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Pathogenesis of fibrostenosing Crohn's disease

  • Jiannan Li
    Affiliations
    Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio

    Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio
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  • Ren Mao
    Affiliations
    Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio

    Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio

    Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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  • Satya Kurada
    Affiliations
    Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio

    Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio
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  • Jie Wang
    Affiliations
    Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio

    Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio

    School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
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  • Sinan Lin
    Affiliations
    Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio

    Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio

    Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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  • Jyotsna Chandra
    Affiliations
    Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio

    Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio
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  • Florian Rieder
    Correspondence
    Reprint requests: Florian Rieder, Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue - NC22, Cleveland, OH 44195.
    Affiliations
    Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio

    Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio
    Search for articles by this author
Published:March 26, 2019DOI:https://doi.org/10.1016/j.trsl.2019.03.005

      Abstract

      Crohn's disease (CD) is a chronic inflammatory disease, which could affect any part of the gastrointestinal tract. A severe complication of CD is fibrosis-associated strictures, which can cause bowel obstruction. Unfortunately, there is no specific antifibrotic therapy available. More than 80% of the patients with CD will have to undergo at least 1 surgery in their life and recurrence of strictures after surgery is common. Investigations on the mechanism of fibrostenosing CD have revealed that fibrosis is mainly driven by expansion of mesenchymal cells including fibroblasts, myofibroblasts, and smooth muscle cells. Being exposed to a pro-fibrotic milieu, these cells increase the secretion of extracellular matrix, as well as crosslinking enzymes, which drive tissue stiffness and remodeling. Fibrogenesis can become independent of inflammation in later stages of disease, which offers unique therapeutic potential. Exciting new evidence suggests smooth muscle cell hyperplasia as a strong contributor to luminal narrowing in fibrostenotic CD. Approval of new drugs in other fibrotic diseases, such as idiopathic pulmonary fibrosis, as well as new targets associated with fibrosis found in CD, such as cadherins or specific integrins, shed light on the development of novel antifibrotic approaches in CD.

      Abbreviations:

      ANG (Angiotensin), α-SMA (α-smooth muscle actin), CD (Crohn's disease), CTGF (Connective tissue growth factor), DAMP (Damage-associated molecular pattern), DSS (Dextran sodium sulfate), ECM (Extracellular matrix), EGF (Epidermal growth factor), EMT (Epithelial to mesenchymal transition), ET (Endothelins), GI (Gastrointestinal), GWAS (Genome wide association study), HDAC (Histone deacetylase), HMGB (High mobility group box), HSC (Hepatic stellate cells), IBD (Inflammatory bowel disease), ICAM-1 (Intercellular adhesion molecule-1), IFN (interferon), IGF (Insulin like growth factor), IL (Interleukin), IPF (idiopathic pulmonary fibrosis), LOX (Lysyl oxidase), LPS (Lipopolysaccharide), ISMC (Intestinal smooth muscle cell), MAPK (Mitogen-activated protein kinase), MMP (Matrix metalloproteinase), MS (multiple sclerosis), PAMPs (Pathogen-associated molecular patterns), PDGF (Platelet-derived growth factor), PPAR-γ (Peroxisome proliferator activator receptor-γ), PRR (Pattern recognition receptor), RA (rheumatoid arthritis), SCF (Stem cell factor), SMC (Smooth muscle cells), TG (Transglutaminases), TGF- β1 (Transforming growth factor- β1), TIMP-1 (Tissue inhibitor of metalloproteinase), TIR (Intracellular Toll/IL-1 receptor), TIRAP (TIR domain-containing adaptor protein), TLRs (Toll like receptors), TNBS (Trinitrobenzene sulfonic acid), TNF (Tumor necrosis factor), TRAM (TRIF-related adaptor molecule), TRIF (TIR-domain-containing adapter-inducing interferon-β), UC (Ulcerative colitis), VCAM-1 (Vascular cell adhesion molecule-1)
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