Factors Promoting Development of Fibrosis in Crohn’s Disease

Rogler, Gerhard; Hausmann, Martin

doi:10.3389/fmed.2017.00096

Cited by 24 publications

(16 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Intestinal fibrosis associated to Crohn's disease is characterized by an intense submucosal and subserosal ECM deposition. 2,24 Several animal models of intestinal fibrosis have been proposed 25 and we consider that the heterotopic transplant model of fibrosis used in the present study reproduce some features of CD fibrosis, such as transmural inflammation and ECM deposition. 26,27 We observed an important submucosal and subserosal collagen accumulation and high levels of fibrosis markers associated with an increased expression of SUCNR1 in WT grafts 7 days after transplantation.…”

Section: Discussionmentioning

confidence: 99%

Succinate receptor mediates intestinal inflammation and fibrosis

et al. 2019

Self Cite

View full text Add to dashboard Cite

Succinate, an intermediate of the tricarboxylic acid cycle, is accumulated in inflamed areas and its signaling through succinate receptor (SUCNR1) regulates immune function. We analyze SUCNR1 expression in the intestine of Crohn's disease patients and its role in murine intestinal inflammation and fibrosis. We show that both serum and intestinal succinate levels and SUCNR1 expression in intestinal surgical resections were higher in CD patients than in controls. SUCNR1 co-localized with CD86, CD206, and α-SMA+ cells in human intestine and we found a positive and significant correlation between SUCNR1 and α-SMA expression. In human isolated fibroblasts from CD patients SUCNR1 expression was higher than in those from controls and treatment with succinate increased SUCNR1 expression, fibrotic markers and inflammatory cytokines through SUCNR1. This receptor modulated the expression of pro-inflammatory cytokines in resting murine macrophages, macrophage polarization and fibroblast activation and Sucnr1 −/− mice were protected against both acute TNBS-colitis and intestinal fibrosis induced by the heterotopic transplant of colonic tissue. We demonstrate increased succinate levels in serum and SUCNR1 expression in intestinal tissue of CD patients and show a role for SUCNR1 in murine intestinal inflammation and fibrosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Succinate receptor mediates intestinal inflammation and fibrosis

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…49 Rogler and Hausmann 50 posited that new animal models for intestinal fibrosis may provide insight into mechanisms of disease and identify specific therapies for fibrosis in people with CD. 50 Using the SHIP −/− mouse, we have found that targeting PI3Kp110δ activity can reduce CD-like intestinal fibrosis. A new drug targeting PI3Kp110δ activity, idelalisib, has recently been developed and licensed for use in the United States and European Union for the treatment of B cell neoplasms.…”

Section: Discussionmentioning

confidence: 98%

Phosphatidylinositol 3-kinase p110δ drives intestinal fibrosis in SHIP deficiency

Sauvé

Menzies

et al. 2019

Mucosal Immunology

View full text Add to dashboard Cite

Crohn's disease is an immune-mediated disease characterized by inflammation along the gastrointestinal tract. Fibrosis requiring surgery occurs in one-third of people with Crohn's disease but there are no treatments for intestinal fibrosis. Mice deficient in the SH2 domain-containing inositolpolyphosphate 5′-phosphatase (SHIP), a negative regulator of phosphatidylinositol 3-kinase (PI3K) develop spontaneous Crohn's disease-like intestinal inflammation and arginase I (argI)-dependent fibrosis. ArgI is up-regulated in SHIP deficiency by PI3Kp110δ activity. Thus, we hypothesized that SHIP-deficient mice develop fibrosis due to increased PI3Kp110δ activity. In SHIP-deficient mice, genetic ablation or pharmacological inhibition of PI3Kp110δ activity reduced intestinal fibrosis, including muscle thickening, accumulation of vimentin + mesenchymal cells, and collagen deposition. PI3Kp110δ deficiency or inhibition also reduced ileal inflammation in SHIP-deficient mice suggesting that PI3Kp110δ may contribute to inflammation. Targeting PI3Kp110δ activity may be an effective strategy to reduce intestinal fibrosis, and may be particularly effective in the subset of people with Crohn's disease, who have low SHIP activity.

show abstract

“…An allele that could lead to overexpression of the main profibrotic mediator, TGF-β, has been identified [8], which could lead to more rapid development of fibrosis and strictures. Another explanation could be that inflammation and fibrosis are initially linked in the pathogenesis, but later become two independent processes [9]. is might explain why fibrosis cannot be reversed by anti-inflammatory drugs.…”

Section: Discussionmentioning

confidence: 99%

Levels of Intestinal Inflammation and Fibrosis in Resection Specimens after Preoperative Anti-Tumor Necrosis Factor Alpha Treatment in Patients with Crohn’s Disease: A Comparative Pilot Study

Torle

Dabir

Korsgaard

et al. 2020

Surgery Research and Practice

View full text Add to dashboard Cite

Background. Strictures are a common complication in Crohn’s disease (CD), found in more than 50% of patients. They are characterized by the excessive deposition of extracellular proteins in the tissue as a result of the chronic inflammatory process. The effect of anti-tumor necrosis factor alpha (TNF-α) therapy on the development of fibrosis is not yet fully understood. Aim. To investigate whether the degree of intestinal inflammation and fibrosis is correlated with preoperative anti-TNF-α therapy in patients with CD who are undergoing bowel resection. Methods. This unblinded, prospective, single tertiary center, pilot cohort study included all adult patients with CD who underwent elective, laparoscopic, or open intestinal resection. Preoperative investigations included measurement of blood TNF-α concentration, specific antidrug antibodies, and the concentration of selected inflammatory cytokines. Three pathologists independently examined the specimens and assessed the degree of inflammation and fibrosis. Results. Histopathological specimens from 10 patients with CD who underwent ileocecal or ileocolic resections were retrieved. Four of those patients were on anti-TNF-α treatment prior to surgery. The last dose of the anti-TNF-α agent was administered 1–9 weeks prior to bowel resection. Patients on anti-TNF-α treatment had a higher fibrosis score than controls (p=0.01). Anti-TNF-α treatment was not associated with an increase in CD68- or CD163-positive macrophages. There was no significant relationship between the time from the final preoperative anti-TNF-α dose to surgery and the fibrosis score. No significant association was found between the concentration of major inflammatory cytokines, including TNF-α, and the fibrosis score or degree of inflammation. Conclusions. Patients who underwent preoperative anti-TNF-α treatment had a higher fibrosis score than controls.

show abstract

Factors Promoting Development of Fibrosis in Crohn’s Disease

Cited by 24 publications

References 52 publications

Succinate receptor mediates intestinal inflammation and fibrosis

Succinate receptor mediates intestinal inflammation and fibrosis

Phosphatidylinositol 3-kinase p110δ drives intestinal fibrosis in SHIP deficiency

Levels of Intestinal Inflammation and Fibrosis in Resection Specimens after Preoperative Anti-Tumor Necrosis Factor Alpha Treatment in Patients with Crohn’s Disease: A Comparative Pilot Study

Contact Info

Product

Resources

About