Impact of adrenomedullin on dextran sulfate sodium-induced inflammatory colitis in mice: insights from in vitro and in vivo experimental studies

Hayashi, Yoshiaki; Narumi, Kenta; Tsuji, Shigetsugu; Tsubokawa, Toshinari; Nakaya, Muneo; Wakayama, Tomohiko; Zuka, Masahiko; Ohshima, Tohru; Yamagishi, Masakazu; Okada, Toshihide

doi:10.1007/s00384-011-1254-0

Cited by 31 publications

(31 citation statements)

References 41 publications

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“…Some of the reported activities of ADM include suppression of certain proinflammatory cytokine production and release (16), antimicrobial effects (56), and enforcement of endothelial barrier function (49). These lines of evidence are consistent with the conjecture that intestinal ADM release via epithelial TRPA1 stimulation is involved in the maintenance and protection of gut functions.…”

Section: G433supporting

confidence: 70%

Epithelial transient receptor potential ankyrin 1 (TRPA1)-dependent adrenomedullin upregulates blood flow in rat small intestine

Kono

Kaneko

Omiya

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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. TU-100 contains multiple TRP activators. In the present study, therefore, we examined the involvement of TRP channels in the ADM-mediated vasodilatatory effect of TU-100. Rats were treated intraduodenally with the TRP vanilloid type 1 (TRPV1) agonist capsaicin (CAP), the TRP ankyrin 1 (TRPA1) agonist allyl-isothiocyanate (AITC), or TU-100, and jejunum IBF was evaluated using laser-Doppler blood flowmetry. All three compounds resulted in vasodilatation, and the vasodilatory effect of TU-100 was abolished by a TRPA1 antagonist but not by a TRPV1 antagonist. Vasodilatation induced by AITC and TU-100 was abrogated by anti-ADM antibody treatment. RT-PCR and flow cytometry revealed that an IEC-6 cell line originated from the small intestine and purified IE cells expressed ADM and TRPA1 but not TRPV1. AITC increased ADM release in IEC cells remarkably, while CAP had no effect. TU-100 and its ingredient 6-shogaol (6SG) increased ADM release dose-dependently, and the effects were abrogated by a TRPA1 antagonist. 6SG showed similar TRPA1-dependent vasodilatation in vivo. These results indicate that TRPA1 in IE cells may play an important role in controlling bowel microcirculation via ADM release. Epithelial TRPA1 appears to be a promising target for the development of novel strategies for the treatment of various gastrointestinal disorders.daikenchuto; TU-100; vasodilatation; 6-shogaol; inflammatory bowel diseases TRANSIENT RECEPTOR POTENTIAL (TRP) channels are nonselective calcium ion channels ubiquitously expressed in many tissues and are known to participate in a broad range of physical, chemical, and environmental stimuli such as taste, temperature, changes in osmolarity, pressure, stretch, and light.

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Section: G433supporting

confidence: 70%

Epithelial transient receptor potential ankyrin 1 (TRPA1)-dependent adrenomedullin upregulates blood flow in rat small intestine

Kono

Kaneko

Omiya

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The height of the mucosa and the submucosa were used as a surrogate measure of inflammation. In addition, tissues were scored using the histopathological colitis scoring method, as described (Hayashi et al, 2011). …”

Section: Methodsmentioning

confidence: 99%

Lack of Adrenomedullin Results in Microbiota Changes and Aggravates Azoxymethane and Dextran Sulfate Sodium-Induced Colitis in Mice

et al. 2016

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The link between intestinal inflammation, microbiota, and colorectal cancer is intriguing and the potential underlying mechanisms remain unknown. Here we evaluate the influence of adrenomedullin (AM) in microbiota composition and its impact on colitis with an inducible knockout (KO) mouse model for AM. Microbiota composition was analyzed in KO and wild type (WT) mice by massive sequencing. Colitis was induced in mice by administration of azoxymethane (AOM) followed by dextran sulfate sodium (DSS) in the drinking water. Colitis was evaluated using a clinical symptoms index, histopathological analyses, and qRT-PCR. Abrogation of the adm gene in the whole body was confirmed by PCR and qRT-PCR. KO mice exhibit significant changes in colonic microbiota: higher proportion of δ-Proteobacteria class; of Coriobacteriales order; and of other families and genera was observed in KO feces. Meanwhile these mice had a lower proportion of beneficial bacteria, such as Lactobacillus gasseri and Bifidobacterium choerinum. TLR4 gene expression was higher (p < 0.05) in KO animals. AM deficient mice treated with DSS exhibited a significantly worse colitis with profound weight loss, severe diarrhea, rectal bleeding, colonic inflammation, edema, infiltration, crypt destruction, and higher levels of pro-inflammatory cytokines. No changes were observed in the expression levels of adhesion molecules. In conclusion, we have shown that lack of AM leads to changes in gut microbiota population and in a worsening of colitis conditions, suggesting that endogenous AM is a protective mediator in this pathology.

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“…23) Cardiac hypertrophy and fibrosis were observed in AM KO heterozygotes when subjected to cardiovascular stress. 24,25) Exogenous AM administration resulted in reduction of inflammation 26,27) and enhancement of wound healing 28) in mouse models. In human acute heart failure, AM enhances recuperation from cardiac damage.…”

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confidence: 99%

Effects of Adrenomedullin on Doxorubicin-Induced Cardiac Damage in Mice

Yoshizawa

Takizawa

Shimada

et al. 2016

Biological & Pharmaceutical Bulletin

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Doxorubicin (DOX) is one of the best known anticancer drugs, and is used in the treatment of lymphoma, lung cancer, stomach cancer, and a number of other cancers. However, DOX has some serious side effects, the worst being lethal heart failure. Occasionally, its side effects result in the cessation of the anticancer treatment, thus having a serious adverse influence on prognosis. Agents that can be administered as alternative prophylactics or to ameliorate the side effects of DOX will be useful in increasing the safety and efficacy of anticancer therapy. Adrenomedullin (AM) is a peptide hormone secreted by many organs, including the heart; it has an organ-protective effect, including antiapoptotic, anti-inflammatory, and antioxidative stress. Blood AM levels increase with heart failure; endogenic AM has been suggested in order to protect the heart. Furthermore, exogenous AM administration has shown therapeutic effects for heart failure in patients. However, it is unclear whether AM can protect the heart against drug-induced cardiac injury in vivo. The present study was performed in order to investigate the effects of AM on DOX-induced cardiac damage. Male BALB/c mice were treated with DOX and/or AM. Exogenous AM improved the survival ratio of DOXtreated mice. In addition, AM reduced serum lactate dehydrogenase (LDH) levels following DOX treatment. On pathological examination, AM was shown to inhibit DOX-induced cardiac tissue damage, mitochondrial abnormality, and cell death. These findings suggest that AM has a protective effect against DOX-induced cardiac damage.

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Impact of adrenomedullin on dextran sulfate sodium-induced inflammatory colitis in mice: insights from in vitro and in vivo experimental studies

Abstract: These results demonstrate that AM could ameliorate DSS-induced experimental colitis possibly through suppression of systemic and local production of cytokines such as TNF-α, associated with acceleration of ulcer reepithelialization and colon tissue regeneration.

Cited by 31 publications

References 41 publications

Epithelial transient receptor potential ankyrin 1 (TRPA1)-dependent adrenomedullin upregulates blood flow in rat small intestine

Epithelial transient receptor potential ankyrin 1 (TRPA1)-dependent adrenomedullin upregulates blood flow in rat small intestine

Lack of Adrenomedullin Results in Microbiota Changes and Aggravates Azoxymethane and Dextran Sulfate Sodium-Induced Colitis in Mice

Effects of Adrenomedullin on Doxorubicin-Induced Cardiac Damage in Mice

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