Smad3 loss confers resistance to the development of trinitrobenzene sulfonic acid-induced colorectal fibrosis
Smad3 loss confers resistance to the development of trinitrobenzene sulfonic acid-induced colorectal fibrosis
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DOI：
10.1111/j.1365-2362.2008.02076.x
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发表时间：
2009-02-01
影响因子：
5.5
通讯作者：
Gaudio, E.
中科院分区：
文献类型：
--
作者：
Latella, G.;Vetuschi, A.;Gaudio, E.
转化生长因子-β(转化生长因子-β)/Smad3信号在组织纤维化中起核心作用，是细胞外基质(ECM)蛋白积聚的有力刺激因素。本研究旨在探讨Smad3在三硝基苯磺酸(TNBS)诱导的Smad3基因缺失小鼠结肠纤维化发病机制中的作用。每只小鼠在6周的时间里接受了递增剂量的TNBS(每周0.5-1.0 mg)。切除结肠进行大体检查、组织学、形态计量学和免疫组织化学分析。免疫组织化学：α-平滑肌肌动蛋白(α-SMA)、I型-III型胶原、转化生长因子-β1、结缔组织生长因子(CTGF)、Smad3、Smad7和CD3抗体。肉眼观察，Smad3野生型小鼠的结肠明显比Smad3缺陷型小鼠的结肠更硬、更厚、更短。在野生型小鼠中，50%的小鼠出现了结肠粘连和狭窄。组织学和形态计量学评估显示，与空白小鼠相比，Smad3野生型小鼠的结肠纤维化和胶原堆积程度明显更高，而两组小鼠的结肠炎症程度没有差异。免疫组织化学检测显示，Smad3野生型小鼠结肠CTGF、I-III型胶原、转化生长因子-β和Smad3的表达较空白小鼠显著增加，而Smad7的表达仅在空白小鼠中增加，提示Smad3的缺失对TNBS诱导的结肠纤维化的形成具有抵抗作用。纤维化反应的减少似乎是由于纤维形成的间充质细胞激活和ECM的产生和积聚减少。SMAD3可能成为治疗肠道纤维化，特别是炎症性肠病的新靶点.欧洲临床医学杂志，2009；39(2)：145-156.
Transforming growth factor-beta (TGF-beta)/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.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 (alpha-SMA), collagen types I-III, TGF-beta 1, connective tissue growth factor (CTGF), Smad3, Smad7, and CD3 antibodies were used.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-beta and Smad3 staining in the colon of Smad3 wild-type compared to null mice, whereas Smad7 was increased only in null mice.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.Eur J Clin Invest 2009; 39 (2): 145-156.