HSP70 confers protection against indomethacin-induced lesions of the small intestine

Teita Asano, Ken Ichiro Tanaka, Naoki Yamakawa, Hiroaki Adachi, Gen Sobue, Hidemi Goto, Koji Takeuchi, Tohru Mizushima

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

In line with improvements in diagnostic procedures to detect intestinal lesions, it has become clear that nonsteroidal antiinflammatory drugs (NSAIDs) such as indomethacin induce lesions not only in the stomach but also in the small intestine. However, clinical protocols for the treatment of NSAID-induced lesions of the small intestine have not been established. It is known that heat shock proteins (HSPs), particularly HSP70, confer protection against various stressors, and more recently, the anti-inflammatory activity of HSP70 was revealed. In this study, we examined the effect of expression of HSP70 on indomethacin-induced lesions of the small intestine. The extent of indomethacin-induced lesions to the small intestine was reduced in transgenic mice expressing HSP70 compared with controls. Oral administration of indomethacin increased the expression of HSP70 in the small intestine. Administration of indomethacin also induced mucosal cell apoptosis and expression of proinflammatory cytokines in the small intestines of control mice, with both of these responses suppressed in the transgenic mice. Geranylgeranylacetone (GGA), a clinically used antiulcer drug, increased expression of HSP70 in the small intestine and suppressed indomethacin-induced lesions of the small intestines in wild-type mice. These results suggest that indomethacin-induced increase in HSP70 expression reduces the extent of lesions to the small intestine by suppressing mucosal cell apoptosis and inflammatory responses. The HSP-inducing activity of GGA seems to contribute to the protective effect of drug against the lesions. Based on these results, we propose that nontoxic HSP70-inducers, such as GGA, would be therapeutically beneficial for treating NSAID-induced lesions of the small intestine.

Original languageEnglish
Pages (from-to)458-467
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume330
Issue number2
DOIs
Publication statusPublished - 2009 Aug
Externally publishedYes

Fingerprint

Indomethacin
Small Intestine
geranylgeranylacetone
Anti-Inflammatory Agents
Pharmaceutical Preparations
Transgenic Mice
Protective Agents
HSP70 Heat-Shock Proteins
Clinical Protocols
Heat-Shock Proteins
Oral Administration
Stomach
Apoptosis
Cytokines

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Asano, T., Tanaka, K. I., Yamakawa, N., Adachi, H., Sobue, G., Goto, H., ... Mizushima, T. (2009). HSP70 confers protection against indomethacin-induced lesions of the small intestine. Journal of Pharmacology and Experimental Therapeutics, 330(2), 458-467. https://doi.org/10.1124/jpet.109.152181

HSP70 confers protection against indomethacin-induced lesions of the small intestine. / Asano, Teita; Tanaka, Ken Ichiro; Yamakawa, Naoki; Adachi, Hiroaki; Sobue, Gen; Goto, Hidemi; Takeuchi, Koji; Mizushima, Tohru.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 330, No. 2, 08.2009, p. 458-467.

Research output: Contribution to journalArticle

Asano, T, Tanaka, KI, Yamakawa, N, Adachi, H, Sobue, G, Goto, H, Takeuchi, K & Mizushima, T 2009, 'HSP70 confers protection against indomethacin-induced lesions of the small intestine', Journal of Pharmacology and Experimental Therapeutics, vol. 330, no. 2, pp. 458-467. https://doi.org/10.1124/jpet.109.152181
Asano, Teita ; Tanaka, Ken Ichiro ; Yamakawa, Naoki ; Adachi, Hiroaki ; Sobue, Gen ; Goto, Hidemi ; Takeuchi, Koji ; Mizushima, Tohru. / HSP70 confers protection against indomethacin-induced lesions of the small intestine. In: Journal of Pharmacology and Experimental Therapeutics. 2009 ; Vol. 330, No. 2. pp. 458-467.
@article{31d82c0a3bdc4e3aa538a089774970a1,
title = "HSP70 confers protection against indomethacin-induced lesions of the small intestine",
abstract = "In line with improvements in diagnostic procedures to detect intestinal lesions, it has become clear that nonsteroidal antiinflammatory drugs (NSAIDs) such as indomethacin induce lesions not only in the stomach but also in the small intestine. However, clinical protocols for the treatment of NSAID-induced lesions of the small intestine have not been established. It is known that heat shock proteins (HSPs), particularly HSP70, confer protection against various stressors, and more recently, the anti-inflammatory activity of HSP70 was revealed. In this study, we examined the effect of expression of HSP70 on indomethacin-induced lesions of the small intestine. The extent of indomethacin-induced lesions to the small intestine was reduced in transgenic mice expressing HSP70 compared with controls. Oral administration of indomethacin increased the expression of HSP70 in the small intestine. Administration of indomethacin also induced mucosal cell apoptosis and expression of proinflammatory cytokines in the small intestines of control mice, with both of these responses suppressed in the transgenic mice. Geranylgeranylacetone (GGA), a clinically used antiulcer drug, increased expression of HSP70 in the small intestine and suppressed indomethacin-induced lesions of the small intestines in wild-type mice. These results suggest that indomethacin-induced increase in HSP70 expression reduces the extent of lesions to the small intestine by suppressing mucosal cell apoptosis and inflammatory responses. The HSP-inducing activity of GGA seems to contribute to the protective effect of drug against the lesions. Based on these results, we propose that nontoxic HSP70-inducers, such as GGA, would be therapeutically beneficial for treating NSAID-induced lesions of the small intestine.",
author = "Teita Asano and Tanaka, {Ken Ichiro} and Naoki Yamakawa and Hiroaki Adachi and Gen Sobue and Hidemi Goto and Koji Takeuchi and Tohru Mizushima",
year = "2009",
month = "8",
doi = "10.1124/jpet.109.152181",
language = "English",
volume = "330",
pages = "458--467",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - HSP70 confers protection against indomethacin-induced lesions of the small intestine

AU - Asano, Teita

AU - Tanaka, Ken Ichiro

AU - Yamakawa, Naoki

AU - Adachi, Hiroaki

AU - Sobue, Gen

AU - Goto, Hidemi

AU - Takeuchi, Koji

AU - Mizushima, Tohru

PY - 2009/8

Y1 - 2009/8

N2 - In line with improvements in diagnostic procedures to detect intestinal lesions, it has become clear that nonsteroidal antiinflammatory drugs (NSAIDs) such as indomethacin induce lesions not only in the stomach but also in the small intestine. However, clinical protocols for the treatment of NSAID-induced lesions of the small intestine have not been established. It is known that heat shock proteins (HSPs), particularly HSP70, confer protection against various stressors, and more recently, the anti-inflammatory activity of HSP70 was revealed. In this study, we examined the effect of expression of HSP70 on indomethacin-induced lesions of the small intestine. The extent of indomethacin-induced lesions to the small intestine was reduced in transgenic mice expressing HSP70 compared with controls. Oral administration of indomethacin increased the expression of HSP70 in the small intestine. Administration of indomethacin also induced mucosal cell apoptosis and expression of proinflammatory cytokines in the small intestines of control mice, with both of these responses suppressed in the transgenic mice. Geranylgeranylacetone (GGA), a clinically used antiulcer drug, increased expression of HSP70 in the small intestine and suppressed indomethacin-induced lesions of the small intestines in wild-type mice. These results suggest that indomethacin-induced increase in HSP70 expression reduces the extent of lesions to the small intestine by suppressing mucosal cell apoptosis and inflammatory responses. The HSP-inducing activity of GGA seems to contribute to the protective effect of drug against the lesions. Based on these results, we propose that nontoxic HSP70-inducers, such as GGA, would be therapeutically beneficial for treating NSAID-induced lesions of the small intestine.

AB - In line with improvements in diagnostic procedures to detect intestinal lesions, it has become clear that nonsteroidal antiinflammatory drugs (NSAIDs) such as indomethacin induce lesions not only in the stomach but also in the small intestine. However, clinical protocols for the treatment of NSAID-induced lesions of the small intestine have not been established. It is known that heat shock proteins (HSPs), particularly HSP70, confer protection against various stressors, and more recently, the anti-inflammatory activity of HSP70 was revealed. In this study, we examined the effect of expression of HSP70 on indomethacin-induced lesions of the small intestine. The extent of indomethacin-induced lesions to the small intestine was reduced in transgenic mice expressing HSP70 compared with controls. Oral administration of indomethacin increased the expression of HSP70 in the small intestine. Administration of indomethacin also induced mucosal cell apoptosis and expression of proinflammatory cytokines in the small intestines of control mice, with both of these responses suppressed in the transgenic mice. Geranylgeranylacetone (GGA), a clinically used antiulcer drug, increased expression of HSP70 in the small intestine and suppressed indomethacin-induced lesions of the small intestines in wild-type mice. These results suggest that indomethacin-induced increase in HSP70 expression reduces the extent of lesions to the small intestine by suppressing mucosal cell apoptosis and inflammatory responses. The HSP-inducing activity of GGA seems to contribute to the protective effect of drug against the lesions. Based on these results, we propose that nontoxic HSP70-inducers, such as GGA, would be therapeutically beneficial for treating NSAID-induced lesions of the small intestine.

UR - http://www.scopus.com/inward/record.url?scp=67651024137&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67651024137&partnerID=8YFLogxK

U2 - 10.1124/jpet.109.152181

DO - 10.1124/jpet.109.152181

M3 - Article

VL - 330

SP - 458

EP - 467

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

ER -