TGF-beta1 gene transfer to the mouse colon leads to intestinal fibrosis.
ABSTRACT Crohn's disease (CD) is a chronic, relapsing inflammatory bowel disease, characterized by transmural inflammation. In CD, the recurrent inflammatory injury and tissue repair that occurs in the intestine can progress uncontrollably, leading to the proliferation of mesenchymal cells as well as fibrosis, characterized by excessive extracellular matrix deposition. These processes thicken the bowel wall, reducing flexibility, and often culminate in obstructive strictures. Because no effective measures are currently available to specifically treat or prevent intestinal stricturing, we sought to gain a better understanding of its pathogenesis by developing a mouse model of intestinal fibrosis. Because transforming growth factor (TGF)-beta1 can mediate both fibrosis and mesenchymal cell proliferation; we studied the effects of delivering adenoviral vectors encoding spontaneously active TGF-beta1 into the colons of mice. We first demonstrated that enema delivery of marker adenoviral vectors led to the transfection of the colonic epithelium and transient transgene expression. Histologically, control vectors caused an acute inflammatory response, involving the recruitment of neutrophils and mononuclear cells into the colonic lamina propria; however, infection caused little if any fibrosis. In contrast, the TGF-beta1 vector caused a more severe and prolonged inflammatory response as well as localized collagen deposition, leading to severe and progressive fibrosis. This was accompanied by the emergence of cells with a myofibroblast phenotype. Ultimately the fibrosis resulted in many of the TGF-beta1-transfected mice developing profound colonic obstruction. Through adenoviral gene transfer technology, we describe a novel mouse model of colitis and implicate TGF-beta1 in the pathogenesis of obstructive intestinal fibrosis.
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ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing disease with disappointing survival rate, and uneffective therapeutic progress has been made in the last few years, forcing the urgent need to improve research to this disease. The commonly accepted pathogenic hypothesis of IPF is the trigger from continuous alveolar epithelium microinjuries and in the following series events, many signaling pathways were reported to lead to abnormal tissue repair and lung structure derangement in IPF, such as TGF-β, wnt, VEGF and PI3K-Akt signaling pathways. Traditional research of IPF related signaling pathway always focus on the independent function of pathway and disease signals, but the crosstalks and interactions among them were rarely valued. In this review, we summarize the signaling pathways which were reported to play important roles in the pathologic changes of IPF and the synergistic effect among those pathways. Next we discuss the application of genomics research and bioinformatics tools on IPF related pathway analysis, and give a systems biology perspective by integrating multi-level disease related datas. The novel prospective of pathway analysis could tease out the complex pathway interaction profiles of IPF, and is powerful to detect IPF related biomarkers for early diagnose and potential therapeutic targets.Autoimmunity Reviews 10/2014; 13(10). · 7.10 Impact Factor
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ABSTRACT: Abstract Background: Transforming growth factor β1 (TGFβ1) was one of the main factors for accelerating atrial fibrosis and has been reported with significantly higher level in plasma of the patients with essential hypertension (EH), especially in those with target organ damage. The contribution of TGFβ1 in the pathogenesis of atrial fibrillation (AF) in EH patients remains unknown. Methods: 75 EH patients with documented AF were divided into the paroxysmal AF group (EH+pAF, n = 44) or the chronic AF group (EH+cAF, n = 31), and 37 EH patients with sinus rhythm (SR) were assigned into the EH+SR group. All data including EH duration, blood pressure, lipids, glucose and left atrial diameter (LAD) measured by ultrasonic cardiogram were recorded. The serum levels of TGFβ1 and connective tissue growth factor (CTGF) were detected, and compared with normal controls (NC group, n = 36). Results: The serum levels of TGFβ1 and CTGF in all EH groups were significantly higher than those in the NC group (p < 0.001, respectively). Among the EH groups, TGFβ1 and CTGF levels were highest in the cAF group, followed by the pAF and the SR groups (p < 0.005). However, no significant difference was observed in TGFβ1 and CTGF levels between the cAF group and the pAF group. The serum TGFβ1 in AF patients was independently correlated with LAD, the presence of AF, aldosterone, CTGF and age. Conclusion: The serum TGFβ1 promotes CTGF synthesis and causes left atrial enlargement and remodeling, which is possibly involved in the pathogenesis of AF in EH patients.Clinical and Experimental Hypertension 12/2014; 37(1):1-6. · 1.46 Impact Factor
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ABSTRACT: Abstract Intestinal fibrosis is a common complication of the inflammatory bowel diseases (IBDs). It becomes clinically apparent in >30% of patients with Crohn's disease (CD) and in about 5% with ulcerative colitis (UC). Fibrosis is a consequence of local chronic inflammation and is characterized by excessive extracellular matrix (ECM) protein deposition. ECM is produced by activated myofibroblasts, which are modulated by both, profibrotic and antifibrotic factors. Fibrosis depends on the balance between the production and degradation of ECM proteins. This equilibrium can be impacted by a complex and dynamic interaction between profibrotic and antifibrotic mediators. Despite the major therapeutic advances in the treatment of active inflammation in IBD over the past two decades, the incidence of intestinal strictures in CD has not significantly changed as the current anti-inflammatory therapies neither prevent nor reverse the established fibrosis and strictures. 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 also gradually changing in light of an improved understanding of the cellular and molecular mechanisms that underline the pathogenesis of fibrosis. Comprehension of the mechanisms of intestinal fibrosis is thus vital and may pave the way for the developments of antifibrotic agents and new therapeutic approaches in IBD.Scandinavian Journal of Gastroenterology 01/2015; 50(1):53-65. · 2.33 Impact Factor