TGF-β, Smad3 and the process of progressive fibrosis
TGF-β, Smad3 and the process of progressive fibrosis
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DOI：
10.1042/bst0350661
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发表时间：
2007-08-01
影响因子：
3.9
通讯作者：
Kolb, M.
中科院分区：
文献类型：
--
作者：
Gauldie, J.;Bonniaud, P.;Kolb, M.
活性TGF-β 1（转化生长因子-β 1）的瞬时腺苷介导的基因转移在啮齿动物肺中诱导严重和进行性纤维化，而无明显炎症。或者，IL-1 β（白细胞介素1 β）的转移诱导显著的组织损伤和炎症，其发展为进行性纤维化，与肺液和组织中TGF 1 β浓度的增加相关。两种载体治疗均诱导纤维化反应，涉及肌成纤维细胞和进行性基质沉积，从支气管周围表达部位开始，持续数天，涉及整个肺和胸膜表面。将TGF-β 1载体施用至胸膜空间诱导进行性胸膜纤维化，其最小程度地延伸到肺实质中。参与进行性纤维化的机制需要考虑纤维化对特定器官的限制（肺纤维化而不是肝纤维化，反之亦然）以及抗炎治疗在调节进行性纤维化方面缺乏效果。TGF-β 1是纤维形成过程中的关键细胞因子，使用涉及ALKS受体和信号分子Smac 2和Smad 3的细胞内信号传导途径。将TGF β 1或IL-1 β瞬时基因转移至Smad 3缺失小鼠肺几乎没有提供进行性纤维化的证据，并且没有诱导纤维化相关基因。这些结果表明，进行性纤维化的机制涉及在基质的背景下，定义进行性基质沉积的微环境中提出的因素。
Transient adencivinds-mriediated gene transfer of active TGF-beta 1 (transforming growth factor-beta 1) induces severe and progressive fibrosis in rodent lung without apparent inflammation. Alternatively, transfer of IL-1 beta (interleukin 1 beta) induces marked tissue injury and inflammation, which develops into progressive fibrosis, associated with an increase in TGF1 beta concentrations in lung fluid and tissue. Both vector treatments induce a fibrotic response involving myofibroblasts and progressive matrix deposition starting at the peri-bronchial site of expression and extending over days to involve the entire lung and pleural surface. Administration of the TGF-beta 1 vector to the pleural space induces progressive pleural fibrosis, which minimally extends into the lung parenchyma. The mechanisms involved in progressive fibrosis need to account for the limitation of fibrosis to specific organs (lung fibrosis and not liver fibrosis or vice versa) and the lack of effect of anti-inflammatofy treatments in regulating progressive fibrosis. TGF-beta 1 is a key cytokine in the process of fibrogenesis, using intracellular signalling pathways involving the ALKS receptor and signalling molecules Smac2 and Smad3. Transient gene transfer of either TGF beta 1 or IL-1 beta to Smad3-null mouse lung provides little evidence of progressive fibrosis and no fibrogenesis-associated genes are induced. These results suggest that mechanisms of progressive fibrosis involve factors presented within the context of the matrix that define the microenvironment for progressive matrix deposition.