Intestinal Fibrosis and Liver Fibrosis: Consequences of Chronic Inflammation or Independent Pathophysiology?

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Abstract

Background: Intestinal fibrosis and liver fibrosis represent a significant burden for our patients and health-care systems. Despite the severe clinical problem and the observation that fibrosis is reversible, no specific antifibrotic therapies exist. Summary: In this review, using an ‘East-West' scientific collaboration, we summarize the current knowledge on principal mechanisms shared by intestinal fibrosis and liver fibrosis. We furthermore discuss inflammation as the cause of fibrogenesis in both entities, depict unique features of intestinal and hepatic fibrosis, and provide a future outlook on the development of antifibrotic therapies. Key Messages: A collaborative effort in the field of fibrosis, covering multiple organ systems, will have the highest chance of leading to the development of a successful antifibrotic intervention.

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Most cited references 83

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Pathobiology of liver fibrosis: a translational success story.

Youngmin Lee, Michael Wallace, Scott Friedman (2015)

Reversibility of hepatic fibrosis and cirrhosis following antiviral therapy for hepatitis B or C has advanced the prospect of developing antifibrotic therapies for patients with chronic liver diseases, especially non-alcoholic steatohepatitis. Mechanisms of fibrosis have focused on hepatic stellate cells, which become fibrogenic myofibroblasts during injury through 'activation', and are at the nexus of efforts to define novel drug targets. Recent studies have clarified pathways of stellate cell gene regulation and epigenetics, emerging pathways of fibrosis regression through the recruitment and amplification of fibrolytic macrophages, nuanced responses of discrete inflammatory cell subsets and the identification of the 'ductular reaction' as a marker of severe injury and repair. Based on our expanded knowledge of fibrosis pathogenesis, attention is now directed towards strategies for antifibrotic therapies and regulatory challenges for conducting clinical trials with these agents. New therapies are attempting to: 1) Control or cure the primary disease or reduce tissue injury; 2) Target receptor-ligand interactions and intracellular signaling; 3) Inhibit fibrogenesis; and 4) Promote resolution of fibrosis. Progress is urgently needed in validating non-invasive markers of fibrosis progression and regression that can supplant biopsy and shorten the duration of clinical trials. Both scientific and clinical challenges remain, however the past three decades of steady progress in understanding liver fibrosis have contributed to an emerging translational success story, with realistic hopes for antifibrotic therapies to treat patients with chronic liver disease in the near future.

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IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis.

Stefan Fichtner-Feigl, Warren Strober, Koji Kawakami … (2006)

Interleukin (IL)-13 is a major inducer of fibrosis in many chronic infectious and autoimmune diseases. In studies of the mechanisms underlying such induction, we found that IL-13 induces transforming growth factor (TGF)-beta(1) in macrophages through a two-stage process involving, first, the induction of a receptor formerly considered to function only as a decoy receptor, IL-13Ralpha(2). Such induction requires IL-13 (or IL-4) and tumor necrosis factor (TNF)-alpha. Second, it involves IL-13 signaling through IL-13Ralpha(2) to activate an AP-1 variant containing c-jun and Fra-2, which then activates the TGFB1 promoter. In vivo, we found that prevention of IL-13Ralpha(2) expression reduced production of TGF-beta(1) in oxazolone-induced colitis and that prevention of IL-13Ralpha(2) expression, Il13ra2 gene silencing or blockade of IL-13Ralpha(2) signaling led to marked downregulation of TGF-beta(1) production and collagen deposition in bleomycin-induced lung fibrosis. These data suggest that IL-13Ralpha(2) signaling during prolonged inflammation is an important therapeutic target for the prevention of TGF-beta(1)-mediated fibrosis.

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Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice.

Fanli Meng, Kai Wang, Tomonori Aoyama … (2012)

Interleukin (IL)-17 signaling has been implicated in lung and skin fibrosis. We examined the role of IL-17 signaling in the pathogenesis of liver fibrosis in mice. Using cholestatic and hepatotoxic models of liver injury, we compared the development of liver fibrosis in wild-type mice with that of IL-17RA(-/-) mice and of bone marrow chimeric mice devoid of IL-17 signaling in immune and Kupffer cells (IL-17RA(-/-) to wild-type and IL-17A(-/-) to wild-type mice) or liver resident cells (wild-type to IL-17RA(-/-) mice). In response to liver injury, levels of Il-17A and its receptor increased. IL-17A increased appeared to promote fibrosis by activating inflammatory and liver resident cells. IL-17 signaling facilitated production of IL-6, IL-1, and tumor necrosis factor-α by inflammatory cells and increased the expression of transforming growth factor-1, a fibrogenic cytokine. IL-17 directly induced production of collagen type I in hepatic stellate cells by activating the signal transducer and activator of transcription 3 (Stat3) signaling pathway. Mice devoid of Stat3 signaling in hepatic stellate cells (GFAPStat3(-/-) mice) were less susceptible to fibrosis. Furthermore, deletion of IL-23 from immune cells attenuated liver fibrosis, whereas deletion of IL-22 exacerbated fibrosis. Administration of IL-22 and IL-17E (IL-25, a negative regulator of IL-23) protected mice from bile duct ligation-induced liver fibrosis. IL-17 induces liver fibrosis through multiple mechanisms in mice. Reagents that block these pathways might be developed as therapeutics for patients with cirrhosis. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

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Author and article information

Journal

Journal ID (publisher-id): IID

Journal ID (pmc): IID

Journal ID (doi): 10.1159/issn.2296-9365

Title: Inflammatory Intestinal Diseases

Publisher: S. Karger AG

ISSN (Print): 2296-9403

ISSN (Electronic): 2296-9365

Publication date Subscription-year: 2016

Publication date (Print): April 2016

Publication date (Electronic): 19 March 2016

Volume: 1

Issue: 1

Pages: 41-49

Affiliations

^aDepartment of Gastroenterology and Hepatology, Digestive Disease Institute, and ^bDepartment of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA; ^cDepartment of Medicine B, University Hospital of Münster, Münster, Germany; ^dCenter for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, and Departments of ^eGastroenterology and ^fRegenerative Medicine, Tokai University School of Medicine, Isehara, Japan

Author notes

*Florian Rieder, MD, Department of Pathobiology, Lerner Research Institute, NC22, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195 (USA), E-Mail riederf@ccf.org, Yutaka Inagaki, MD, PhD, Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, 143 Shimo-kasuya, Isehara, Kanagawa 259-1193 (Japan), E-Mail yutakai@is.icc.u-tokai.ac.jp

Article

Publisher ID: 445135 Pmcid ID: PMC5988123 Other ID: Inflamm Intest Dis 2016;1:41-49

DOI: 10.1159/000445135

PMC ID: PMC5988123

PubMed ID: 29922656

SO-VID: 86ade5b5-96b8-4eb8-875f-e611e33151d2

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 11 February 2016

Date accepted : 02 March 2016

Page count

Figures: 2, References: 109, Pages: 9

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Intestinal Fibrosis and Liver Fibrosis: Consequences of Chronic Inflammation or Independent Pathophysiology?

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Abstract

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Karger: Gastroenterology

Most cited references 83

Pathobiology of liver fibrosis: a translational success story.

IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis.

Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice.

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Cited by 7

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