Mesenchymal cell proliferation and programmed cell death: key players in fibrogenesis and new targets for therapeutic intervention

Luna, J. D.; Masamunt, Maria Carme; Lawrance, Ian C.; Sans, Miquel

doi:10.1152/ajpgi.00504.2010

Cited by 14 publications

(14 citation statements)

References 85 publications

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“…Excessive fibroblast/myofibroblasts accumulation, which is secondary to increased proliferation and/or inhibited apoptosis, gradually leads to excessive ECM synthesis and deposition and thus progressive distortion of intestinal structure. Given that apoptosis is responsible for mediating the reduction in myofibroblasts number, induction of myofibroblasts apoptosis would have an antifibrotic effect during the resolution of fibrosis ( 29 ). Suppression of activation and proliferation and induction of apoptosis could be helpful to reduce activated fibroblasts and their profibrogenic effects.…”

Section: Discussionmentioning

confidence: 99%

Pirfenidone suppresses TGF‑β1‑induced human intestinal fibroblasts activities by regulating proliferation and apoptosis via the inhibition of the Smad and PI3K/AKT signaling pathway

2018

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Intestinal fibroblasts, the main effector cells of intestinal fibrosis, are considered to be a good target for anti-fibrotic therapy. The aim of the present study was to examine the effects of pirfenidone (PFD) on human intestinal fibroblasts (HIFs) stimulated by transforming growth factor (TGF)-β1 and to explore the potential mechanism. Prior to stimulation with TGF-β1 (10 ng/ml), HIFs were treated with or without PFD (1 mg/ml). Cell proliferation was determined by Cell Counting Kit (CCK)-8 and colony formation assays, and cell apoptosis was assessed using flow cytometry and a TUNEL assay. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to evaluate the mRNA and protein expressions of α-smooth muscle actin (α-SMA), collagen I and fibronectin. The protein expression of TGF-β1/mothers against decapentaplegic homolog (Smad) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways was evaluated by western blotting. CCK-8 and colony formation assays demonstrated that PFD significantly inhibited cell proliferation in HIFs stimulated with TGF-β1. Flow cytometry and TUNEL assays revealed that PFD treatment significantly enhanced apoptosis in TGF-β1-stimulated HIFs. In addition, PFD markedly reduced TGF-β1-induced HIF activities, such as myofibroblast differentiation (α-SMA), and collagen production (collagen I and fibronectin). These effects of PFD were mediated by the inhibition of the TGF-β1/Smad and PI3K/AKT signaling pathways. Therefore, the present study demonstrated that PFD reduced TGF-β1-induced fibrogenic activities of HIFs, suggesting that PFD may be a potential therapeutic agent for intestinal fibrosis.

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Section: Discussionmentioning

confidence: 99%

Pirfenidone suppresses TGF‑β1‑induced human intestinal fibroblasts activities by regulating proliferation and apoptosis via the inhibition of the Smad and PI3K/AKT signaling pathway

2018

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“… 10,15,16 As apoptosis mediates the reduction in myofibroblast numbers during fibrosis resolution, the induction of myofibroblasts apoptosis could be profoundly anti-fibrotic. 35 …”

Section: Cellular Proliferation Apoptosis and Autophagymentioning

confidence: 99%

“…NOD2 and ATG16L1 (an autophagy gene) are also expressed by myofibroblasts and enhance apoptosis through the induction of caspase activation. 35 In CD, variants of these genes increase the risk of small bowel fibrostenosis. 59 Tissue inhibitors of metalloproteinases (TIMPs) are also important in fibrosis as they inhibit matrix degradation.…”

Section: Cellular Proliferation Apoptosis and Autophagymentioning

confidence: 99%

Cellular and Molecular Mediators of Intestinal Fibrosis

Lawrance

Rogler

Bamias

et al. 2015

ECCOJC

112

162

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Intestinal fibrosis is a major complication of the inflammatory bowel diseases (IBD) and although inflammation is necessary for its development, it would appear that it plays a minor role in its progression as anti-inflammatory treatments in IBD do not prevent fibrosis once it has started. The processes that regulate fibrosis would thus appear to be distinct from those regulating inflammation and, therefore, a detailed understanding of these pathways is vital to the development of anti-fibrogenic strategies. There have been several recent reviews exploring what is known, and what remains unknown, about the development of intestinal fibrosis. This review is designed to add to this literature but with a focus on the cellular components that are involved in the development of fibrogenesis and the major molecular mediators that impact on these cells. The aim is to heighten the understanding of the factors involved in intestinal fibrogenesis so that detailed research can be encouraged in order to advance the processes that could lead to effective treatments.

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“…The inflammatory changes in intestinal physiology result in the majority of the symptomatology associated with CD (26) and significant morbidity results from the irreversible tissue injury and fibrosis that frequently occur in chronically inflamed bowel segments (25,27). For reasons unknown, the reparative process associated with CD can progress uncontrollably, leading to enhanced proliferation along with defective programmed cell death of mesenchymal cells, and the unrestrained deposition of ECM (28,29). The recurrence of fibrosis is the predominant reason for obstruction, however, few therapies have reliable effect on the inhibition of fibrosis (30–33).…”

Section: Discussionmentioning

confidence: 99%

Triptolide ameliorates colonic fibrosis in an experimental rat model

Tao

Wang

Zheng

et al. 2015

Molecular Medicine Reports

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Triptolide is known to exert anti-inflammatory and immunomodulatory activities; however, its impact on intestinal fibrosis has not been previously examined. Based on our previous studies of the suppressive activity of triptolide on human colonic subepithelial myofibroblasts and the therapeutic efficacy of triptolide in Crohn’s disease, it was hypothesized that triptolide may have beneficial effects on intestinal fibrosis. In the present study, colonic fibrosis was induced in rats by 6 weekly repeated administration with a low-dose of 2,4,6-trinitrobenzene sulfonic acid (TNBS) and was then treated with triptolide or PBS daily (control) simultaneously. Extracellular matrix (ECM) deposition in the colon was examined with image analysis of Masson Trichrome staining. Total collagen levels in colonic homogenates were measured by a Sircol assay. Collagen Iα1 transcripts and collagen I protein were measured ex vivo in the isolated colonic subepithelial myofibroblasts by reverse transcription-quantitative polymerase chain reaction and immunoblot analysis, respectively. The results indicated that triptolide decreased ECM deposition and collagen production in the colon, and inhibited collagen Iα1 transcripts and collagen I protein expression in the isolated subepithelial myofibroblasts of the rats with colonic fibrosis. In conclusion, triptolide ameliorates colonic fibrosis in the experimental rat model, suggesting triptolide may be a promising compound for inflammatory bowel disease treatment.

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Mesenchymal cell proliferation and programmed cell death: key players in fibrogenesis and new targets for therapeutic intervention

Abstract: Luna J, Masamunt MC, Lawrance IC, Sans M. Mesenchymal cell proliferation and programmed cell death: key players in fibrogenesis and new targets for therapeutic intervention.

Cited by 14 publications

References 85 publications

Pirfenidone suppresses TGF‑β1‑induced human intestinal fibroblasts activities by regulating proliferation and apoptosis via the inhibition of the Smad and PI3K/AKT signaling pathway

Pirfenidone suppresses TGF‑β1‑induced human intestinal fibroblasts activities by regulating proliferation and apoptosis via the inhibition of the Smad and PI3K/AKT signaling pathway

Cellular and Molecular Mediators of Intestinal Fibrosis

Triptolide ameliorates colonic fibrosis in an experimental rat model

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