Mechanistic Insight into the Development of TNBS-Mediated Intestinal Fibrosis and Evaluating the Inhibitory Effects of Rapamycin

Mathur, Ramkumar; Alam, Mahabub Maraj; Zhao, Xiaofeng; Huang, Yunfei; Zhu, Xingen

doi:10.3791/60067

Cited by 3 publications

(1 citation statement)

References 14 publications

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“…Given that colon fibrosis and intestinal inflammation often occur together in IBD patients, it is believed that fibrosis is caused by the chronic inflammation of colon cells and delayed colonic healing ( 7 ). The injured colon tissue is recovered through the healing program of the intestine under normal conditions; but if the damage is uncontrolled, it may lead to chronic colon inflammation, together with permanent injury and continuous repair cycle, and eventually intestinal fibrosis ( 10 , 11 ).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Targeting of Nrf2 Signaling by Maggot Extracts Ameliorates Inflammation-Associated Intestinal Fibrosis in Chronic DSS-Induced Colitis

Wang

et al. 2021

Front. Immunol.

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Intestinal fibrosis is induced by excessive myofibroblast proliferation and collagen deposition, which has been regarded as a general pathological feature in inflammatory bowel disease (IBD). Therefore, identifying clinical markers and targets to treat and prevent intestinal fibrosis is urgently needed. The traditional Chinese medicine maggot, commonly known as “wu gu chong”, has been shown to reduce oxidative stress and alleviate inflammation in chronic colitis. This study investigated the mechanisms underlying the effects of maggot extract (ME) on inflammation-associated intestinal fibrosis in TGF-β1-stimulated human intestinal fibroblasts (CCD-18Co cells) and dextran sodium sulphate (DSS)-induced chronic colitis murine model. To assess the severity of inflammation and fibrosis, histological and macroscopic evaluation were carried out. The results showed that ME was a significant inhibitor of body weight loss and colon length shortening in mice with chronic colitis. In addition, ME suppressed the intestinal fibrosis by downregulating TGF-β1/SMADs pathway via upregulation of Nrf2 expression at both protein and mRNA levels. ME markedly increased the expression of Nrf2, thus resulting in a higher level of HO-1. After treatment with Nrf2 inhibitor (ML385) or siRNA-Nrf2 for deactivating Nrf2 pathway, the protective effects of ME were abolished both in vitro and in vivo. Moreover, the histopathological results for the major organs of DSS mice treated with ME showed no signs of clinically important abnormalities. Treatment with ME had no effect on the viability of CCD-18Co cells, suggesting its low in vitro cytotoxicity. Furthermore, ME could mediate intestine health by keeping the balance of the gut microbes through the enhancement of beneficial microbes and suppression of pathogenic microbes. In conclusion, this is the first ever report demonstrating that ME ameliorates inflammation-associated intestinal fibrosis by suppressing TGF-β1/SMAD pathway via upregulation of Nrf2 expression. Our findings highlight the potential of Nrf2 as an effective therapeutic target for alleviating intestinal fibrosis.

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Section: Introductionmentioning

confidence: 99%

Therapeutic Targeting of Nrf2 Signaling by Maggot Extracts Ameliorates Inflammation-Associated Intestinal Fibrosis in Chronic DSS-Induced Colitis

Wang

et al. 2021

Front. Immunol.

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Targeting Pathogenic Inflammation for Therapeutic Intervention Against Colon Cancer

Fleecs

Abrham

Kuntz

et al. 2022

Colon Cancer Diagnosis and Therapy Vol. 3

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Inhibition of Fibrotic Contraction by Sirolimus (Rapamycin) in an Ex Vivo Model of Thyroid Eye Disease

Roos

Eglitis

Murthy

2020

Ophthalmic Plastic &Amp; Reconstructive Surgery

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Background: Thyroid eye disease (TED) is characterized by orbital inflammation and complicated by extraocular muscle fibrosis. Treatment with rapamycin/sirolimus has been reported to improve ocular motility and disease manifestations in TED. Whether this resulted from a primary antifibrotic effect on fibroblasts or was secondary to immune-suppression is unclear. Methods: In vitro contractility studies of primary orbital fibroblasts. Cells from patients with TED and controls were treated with rapamycin [mechanistic target of rapamycin an (mTOR) inhibitor] and MHY1485 (an mTOR stimulator) as well as inhibitors upstream in the same signaling cascade (saracatinib and befatinib). Results: At concentrations consistent with the therapeutic dosing range in humans, rapamycin/sirolimus significantly reduces fibrosis in orbital fibroblasts from TED patients and controls in vitro. This effect is separate from, and in addition to, its immune suppressive effect. mTOR-driven fibrotic activity is greater in TED-derived fibroblasts and can be blocked also upstream of mTOR by inhibition of src. There was no adverse effect on cell survival. Conclusion: The authors present evidence for a direct antifibrotic effect of rapamycin/sirolimus in primary orbital fibroblasts. Targeting mTOR signaling presents a further and adjunctive treatment of TED alongside other immune-suppressive agents. By acting downstream of IGF1-R, sirolimus may offer a cost-effective alternative to teprotumumab therapy. Clinical case reports, now supplemented by this in vitro evidence, support the initiation of a clinical trial to treat the fibrotic sequelae of TED with this already-approved agent. Such an “off-the-shelf” therapy is a welcome prospect for TED treatment, particularly one available at a low price.

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Mechanistic Insight into the Development of TNBS-Mediated Intestinal Fibrosis and Evaluating the Inhibitory Effects of Rapamycin

Cited by 3 publications

References 14 publications

Therapeutic Targeting of Nrf2 Signaling by Maggot Extracts Ameliorates Inflammation-Associated Intestinal Fibrosis in Chronic DSS-Induced Colitis

Therapeutic Targeting of Nrf2 Signaling by Maggot Extracts Ameliorates Inflammation-Associated Intestinal Fibrosis in Chronic DSS-Induced Colitis

Targeting Pathogenic Inflammation for Therapeutic Intervention Against Colon Cancer

Inhibition of Fibrotic Contraction by Sirolimus (Rapamycin) in an Ex Vivo Model of Thyroid Eye Disease

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