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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Autophagy Deficiency Diminishes Indomethacin-Induced Intestinal Epithelial Cell Damage through Activation of the ERK/Nrf2/HO-1 Pathway

Satoshi Harada, Takatoshi Nakagawa, Shunichi Yokoe, Shoko Edogawa, Toshihisa Takeuchi, Takuya Inoue, Kazuhide Higuchi and Michio Asahi
Journal of Pharmacology and Experimental Therapeutics December 2015, 355 (3) 353-361; DOI: https://doi.org/10.1124/jpet.115.226431
Satoshi Harada
Departments of Internal Medicine II (S.H., S.E., T.T., T.I., K.H.) and Pharmacology (T.N., S.Y., M.A.), Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
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Takatoshi Nakagawa
Departments of Internal Medicine II (S.H., S.E., T.T., T.I., K.H.) and Pharmacology (T.N., S.Y., M.A.), Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
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Shunichi Yokoe
Departments of Internal Medicine II (S.H., S.E., T.T., T.I., K.H.) and Pharmacology (T.N., S.Y., M.A.), Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
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Shoko Edogawa
Departments of Internal Medicine II (S.H., S.E., T.T., T.I., K.H.) and Pharmacology (T.N., S.Y., M.A.), Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
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Toshihisa Takeuchi
Departments of Internal Medicine II (S.H., S.E., T.T., T.I., K.H.) and Pharmacology (T.N., S.Y., M.A.), Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
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Takuya Inoue
Departments of Internal Medicine II (S.H., S.E., T.T., T.I., K.H.) and Pharmacology (T.N., S.Y., M.A.), Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
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Kazuhide Higuchi
Departments of Internal Medicine II (S.H., S.E., T.T., T.I., K.H.) and Pharmacology (T.N., S.Y., M.A.), Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
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Michio Asahi
Departments of Internal Medicine II (S.H., S.E., T.T., T.I., K.H.) and Pharmacology (T.N., S.Y., M.A.), Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka, Japan
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Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause epithelial cell damage in the stomach, intestine, and colon. NSAIDs are reported to induce autophagy and apoptosis in intestinal epithelial cells; however, their role in cell damage is poorly understood. To examine the role of autophagy in cell damage, we used autophagy-related gene Atg5-conditional knockout mice, in which the Atg5 gene is only knocked out in intestinal epithelial cells. In an indomethacin (IM)–induced gastrointestinal ulcer mouse model, intestinal epithelium damage was reduced in Atg5-conditional knockout mice compared with wild-type mice. IM-induced damage in IEC6 rat intestinal epithelial cells was reduced when Atg5 was silenced (IEC6shAtg5 cells). Western blot analyses indicated that IM-induced apoptosis decreased, and the potent, oxidative stress–related extracellular signal–regulated kinase (ERK)/nuclear factor-erythroid2-like2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway was upregulated in IEC6shAtg5 cells. An experiment using a reactive oxygen species (ROS)-sensitive fluorescent dye in IEC6shAtg5 cells revealed that the amount of ROS at the baseline and the rate of increase after IM treatment were lower than in intact IEC6 cells. The mitochondrial membrane potential at the baseline and the reduction rate in IM-treated IEC6shAtg5 cells were lower than in intact IEC6 cells, indicating that autophagy deficiency increased ROS production caused by mitochondrial disturbance. Furthermore, MnTMPyP, a manganese–superoxide dismutase mimetic, significantly inhibited IM-induced autophagy and subsequent apoptosis as well as activation of the ERK/Nrf2/HO-1 pathway. These data suggest that autophagy deficiency and subsequent activation of the ERK/Nrf2/HO-1 pathway diminished IM-induced, apoptosis-mediated intestinal epithelial cell damage, and genetic analyses of single nucleotide polymorphisms in autophagy-related genes could predict NSAID-induced intestinal injury.

Footnotes

    • Received June 2, 2015.
    • Accepted September 23, 2015.
  • This research was supported in part by the Japan Society for the Promotion of Science [Grant-in-Aid for Scientific Research (C) 25460397 (to M.A.)] and the Ministry of Education, Science, Culture, Sports and Technology of Japan.

  • dx.doi.org/10.1124/jpet.115.226431.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 355 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 355, Issue 3
1 Dec 2015
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Amelioration of Indomethacin-Induced Injury by Autophagy Deficiency

Satoshi Harada, Takatoshi Nakagawa, Shunichi Yokoe, Shoko Edogawa, Toshihisa Takeuchi, Takuya Inoue, Kazuhide Higuchi and Michio Asahi
Journal of Pharmacology and Experimental Therapeutics December 1, 2015, 355 (3) 353-361; DOI: https://doi.org/10.1124/jpet.115.226431

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Amelioration of Indomethacin-Induced Injury by Autophagy Deficiency

Satoshi Harada, Takatoshi Nakagawa, Shunichi Yokoe, Shoko Edogawa, Toshihisa Takeuchi, Takuya Inoue, Kazuhide Higuchi and Michio Asahi
Journal of Pharmacology and Experimental Therapeutics December 1, 2015, 355 (3) 353-361; DOI: https://doi.org/10.1124/jpet.115.226431
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