Intestinal fibrosis is a process characterized by an excessive deposition of Extracellular Matrix (ECM) proteins by activated myofibroblasts and represents a consequence of a chronic inflammation ...that usually occurs during Inflammatory Bowel Disease (IBD). The relationship between inflammation and fibrosis in IBD remains still unclear and nevertheless the recent pharmacological progresses, currently the only resolutive therapeutic strategy is surgery, especially when complications (stricture, stenosis and obstruction of intestinal tracts) appear. As many different cellular types and molecular mechanisms are implicated in the pathogenesis of IBD, the identification of molecules able to counteract this process could be crucial.
This is a literature review of several articles published on PubMed databases.
A number of researches suggest that Proliferator-Activated Receptor-gamma (PPAR-γ) has both anti-inflammatory and anti-fibrotic effects in many organs. PPAR-γ has been demonstrated to be able to downregulate pro-inflammatory cytokines production such as Interleukin (IL)-4,-5,-6 but also to interfere with profibrotic molecules as Platelet-Derived Growth Factor (PDGF), IL-1 and Transforming Growth Factor Beta (TGF-β), the main promoter of fibrosis. In preliminary clinical trials and in experimental models of intestinal fibrosis, natural and chemical PPAR-γ ligands have ameliorated the fibrotic process.
Since PPAR-γ could play a crucial role in the development of the disease, the research of new molecules, capable of ameliorating both inflammation and fibrosis lesions, as PPAR-γ agonists, could represent a valid and effective therapeutic approach for the prevention and treatment of IBD and intestinal fibrosis.
Intestinal fibrosis is a common complication of in inflammatory bowel disease (IBD) and can occur in both ulcerative colitis (UC) and Crohn's disease (CD), but is much more prevalent in CD. Fibrosis ...is a consequence of local chronic inflammation and is characterized by abnormal deposition of extracellular matrix (ECM) proteins producted by activated myofibroblasts. Current anti-inflammatory therapies used in IBD do not prevent nor they reverse established fibrosis and strictures. Despite the therapeutic advance in the treatment of IBD in the last two decades, the incidence of intestinal strictures in CD has not significantly changed. This implies that control of intestinal inflammation does not necessarily affect the associated fibrotic process. The conventional view that intestinal fibrosis is an inevitable and irreversible process in patients with IBD is progressively changing in light of improved understanding of the cellular and molecular mechanisms that underline the pathogenesis of fibrosis. Comprehension of the mechanisms of intestinal fibrosis may pave the way for the developments of anti-fibrotic agents and of new possible therapeutic approches in IBD. Nevertheless, there are important clinical issues that need further investigations, in particular the identification of factors relevant for the development of the intestinal fibrosis in IBD and the need of accurate and effective monitoring of the fibrotic progression and of effectiveness of the new proposed treatments.
The objective of this study was to evaluate the morphological and immunohistochemical alterations of tissue removed from the upper third of anterior vaginal wall in a sample group of the female ...population presenting homogenous risk factors associated with Pelvic Organ Prolapse (POP). The case study consisted of 14 patients with POP and there were 10 patients in the control group. Patient selection was carried on the basis of specific criteria and all of the patients involved in the study presented one or more of the recognized POP risk factors. Samples were taken from POP patients during vaginal plastic surgery following colpohysterectomy, and from control patients during closure of the posterior fornix following hysterectomy. Samples were processed for histological and immunohistochemical analyses for Collagen I and Collagen III, α-Smooth Muscle Actin (α-SMA), Platelet-Derived-Growth-Factor (PDGF), matrix metalloproteinase 3 (MMP3), Caspase3. Immunofluorescence analyses for Collagen I and III and PDGF were also carried out. In prolapsed specimens our results show a disorganization of smooth muscle cells that appeared to have been displaced by an increased collagen III deposition resulting in rearrangement of the muscularis propria architecture. These findings suggest that the increase in the expression of collagen fibers in muscularis could probably due to a phenotypic switch resulting in the dedifferentiation of smooth muscle cells into myofibroblasts. These alterations could be responsible for the compromising of the dynamic functionality of the pelvic floor.
Mesenchymal cells transdifferentiation and extracellular matrix deposition are involved in the fibrotic process of Crohn's disease (CD). Mesenchymal smooth muscle cells (SMCs) de-differentiation, ...driven by Platelet-derived growth factor (PDGF) that counteracts Transforming growth factor (TGF-β) has been studied in vascular muscle. The role of SMCs in intestinal fibrogenesis is still not clearly elucidated. Aim of the study was to evaluate the possible myogenic contribution to CD fibrotic process through the comparative analysis of histological, morphometric and molecular alterations occurring in human smooth muscle. Full thickness specimens were obtained from CD (non-involved and stenotic tracts) and healthy (control) ileum. Tissues were processed for histological and immunohistochemical (IHC) analyses and SMCs were isolated from the muscularis propria for morphofunctional and molecular (qPCR) analyses. CD stenotic ileum showed a significant increased thickness of all layers compared to CD non-involved and control ileum. IHC revealed an overexpression of α-smooth muscle actin and collagens I-III throughout all intestinal layers only in stenotic tracts. The two growth factors, PDGF and TGF-β, showed a progressive increase in expression in the muscle layer from CD non-involved to stenotic tracts. Freshly isolated SMCs presented alterations in CD non-involved tracts that progressively increased in the stenotic tracts consisting in a statistical increase in mRNA encoding for PDGF-β and collagen III, paralleled to a decrease in TGF-β and Tribbles-like protein-3 mRNA, and altered morphofunctional parameters consisting in progressive decreases in cell length and contraction to acetylcholine. These findings indicate that intrinsic myogenic alterations occur in CD ileum, that they likely precede stricture formation, and might represent suitable new targets for anti-fibrotic interventions.
Background Transforming growth factor‐β (TGF‐β)/Smad3 signalling plays a central role in tissue fibrogenesis, acting as a potent stimulus of extracellular matrix (ECM) protein accumulation. The aim ...of this study was to evaluate the potential role of Smad3 in the pathogenesis of colonic fibrosis induced by trinitrobenzene sulfonic acid (TNBS) in Smad3 null mice.
Materials and methods Chronic colitis‐associated fibrosis was induced in 15 Smad3 null and 13 wild‐type mice by intra‐rectal administration of TNBS. Each mouse received an incremental dose of TNBS (0·5–1·0 mg per week) over a 6‐week period. The colon was excised for macroscopic examination and histological, morphometric and immunohistochemical analyses. For immunohistochemistry, alpha‐smooth muscle actin (α‐SMA), collagen types I–III, TGF‐β1, connective tissue growth factor (CTGF), Smad3, Smad7, and CD3 antibodies were used.
Results At macroscopic examination, the colon of Smad3 wild‐type mice appeared significantly harder, thicker and shorter than that of the Smad3 null mice. Of the wild‐type mice, 50% presented colonic adhesions and strictures. Histological and morphometric evaluation revealed a significantly higher degree of colonic fibrosis and accumulation of collagen in the Smad3 wild‐type compared to null mice, whereas the degree of colonic inflammation did not differ between the two groups of mice. Immunohistochemical evaluation showed a marked increase in CTGF, collagen I–III, TGF‐β and Smad3 staining in the colon of Smad3 wild‐type compared to null mice, whereas Smad7 was increased only in null mice.
Conclusions These results indicate that Smad3 loss confers resistance to the development of TNBS‐induced colonic fibrosis. The reduced fibrotic response appears to be due to a reduction in fibrogenic mesenchymal cell activation and ECM production and accumulation. Smad3 could be a novel target for potential treatment of intestinal fibrosis, especially in inflammatory bowel disease.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Hepatic fibrosis is characterised by a progressive accumulation of fibrillar extracellular matrix (ECM) proteins, including collagen that occurs in chronic liver diseases. Transforming growth ...factor-beta1 (TGF-beta)/Smad3 signalling plays a major role in tissue fibrogenesis acting as a potent stimulus of ECM accumulation.
To evaluate the effects of a combined therapy with anti-inflammatory Boswellia and anti-fibrotic Salvia extracts on the course of chronic hepatitis-associated fibrosis induced by dimethylnitrosamine (DMN) in mice, as well as on the hepatic expression of TGF-beta1 and Smad proteins.
Chronic hepatitis-associated fibrosis was induced in mice by intraperitoneal DMN administration. Mice were assigned to 5 groups: controls; DMN without any treatment; DMN treated orally with Boswellia extracts (50 mg/kg/day); DMN treated orally with Salvia extracts (150 mg/ kg/day); DMN treated orally with both Boswellia (50 mg/kg/day) and Salvia extracts (150 mg/kg/ day). The liver was excised for macroscopic examination and histological, morphometric and immunohistochemical (IHC) analyses. For IHC, alpha-smooth muscle actin (alpha-SMA), collagen types I-III, TGF-beta1, connective tissue growth factor (CTGF), Smad3, Smad7, CD3, PCNA and TUNEL antibodies were used.
The combined oral administration of Boswellia and Salvia extracts improved the course and macroscopic findings of DMN-induced chronic hepatitis-associated fibrosis. The histological severity of the hepatic fibrosis showed a marked improvement following treatment and was associated with a reduction in the hepatic expression of alpha-SMA, collagen I-III, CTGF, TGF-beta1, Smad3, and Smad7.
These data demonstrate that co-treatment of Boswellia plus Salvia extracts is effective in preventing hepatic fibrosis in DMN-induced chronic hepatitis. The anti-fibrotic properties are mainly related to Salvia extracts and appear to be mediated by the inhibition of the TGF-beta1/Smad3 pathway.
ABSTRACT
Background Currently, no effective preventive measures or medical therapies are available for intestinal fibrosis and, thus, surgery remains the only available strategy in the management of ...fibrostenotic enteropathies, especially Crohn's disease. The aim of this study was to evaluate the efficacy of a combined therapy of anti‐inflammatory Boswellia and antifibrotic Scutellaria extracts on the development of colonic fibrosis in rats.
Materials and methods Chronic colonic inflammation‐associated fibrosis was induced in rats by intracolonic administration of 2,4,5‐trinitrobenzene sulphonic acid (TNBS). Sixty‐four healthy male Sprague‐Dawley rats were assigned to five groups: 8 controls, 14 TNBS, 14 TNBS orally treated with Boswellia extracts (50 mg kg−1 day−1), 14 TNBS orally treated with Scutellaria extracts (150 mg kg−1 day−1), and 14 TNBS orally treated with both Boswellia (50 mg kg−1 day−1) and Scutellaria extracts (150 mg kg−1 day−1). The colon was removed after 21 days of treatment and assessed by macroscopic, histological, morphometric and immunohistochemical analyses. For immunohistochemical analysis, alpha‐smooth muscle actin (α‐SMA), collagen types I–III, connective tissue growth factor (CTGF), transforming growth factor‐beta1 (TGF‐β1), Smad3, Smad7 and CD3 antibodies were used.
Results Combined oral administration of Boswellia and Scutellaria significantly improved the course and macroscopic findings of TNBS‐induced chronic colitis assessed by disease activity index, colon weight, length, adhesions, strictures, dilatation, thickness, oedema, ulcerations and extension of damage. The histological severity of the colonic fibrosis was also notably improved by the treatment and associated with a significant reduction in the colonic expression of α‐SMA, collagen I–III, CTGF, TGF‐β1, Smad3, and Smad7.
Conclusions These data demonstrate that the prophylactic administration of anti‐inflammatory Boswellia and antifibrotic Scutellaria extracts is effective in preventing colonic fibrosis in TNBS‐induced colitis. Their antifibrotic mechanism of action seems to be mediated by the inhibition of TGF‐β1/Smad3 pathway.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
A simultaneous action of several pro-fibrotic mediators appears relevant in the development of fibrosis. There are evidences that transforming growth factor-β (TGF-β)/Smad3 pathway forms with αvβ6 ...integrin, mammalian target of Rapamycin (mTOR) and peroxisome proliferator-activated receptor-γ (PPARγ) a complex signalling network with extensive crosstalk and strong effects on fibrosis development. The present study evaluated the expression of TGFβ, Smad3, αvβ6 integrin, mTOR and PPARγ in 2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced colorectal fibrosis in Smad3 wild-type (WT) and null mice. Smad3 WT mice treated with TNBS developed a marked colorectal fibrosis and showed a concomitant up-regulation of TGFβ, Smad3, αvβ6 and mTOR and a reduction of PPARγ expression. On the other hand, Smad3 Null mice similarly treated with TNBS did not develop fibrosis and showed a very low or even absent expression of TGFβ, Smad3, αvβ6 and mTOR and a marked over-expression of PPARγ. At the same time the expression of α-smooth muscle actin (a marker of activated myofibroblasts), collagen I-III and connective tissue growth factor (a downstream effector of TGFβ/Smad3-induced extracellular matrix proteins) were up-regulated in Smad3 WT mice treated with TNBS compared to Null TNBS-treated mice. These preliminary results suggest a possible interaction between these pro-fibrotic molecules in the development of intestinal fibrosis.
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