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Relationship among several pro-fibrotic and anti-fibrotic mediators in the development of fibrosis. IL-13 = Interleukin-13; TGF-β = transforming growt factor-β; CTGF = connective tissue growth factor; PDGF = platelet derived growth factor; IGF-I = insulin-like growth factors I, EGF = epidermal growth factor; bFGF = basic fibroblast growth factor; ETs = endothelins; ACE = angiotensin convertingenzyme ; AT-II = angiotensin-II; mTOR = mammalian target of rapamycin; PPAR-γ = peroxisome proliferator activator receptor-γ; INF-α and β = interferon-α and β; HGF = hepatic growt factor.
Source publication
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 activate...
Context in source publication
Context 1
... TGF-β/Smad pathway represents the driving force of fibrotic process ("core path- way"), several pro-fibrogenic molecules, such as activins, CTGF, PDGF, bFGF, IGF-1, inter- leukins (IL-1, IL-6, IL-13), TNF-α, angiotensin converting enzyme, angiotensin II, αvβ6 integrin and mTOR, as well as anti-fibrogenic molecules (PPAR-γ, Smad7, IL-7, IL-10, IL-12, INF-α and γ, HGF) seem to interact directly with TGFβ/Smad pathway (Figure 4). ...
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Fibrosis is a pathologic condition resulting from aberrant wound healing responses that lead to excessive accumulation of extracellular matrix components, distortion of organ architecture, and loss of organ function. Fibrotic disease can affect every organ system; moreover, fibrosis is an important microenvironmental component of many cancers, incl...
Citations
... When the wound is closed, myofibroblasts undergo apoptosis, and the wound-healing response ends. In the case of CD, as there is chronic inflammation, the continuous wound-healing response eventually leads to fibrosis [7,8]. ...
In Crohn's Disease (CD), intestinal fibrosis is a prevalent yet unresolved complication arising from chronic and transmural inflammation. The histological assessment of CD intestines shows changes in tissue morphology in all the layers, including the mucosa and muscularis. This study aimed to determine the differences in fibrogenesis between mucosa and muscularis. Human precision-cut intestinal slices (hPCIS) were prepared from human intestine mucosa and muscularis and treated with TGF-β1 and/or PDGF-BB for 72 h. Gene and protein expression and matrix metalloproteinase (MMP) activity were determined. The basal gene expression of various fibrosis markers was higher in muscularis compared to mucosa hPCIS. During incubation, Pro-Collagen-1A1 secretion increased in muscularis but not in mucosa hPCIS. MMP gene expression increased during incubation in mucosa and muscularis hPCIS, except for MMP9, MMP12, and MMP13 in muscularis hPCIS. Incubation with TGF-β1 caused increased COL1A1 expression in the mucosa but not in muscularis hPCIS. In muscularis hPCIS, TGF-β1 treatment caused a decrease in MMP1 and CTSK expression, while MMP13 was increased. In the presence of TGF-β1, protease inhibitor expression was stable, except for SERPINE1, which was increased in muscularis hPCIS. We conclude that fibrogenesis is more pronounced in muscularis hPCIS compared to mucosa hPCIS, especially when stimulated with TGF-β1.
... Inflammatory bowel disease (IBD), the main forms of which are Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory gastrointestinal disease of unknown etiology with significant morbidity and mortality worldwide [1][2][3][4]. IBD was originally endemic only in the Western world, but has now spread worldwide, for reasons which are not clear, but may be related to environmental and social changes, such as the adoption of Western lifestyles and eating habits [5]. Intestinal fibrosis (excessive accumulation of scar tissue in the intestinal wall) is a common and serious complication of IBD, resulting from chronic inflammation, and which is more common in CD [6,7]. ...
Objective
Intestinal fibrosis, a common and serious complication of inflammatory bowel disease (IBD), results from chronic inflammation. A high-cholesterol diet may be a risk factor for IBD and 27-hydroxylcholesterol (27HC) is the main human cholesterol metabolite. This study investigated whether 27HC can induce intestinal fibrosis.
Methods
The effects of cholesterol and 27HC on intestinal fibrosis were assessed in zebrafish and human intestinal epithelial Caco-2 cells.
Results
Cholesterol and 27HC induced intestinal inflammation and collagen deposition, inhibited E-cadherin (E-ca) expression in the intestinal epithelium, and promoted nuclear translocation of β-catenin in zebrafish. Cholesterol and 27HC up-regulated expression of COL-1, α-SMA, CTGF, TIMP1, N-cadherin, vimentin, glycogen synthesis kinase-3β (GSK-3β) and β-catenin, but inhibited E-ca, in Caco-2 cells. The expression of these proteins was inhibited by CYP27A1 knockdown and β-catenin knockdown. 27HC-induced nuclear translocation of β-catenin occurs in Caco-2 cells. p38, ERK, and AKT activate β-catenin and thereby participate in 27HC-induced epithelia–mesenchymal transition (EMT) and fibrosis. 27HC-increased oxidative stress and the fibrosis and EMT markers, the nuclear translocation of β-catenin, and the up-regulation of p-cell kinase proteins promoted by 27HC were inhibited by N-acetyl-L-cysteine (NAC). Folic acid (FA), resveratrol (RES), and NAC all ameliorated the 27HC-induced effects in Caco-2 cells and zebrafish.
Conclusion
A high-cholesterol diet caused intestinal fibrosis in zebrafish, mediated by a major cholesterol metabolite, 27HC. 27HC increased oxidative stress and activated p38, ERK, AKT, and β-catenin, leading to EMT of epithelial cells and intestinal fibrosis. FA and RES both ameliorated intestinal fibrosis by restraining 27HC-induced β-catenin activation.
... During chronic in ammation, local gut mesenchymal cells including broblasts, myo broblasts, and smooth muscle cells are activated, undergo proliferation, and synthesize large amounts of ECM components, which contribute to tissue brosis [27]. In ammatory responses play a key role in the initiation of intestinal brosis but play a minor role in the development of intestinal brosis [28,29] .Although signi cant progress has been made in anti-in ammatory therapy in recent years, the incidence of intestinal brosis in IBD has not decreased, indicating that controlling in ammation does not prevent the progression of brosis [30]. ...
Objective: Intestinal fibrosis is a common complication of inflammatory bowel disease and is characterized by tissue stiffening and luminal narrowing. Dihydromyricetin (DHM) can alleviate liver fibrosis and renal interstitial fibrosis by inducing autophagy. However, whether DHM can alleviate intestinal fibrosis remains unclear. This study aimed to evaluate the role and mechanism of action of DHM in inflammatory bowel disease-associated intestinal fibrosis .
Methods: Mice were administered Dextran sulphate Sodium (DSS) in drinking water to induce inflammatory bowel disease-associated intestinal fibrosis. HE staining, qPCR and Western blotting were used to analyze colon inflammation. Masson’ s trichrome staining, qPCR, Western blotting and immunofluorescence staining were used to evaluate the severity of fibrosis. Transmission electron microscopy and Western blotting were used to assess the activation of autophagosomes. The human colonic fibroblast line CCD-18Co, was cultured in the presence of TGF-β1 to develop a fibrotic phenotype.Immunofluorescence staining, Western blotting and qPCR were used to assess the alteration of fibrosis markers and used to investigate whether DHM-induced autophagy was involved in the inactivation of CCD-18Co cells. Additionally, the role of the PI3K/AKT/mTOR pathway was investigated.
Results: DHM alleviated intestinal inflammation and inhibited the progression of intestinal fibrosis. Additionally, DHM induced the activation of autophagy, thereby alleviating intestinal fibrosis, and downregulated the PI3K/AKT/mTOR signaling pathway in vitro.
Conclusions: Overall, this study demonstrated that DHM can inhibit the progression of intestinal fibrosis and activation of colonic fibroblasts by inducing autophagy through the PI3K/AKT/mTOR signaling pathway, thereby playing a preventive and therapeutic role in intestinal fibrosis.
... In CD, due to the submucosal involvement and full-thickness fibrotic disease, the destruction or blockage of lymphatics may be seen. This possibly has a restrictive effect on intestinal protein loss [35][36][37] . This gradual destruction of the intestinal wall and lymphatic obstruction may be why we do not usually see severe and resistant hypoalbuminemia in CD. ...
Background:
Non-steroidal anti-inflammatory drug (NSAID) use may cause diaphragm-like lesions in the bowel. Although NSAID-enteropathy is among the causes of protein-losing enteropathy (PLE), intractable hypoalbuminemia is rare.
Case report:
Here, we discuss a case of NSAID-enteropathy with a diaphragm-like disease that presented with Protein Losing Enteropathy (PLE) rather than obstruction. The hypoalbuminemia recovered immediately after resection of the obstructive segment, despite ongoing annular ulcerations in the early postoperative period. Thus, it was not clear whether obstructive mechanisms influenced resistant hypoalbuminemia besides the ulcers. We also reviewed the English-written literature for "diaphragm-type lesion, NSAID-enteropathy, obstruction, and protein-losing enteropathy". We noted that the role of obstruction in the pathophysiology of PLE was not clear.
Conclusions:
As our case and a couple of cases reported in literature, slow-onset obstructive pathology seems to contribute to well-known factors: inflammatory response, exudation, tight-junction dysfunction, and increase in permeability in the physiopathology of NSAID-induced PLE. Factors such as distention-induced low-flow ischemia and reperfusion, cholecystectomy-related continuous bile flow, bacterial overgrowth-related bile deconjugation and concomitant inflammation are among other potential influencers. The possible role of a slow-onset obstructive pathology in the physiopathology of NSAID-induced and other PLE needs to be further elucidated.
... Синергічна дія всіх ММП-продукуючих фіброгенних клітин стінки кишечника контролюється численними медіаторними молекулами. Серед них: трансформуючий фактор росту β (TGF-β); активні фактори росту сполучної тканини (CNGF); тромбоцитарний фактор росту (PDGF); інсуліноподібний фактор росту (IGF-1/2); епідермальний фактор росту (ERF); ендотеліни 1, 2, 3; багато цитокінів; продукти окисного стресу; компоненти ренін-ангіотензинової системи; ангіогенні фактори, у тому числі фактори зростання ендотелію судин, та інші [14]. ...
The article deals with chronic inflammatory processes of the intestines and their complications that contribute to the gradual accumulation of deep transmural lesions of the intestinal wall, including narrowings, development of obstruction, abscesses, and fistulas. Both inflammatory bowel diseases and their chronic complications lead to the onset of diarrhea, abdominal pain, anemia caused by intestinal pathology. Detecting the disease activity and complications severity is of crucial importance in the treatment intensity at early and later stages of the illness and when monitoring treatment measures effectiveness. The main molecular mediators of fibrogenesis are studied in the article, the results of development of intestinal fibrosis visualization technologies are summarized, possibilities for expanding the quantitative magnetic resonance imaging, computed tomography, ultrasound and encouraging potential of non-invasive elastography methods are discussed.
... The most frequently used diagnostic tool is endoscopic examination, which is valuable, although very invasive, examination. Therefore, there is a serious need to find new, reliable and non-invasive methods, which would allow the diagnosis, monitoring and prediction of the course of disease [1,2]. ...
... Increased expression of matrix metalloproteinases (MMPs) or other proteases (meprins, NE-neutrophil elastase) contributes to the destruction of the intestinal tissue and to the release of ECM's components into the circulation. Moreover, during intestinal chronic inflammation, pro-inflammatory and profibrotic mediators lead to permanent activation of myofibroblasts (MFs), which shifts the processes of tissue repair toward tissue fibrosis as a result of excessive matrix deposition [1,7]. Since the released components of the ECM turnover reflect metabolic changes at the tissue level, collagens and glycosaminoglycans have been investigated as new diagnostic markers in IBD [8,9]. ...
The aim of our research was to find new biomarkers that could be potentially used in the diagnosis, differentiation and monitoring of inflammatory bowel diseases (IBD). Since extracellular matrix (ECM) remodeling contributes to the pathological changes occurring in IBD, the serum profile of ECM-related proteins may reflect disease activity in the intestinal mucosa. Serum laminin (LM), fibronectin (FN) and gelatinase-associated lipocalin (NGAL) concentrations were determined in 51 patients with IBD before and after a year of treatment, as well as in 48 healthy individuals. A significant difference in serum concentration of FN (130,56 ± 52.87 vs. 287.93 ± 79.69, p < 0.001) and NGAL (133.34 ± 51.51 vs. 102.37.39, p < 0.05) between patients with ulcerative colitis (UC) and healthy individuals was found. In patients with Crohn’s disease (CD), serum concentrations of LM (1329.5 ± 389.36 vs. 1012.07 ± 260.85, p < 0.005) and NGAL (138.94 ± 51.31 vs. 102.65 ± 37.39, p < 0.05) were increased, while FN (89.26 ± 43.86 vs. 287.93 ± 79.69, p < 0.001) was decreased compared to healthy subjects. Moreover, a significant correlation was found between the Mayo score in patients with UC and the levels of NGAL (r = 0.49, p < 0.01) and LM (r = 0.035, p < 0.005), respectively. Another significant correlation was noted between the Crohn’s Disease Activity Index (CDAI) and LM (r = 0.49, p < 0.05) levels in CD group. The results presented in our studies indicate that ECM-related markers might be potential additional tools helpful in diagnosing IBD, differential diagnosis of UC and CD and monitoring the disease activity.
... Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is manifested by chronic inflammation of the gastrointestinal tract with significant morbidity and sometimes life-threatening complications [1,2]. Intestinal fibrosis is a serious and common complication of IBD, which is clinically more definite in CD [2][3][4][5]. ...
... The fibrogenic activation of intestinal myofibroblasts is modulated by Smaddependent and Smad-independent TGF-β signaling pathways [21,22]. Smad-dependent TGF-β signaling causes the phosphorylation of Smad2 and Smad3, which combine with Smad4, and the Smad complex translocates to the nucleus [1,[22][23][24][25]. The Smad3 component of the complex directly binds to gene promoters to induce the transcription of profibrotic molecules, including α-smooth muscle actin (α-SMA), collagens, fibronectin and connective tissue growth factor (CTGF) [26]. ...
Background:
Although intestinal fibrosis is a consequence of recurrent inflammation in Inflammatory bowel disease (IBD), alleviating inflammation alone does not prevent the progression of fibrosis, suggesting that the development of direct anti-fibrotic agents is necessary. This study aimed to evaluate the anti-fibrotic properties of combination treatment with pentoxifylline (PTX) and vitamin E (Vit-E) on human primary intestinal myofibroblasts (HIMFs) and the therapeutic potential of the combination therapy in murine models of IBD.
Methods:
HIMFs were pretreated with PTX, Vit-E, or both, and incubated with TGF-β1. We performed Western blot, qPCR, collagen staining, and immunofluorescence to estimate the anti-fibrotic effects of PTX and Vit-E. The cytotoxicity of these was investigated through MTT assay. To induce murine models of IBD for in vivo study, C57BL/6 mice were treated with repeated cycles of dextran sulfate sodium (DSS), developing chronic colitis. We examined whether the combined PTX and Vit-E treatment would effectively ameliorate colonic fibrosis in vivo.
Results:
We found that the co-treatment with PTX and Vit-E suppressed TGF-β1-induced expression of fibrogenic markers, with decreased expression of pERK, pSmad2, and pJNK, more than either treatment alone in HIMFs. Neither PTX nor Vit-E showed any significant cytotoxicity in given concentrations. Consistently with the in vitro results, the co-administration with PTX and Vit-E effectively attenuated colonic fibrosis with recovery from thickening and shortening of colon in murine models of IBD.
Conclusions:
These findings demonstrated that the combination of PTX and Vit-E exhibits significant anti-fibrotic effects in both HIMFs and in vivo IBD models, providing a promising therapy for IBD.
... Active inflammation is mainly treated with medical therapy aiming at mucosal healing and normalization of bowel habits without pain [3,4]. Unfortunately, there is still a lack of evidence for successful medical treatment of fibrotic strictures [5,6]. Consequently, fibrotic strictures and penetrating disease are considered the main indications for small intestinal surgery in CD [7]. ...
Strictures and abdominal pain often complicate Crohn's disease (CD). The primary aim was to explore whether parameters obtained by preoperative contrast-enhanced (CE) ultrasonography (US) and dynamic CE MR Enterography (DCE-MRE) of strictures associates with biomechanical properties. CD patients undergoing elective small intestinal surgery were preoperatively examined with DCE-MRE and CEUS. The excised intestine was distended utilizing a pressure bag. Luminal and outer bowel wall cross-sectional areas were measured with US. The circumferential stricture stiffness (Young's modulus E) was computed. Stiffness was associated with the initial slope of enhancement on DCE-MRE (ρ = 0.63, p = 0.007), reflecting active disease, but lacked association with CEUS parameters. For structural imaging parameters, inflammation and stricture stiffness were associated with prestenotic dilatation on US (τb = 0.43, p = 0.02) but not with MRE (τb = 0.01, p = 1.0). Strictures identified by US were stiffer, 16.8 (14.0-20.1) kPa, than those graded as no or uncertain strictures, 12.6 (10.5-15.1) kPa, p = 0.02. MRE global score (activity) was associated with E (ρ = 0.55, p = 0.018). Elastography did not correlate with circumferential stiffness. We conclude that increasing activity defined by the initial slope of enhancement on DCE-MRE and MRE global score were associated with stricture stiffness. Prestenotic dilatation on US could be a potential biomarker of CD small intestinal stricture stiffness.
... Abscesses usually in diffusion sequences show limited diffusion with high signal intensity on high b-value images (i.e., a b-value of at least 500 s/mm 2 ) and low signal intensity on the corresponding ADC maps. As already mentioned, weighted DWI sequences represent one of the reference sequences for the evaluation of CD, and are fundamental in those patients with a contraindication to intravenous contrast material infusion [190]. Also in this case, the diffusion study has shown similar results compared with the post-contrast images regarding the complication's detection. ...
Inflammatory bowel disease (IBD) is the term used to identify a form of chronic inflammation of the gastrointestinal tract that primarily contemplates two major entities: ulcerative colitis (UC) and Crohn’s disease (CD). The classic signs are abdominal pain and diarrhoea that correlate with the localization of gastro-enteric disease, although in this pathology extraintestinal symptoms may coexist. The diagnosis of CD relies on a synergistic combination of clinical, laboratory (stool and biochemical), cross-sectional imaging evaluation, as well as endoscopic and histologic assessments. The purpose of this paper is to prove the role of imaging in the diagnosis and follow-up of patients with CD with particular focus on recent innovations of magnetic resonance enterography (MRE) as a pivotal diagnostic tool, analysing the MRE study protocol and imaging features during the various phases of disease activity and its complications.
... The intestinal inflammatory model is associated with fibrosis, which is occurred secondary to inflammatory cytokines secretion and mucosal injury with subsequent activation of tissue growth factor β (TGF-β) which is a central mediator of fibrosis. 65 HFD and orly are associated with increased production of reactive oxygen species (ROS) with subsequent inflammatory response and fibroblast activation leading to fibrogenesis. 66 NAC was also proved to have antifibrotic properties. ...
Background
Obesity is a major universal health issue linked to a majority of illness.
Aim
To evaluate the histological and biochemical changes occurred in the duodenal mucosa of high fat diet HFD and orlistat fed rats and to assess the possible protective role of N-acetyl cysteine NAC supplementation.
Material and method
Sixty male albino rats weighing 180–200 g were classified randomly into control group I and three experimental groups (HFD group II, HFD + orlistat group III, and HFD + orlistat + NAC group IV). All experimental groups received HFD alone/and treatment for 6 weeks. Group III received orlistat (32 mg/kg/day) before meals and group IV received the same regimen as group III in addition to NAC (230 mg/kg/day) after meals. After completion of the experiment, duodenal sections were processed for histological examination, oxidative stress parameters, and semiqualitative real time PCR for proinflammatory mediators TNFα and IL6 evaluation. Also, plasma lipid parameters were assessed and morphometric duodenal results were analyzed statistically.
Results
By histological examination of HFD and (HFD + orlistat) groups, we found severe to moderate duodenal structural disturbances, increased goblet cells, collagen fibers, and BAX and iNOS immunostaining. By Biochemical examination, both groups showed increased proinflammatory markers level (TNFα and IL6) with decreased all antioxidant parameters and increased MDA. Moreover, NAC treatment in group IV significantly reduced all structural changes, levels of proinflammatory mediators and increased all antioxidant parameter levels and decreased MDA.
Conclusion
All findings elucidated that NAC could be accounted to be a useful drug for protection of duodenal mucosa of HFD and orlistat treated animals.
