in vivo experimental gastric ulcers in male Sprague‐Dawley rats through gastric gavage of IND. Following an 18‐hour fast, IND was administered to experimental rats. They were sacrificed at 3‐, 6‐ and 12‐hour intervals. Parietal cells (H(+), K(+)‐ATPase β‐subunit assay) and apoptosis (TUNEL assay) were determined. The expression of apoptosis‐signalling caspase (caspases 3, 8, 9 and 12), DNA damage (anti–phospho‐histone H2A.X) and autophagy (MAP‐LC3, LAMP‐1 and cathepsin B)‐related molecules in gastric mucosal cells was examined. The administration of IND was associated with gastric mucosal erosions and ulcerations mainly involving the gastric parietal cells (PCs) of the isthmic and upper neck regions and a time‐dependent gradual increase in the number of apoptotic PCs with the induction of both apoptotic (upregulation of caspases 3 and 8) cell death and autophagic (MAP‐LC3‐II, LAMP‐1 and cathepsin B) cell death. Autophagy induced by fasting and IND 3 hours initially prompted the degradation of caspase 8. After 6 and 12 hours, damping down of autophagic activity occurred, resulting in the upregulation of active caspase 8 and its nuclear translocation. In conclusion we report that IND can induce time‐dependent apoptotic and autophagic cell death of PCs. Our study provides the first indication of the interactions between these two homeostatic pathways in this context. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text