Urocortin Prevents Indomethacin-Induced Small Intestinal Lesions in Rats Through Activation of CRF2 Receptors

Kubo, Yoshikazu; Kumano, Aiko; Kamei, Kohei; Amagase, Kikuko; Abe, Naoko; Takeuchi, Koji

doi:10.1007/s10620-009-0930-1

Cited by 14 publications

(21 citation statements)

References 53 publications

(94 reference statements)

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“…Ucn1 binds with equal affinities to both CRF 1 and CRF 2 , but binds with a ten-fold higher affinity to CRF 1 than to CRF (15). Others and we have shown that Ucn1 and CRF 2 are required for normal resolution of GI inflammatory diseases like colitis (9,13,14,16,17). The lack of CRF 2 in the GI tract leads to increased inflammation and delayed healing (9,13,18), perpetuating the insult.…”

Section: Introductionmentioning

confidence: 67%

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Corticotropin-releasing Factor Receptor 2 Mediates Sex-Specific Cellular Stress Responses

Kubat

Mahajan

Liao

et al. 2013

Mol Med

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Although females suffer twice as much as males from stress-related disorders, sex-specific participating and pathogenic cellular stress mechanisms remain uncharacterized. Using corticotropin-releasing factor receptor 2-deficient (Crhr2−/−) and wild-type (WT) mice, we show that CRF receptor type 2 (CRF2) and its high-affinity ligand, urocortin 1 (Ucn1), are key mediators of the endoplasmic reticulum (ER) stress response in a murine model of acute pancreatic inflammation. Ucn1 was expressed de novo in acinar cells of male, but not female WT mice during acute inflammation. Upon insult, acinar Ucn1 induction was markedly attenuated in male but not female Crhr2r−/− mice. Crhr2−/− mice of both sexes show exacerbated acinar cell inflammation and necrosis. Electron microscopy showed mild ER damage in WT male mice and markedly distorted ER structure in Crhr2−/− male mice during pancreatitis. WT and Crhr2−/− female mice showed similarly distorted ER ultrastructure that was less severe than distortion seen in Crhr2−/− male mice. Damage in ER structure was accompanied by increased ubiquitination, peIF2, and mis-targeted localization of vimentin in WT mice that was further exacerbated in Crhr2−/− mice of both sexes during pancreatitis. Exogenous Ucn1 rescued many aspects of histological damage and cellular stress response, including restoration of ER structure in male WT and Crhr2−/− mice, but not in females. Instead, females often showed increased damage. Thus, specific cellular pathways involved in coping and resolution seem to be distinct to each sex. Our results demonstrate the importance of identifying sex-specific pathogenic mechanisms and their value in designing effective therapeutics.

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Section: Introductionmentioning

confidence: 67%

“…Others and we have shown that Ucn1 and CRF 2 are required for resolution of GI inflammatory diseases like gastritis and colitis (9,13,14,16,17,31,49). Loss of CRF 2 leads to increased inflammation, delayed healing, and exacerbates the inflammatory insult (9,18,43).…”

Section: Discussionmentioning

confidence: 87%

Corticotropin-releasing Factor Receptor 2 Mediates Sex-Specific Cellular Stress Responses

Kubat

Mahajan

Liao

et al. 2013

Mol Med

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“…The intestinal ulcerogenic response to indomethacin was also found to be suppressed by urocortin I, a nonselective corticotropin-releasing factor receptor (CRFR) agonist, and aggravated by astressin, a nonselective CRFR antagonist [47]. Furthermore, the protective effects of urocortin I were reversed by astressin-2B (a CRFR2 antagonist), but not by NBI-27914 (a CRFR1 antagonist).…”

Section: Effects Of Various Drugs On Nsaid-induced Small Intestinal Dmentioning

confidence: 99%

NSAID-Induced Small Intestinal Damage - Roles of Various Pathogenic Factors

Takeuchi

Satoh²

2015

Digestion

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Background/Aims: NSAID-induced enteropathy has been the focus of recent basic and clinical research subsequent to the development of the capsule endoscope and double-balloon endoscope. We review the possible pathogenic mechanisms underlying NSAID-induced enteropathy and discuss the role of the inhibition of COX-1/COX-2 and the influences of food as well as various prophylactic treatments on these lesions. Methods: Studies were performed in experimental animals. Results: Multiple factors, such as intestinal hypermotility, decreased mucus secretion, enterobacteria, and upregulation of iNOS/NO expression, are involved in the pathogenesis of NSAID-induced enteropathy, in addition to the decreased production of PGs due to the inhibition of COX. Enterobacterial invasion is the most important pathogenic event, and intestinal hypermotility, which was associated with this event, is essential for the development of these lesions. NSAIDs also upregulate the expression of COX-2, and the inhibition of both COX-1 and COX-2 is required for the intestinal ulcerogenic properties of NSAIDs to manifest. NSAID-induced enteropathy is prevented by PGE₂, atropine, ampicillin, and aminoguanidine as well as soluble dietary fiber, and exacerbated by antisecretory drugs such as proton pump inhibitors. Conclusion: These findings on the pathogenesis of NSAID-induced enteropathy will be useful for the future development of intestinal-sparing alternatives to standard NSAIDs.

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“…CRF and CRF-related peptides are also involved in inflammatory responses in the intestine; however, their roles are not without controversy [ 12 - 16 ]. Kokkotou et al .…”

Section: Introuctionmentioning

confidence: 99%

Influence of Adrenalectomy on Protective Effects of Urocortin I, a Corticotropin-Releasing Factor, Against Indomethacin-Induced Enteropathy in Rats

Takeuchi¹,

Abe²,

Kumano³

2016

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We examined the influence of adrenalectomy on NSAID-induced small intestinal damage in rats and investigated the possible involvement of adrenal glucocorticoids in the protective effects of urocortin I, a corticotropin-releasing factor (CRF) agonist. Male SD rats without fasting were administered indomethacin s.c. and killed 24 h later in order to examine the hemorrhagic lesions that developed in the small intestine. Urocortin I (20 µg/kg) was given i.v. 10 min before the administration of indomethacin. Bilateral adrenalectomy was performed a week before the experiment. Indomethacin (10 mg/kg) caused multiple hemorrhagic lesions in the small intestine, which were accompanied by a decrease in mucus secretion and increases in intestinal motility, enterobacterial invasion, and iNOS expression. Adrenalectomy markedly increased the ulcerogenic and motility responses caused by indomethacin, with further enhancements in bacterial invasion and iNOS expression; severe lesions occurred at 3 mg/kg, a dose that did not induce any damage in sham-operated rats. This worsening effect was also observed by the pretreatment with mifepristone (a glucocorticoid receptor antagonist). Urocortin I prevented indomethacin-induced enteropathy, and this effect was completely abrogated by the pretreatment with astressin 2B, a CRF2 receptor antagonist, but was not significantly affected by either adrenalectomy or the mifepristone pretreatment. These results suggested that adrenalectomy aggravated the intestinal ulcerogenic response to indomethacin, the intestinal hypermotility response may be a key element in the mechanism for this aggravation, and endogenous glucocorticoids played a role in intestinal mucosal defense against indomethacin-induced enteropathy, but did not account for the protective effects of urocortin I, which were mediated by the activation of peripheral CRF2 receptors

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Urocortin Prevents Indomethacin-Induced Small Intestinal Lesions in Rats Through Activation of CRF2 Receptors

Cited by 14 publications

References 53 publications

Corticotropin-releasing Factor Receptor 2 Mediates Sex-Specific Cellular Stress Responses

Corticotropin-releasing Factor Receptor 2 Mediates Sex-Specific Cellular Stress Responses

NSAID-Induced Small Intestinal Damage - Roles of Various Pathogenic Factors

Influence of Adrenalectomy on Protective Effects of Urocortin I, a Corticotropin-Releasing Factor, Against Indomethacin-Induced Enteropathy in Rats

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