Novel mechanisms and clinical trial endpoints in intestinal fibrosis*

Wang, Jie; Lin, Sinan; Brown, J. Mark; Wagoner, David R. Van; Fiocchi, Claudio; Rieder, Florian

doi:10.1111/imr.12974

Cited by 62 publications

(59 citation statements)

References 217 publications

(467 reference statements)

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“…This exacerbated accumulation of ECM differs between UC and CD patients because, while in UC patients it is limited to the submucosal and mucosal layers of the large intestine, in CD patients the ECM components can involve the whole intestinal wall of the gastrointestinal tract [ 172 ]. Intestinal fibrosis presupposes the development of several complications, including stricture formation, perforation, and fistula formation, which in turn require surgery due to the lack of efficient pharmacological drugs that prevent these complications [ 173 ].…”

Section: Macrophages In Intestinal Fibrosismentioning

confidence: 99%

Is the Macrophage Phenotype Determinant for Fibrosis Development?

et al. 2021

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Fibrosis is a pathophysiological process of wound repair that leads to the deposit of connective tissue in the extracellular matrix. This complication is mainly associated with different pathologies affecting several organs such as lung, liver, heart, kidney, and intestine. In this fibrotic process, macrophages play an important role since they can modulate fibrosis due to their high plasticity, being able to adopt different phenotypes depending on the microenvironment in which they are found. In this review, we will try to discuss whether the macrophage phenotype exerts a pivotal role in the fibrosis development in the most important fibrotic scenarios.

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Section: Macrophages In Intestinal Fibrosismentioning

confidence: 99%

Is the Macrophage Phenotype Determinant for Fibrosis Development?

et al. 2021

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“…The increase in mesenchymal cells and excessive secretion of ECM are considered key features of intestinal fibrotic strictures ( Li et al, 2019 ). These alterations result from epithelial–mesenchymal transition (EMT), in which epithelial cells lose typical epithelial cell markers and acquire mesenchymal cell markers, along with the upregulation of collagens, α-SMA, vimentin, and fibronectin ( Wang et al, 2021 ). A similar process in endothelial cells is called the endothelial–mesenchymal transition (EndoMT), during which endothelial cells lose typical endothelial markers and express fibroblast-like markers ( Dejana et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology-Based Strategy to Identify the Pharmacological Mechanisms of Pulsatilla Decoction against Crohn’s Disease

et al. 2022

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Purpose: To explore pharmacological mechanisms of Pulsatilla decoction (PD) against Crohn’s disease (CD) via network pharmacology analysis followed by experimental validation.Methods: Public databases were searched to identify bioactive compounds and related targets of PD as well as related genes in patients with CD. Analyses using the drug–compound–target–disease network, the protein–protein interaction (PPI) network, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to predict the core targets and pathways of PD against CD. Colon tissue resected from patients with CD and tissue samples from a mouse model of CD fibrosis treated with PD were assessed to verify the major targets of PD in CD predicted by network pharmacologic analysis.Results: A search of the targets of bioactive compounds in PD and targets in CD identified 134 intersection targets. The target HSP90AA1, which was common to the drug–compound–target–disease and PPI networks, was used to simulate molecular docking with the corresponding bioactive compound. GO and KEGG enrichment analyses showed that multiple targets in the antifibrotic pathway were enriched and could be experimentally validated in CD patients and in a mouse model of CD fibrosis. Assays of colon tissues from CD patients showed that intestinal fibrosis was greater in stenoses than in nonstenoses, with upregulation of p-AKT, AKT, p-mTOR, mTOR, p-ERK1/2, ERK1/2, p-PKC, and PKC targets. Treatment of CD fibrosis mice with PD reduced the degree of fibrosis, with downregulation of the p-AKT, AKT, p-mTOR, mTOR, p-ERK1/2, ERK1/2, and PKC targets.Conclusion: Network pharmacology analysis was able to predict bioactive compounds in PD and their potential targets in CD. Several of these targets were validated experimentally, providing insight into the pharmacological mechanisms underlying the biological activities of PD in patients with CD.

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“…Cross-sectional imaging modalities, including magnetic resonance enterography, computed tomography enterography (CTE), and US, are widely used to evaluate transmural fibrosis. 11 However, currently, there are no reliable and widely accepted methods for determining intestinal fibrosis in CD. 49 Small-bowel stenosis (SBS) in CD was usually defined as luminal narrowing with upstream bowel dilation on cross-sectional imaging modalities.…”

Section: Search Strategymentioning

confidence: 99%

Intestinal strictures in Crohn’s disease: a 2021 update

Lin

Wang

Liu

et al. 2022

Therap Adv Gastroenterol

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Intestinal strictures remain one of the most intractable and common complications of Crohn’s disease (CD). Approximately 70% of CD patients will develop fibrotic strictures after 10 years of CD diagnosis. Since specific antifibrotic therapies are unavailable, endoscopic balloon dilation and surgery remain the mainstay treatments despite a high recurrence rate. Besides, there are no reliable methods for accurately evaluating intestinal fibrosis. This is largely due to the fact that the mechanisms of initiation and propagation of intestinal fibrosis are poorly understood. There is growing evidence implying that the pathogenesis of stricturing CD involves the intricate interplay of factors including aberrant immune and nonimmune responses, host-microbiome dysbiosis, and genetic susceptibility. Currently, the progress on intestinal strictures has been fueled by the advent of novel techniques, such as single-cell sequencing, multi-omics, and artificial intelligence. Here, we perform a timely and comprehensive review of the substantial advances in intestinal strictures in 2021, aiming to provide prompt information regarding fibrosis and set the stage for the improvement of diagnosis, treatment, and prognosis of intestinal strictures.

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Novel mechanisms and clinical trial endpoints in intestinal fibrosis*

Cited by 62 publications

References 217 publications

Is the Macrophage Phenotype Determinant for Fibrosis Development?

Is the Macrophage Phenotype Determinant for Fibrosis Development?

Network Pharmacology-Based Strategy to Identify the Pharmacological Mechanisms of Pulsatilla Decoction against Crohn’s Disease

Intestinal strictures in Crohn’s disease: a 2021 update

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