title: Genetic ablation or pharmacologic inhibition of autophagy mitigated NSAID-associated gastric damages.
abstract: Non-steroidal anti-inflammatory drug (NSAID)-associated endoplasmic reticulum (ER) stress (a cyclooxygenase-2-independent mechanism) and consequent autophagic cell death are responsible for NSAID-associated gastric damage. Therefore, alleviating cytotoxicity executed via ER stress and autophagy can be a strategy to prevent NSAID-associated gastric damage. Here, we explored whether genetic or pharmacologic inhibition of autophagy can mitigate NSAID-associated gastric damage in in vitro and in vivo models. To examine the effects of genetic inhibition of NSAID-associated autophagy, we administered indomethacin to RGM1 gastric mucosal cells transfected with shPERK, siLC3B, or shATG5 and microtubule-associated protein light chain 3B knock-out (LC3B-/-) mice. 3-Methyladenine (3-MA) or chloroquine (CQ) was used for pharmacologic inhibition of autophagy in both models. Indomethacin administration increased the expression of ER stress proteins including GRP78, ATF6, and CHOP. Indomethacin provoked the appearance of autophagic vesicles with the increased expression of ATG5 and LC3B-II. Genetic ablation of various ER stress genes significantly attenuated indomethacin-induced autophagy and apoptosis (p < 0.01), whereas knock-down of either ATG5 or LC3B significantly reduced indomethacin-induced cytotoxicity (p < 0.01). Testing each of the genes implicated in ER stress and autophagy showed that indomethacin leads to gastric cell apoptosis through autophagy induction consequent to ER stress. Pharmacological inhibition of autophagy with either 3-MA or CQ in rats or genetic ablation of LC3B in mice all had a significant rescuing effect against indomethacin-associated gastric damage (p < 0.01) and a decrease in molecular markers of autophagic and apoptotic gastric cells. In conclusion, preemptive autophagy inhibition can be a potential strategy to mitigate NSAID-associated gastric damage.
  
  
  
  NSAID administration triggered ER stress and subsequent autophagy. Inhibition of autophagy resulted in attenuated NSAID-associated cytotoxicity. Autophagy inhibitors represent a novel strategy to prevent NSAID-associated gastric damage.
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, 110-744, South Korea.
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Ock
authors.affiliation: CHA Cancer Prevention Research Center, CHA Bio Complex and Digestive Disease Center, CHA University Bundang Medical Center, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea.
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Park
authors.affiliation: CHA Cancer Prevention Research Center, CHA Bio Complex and Digestive Disease Center, CHA University Bundang Medical Center, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea.
authors.forename: Young-Min
authors.initials: YM
authors.lastname: Han
authors.affiliation: CHA Cancer Prevention Research Center, CHA Bio Complex and Digestive Disease Center, CHA University Bundang Medical Center, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea.
authors.forename: Migyeong
authors.initials: M
authors.lastname: Jeong
authors.affiliation: Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, 460-740, South Korea.
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Kim
authors.affiliation: Laboratory of Chemoprevention, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 406-740, South Korea.
authors.forename: Ho Jae
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: CHA Cancer Prevention Research Center, CHA Bio Complex and Digestive Disease Center, CHA University Bundang Medical Center, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea. hahmkb@cha.ac.kr.|Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, 460-740, South Korea. hahmkb@cha.ac.kr.
authors.forename: Ki Baik
authors.initials: KB
authors.lastname: Hahm
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D002738:Chloroquine / Q000627:therapeutic use; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000009:adverse effects*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D020011:Protective Agents / Q000627:therapeutic use; D034622:RNA Interference; D000067492:RNAi Therapeutics; D011921:Rats, Inbred WKY; D013270:Stomach / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D020011:Protective Agents; C025946:3-methyladenine; D002738:Chloroquine; D000225:Adenine; D007213:Indomethacin
keywords: 3-MA; Apoptosis; Autophagy inhibition; Chloroquine; ER stress; Gastric damages; LC3B knock-out; NSAID; Rescue