Myofibroblast transdifferentiation in obliterative bronchiolitis:: TGF-β signaling through Smad3-dependent and -independent pathways
Myofibroblast transdifferentiation in obliterative bronchiolitis:: TGF-β signaling through Smad3-dependent and -independent pathways
复制标题
DOI：
10.1111/j.1600-6143.2006.01430.x
复制
发表时间：
2006-09-01
影响因子：
8.8
通讯作者：
Roman, J.
中科院分区：
文献类型：
--
作者：
Ramirez, A. M.;Shen, Z.;Roman, J.
我们已经表明，Smad 3，转化生长因子-β 1（TGF-β 1）的细胞内信号转导，是需要在气管移植模型中引起闭塞性气道疾病的完整组织学表现。这表明慢性同种异体移植排斥导致TGF-β 1诱导的Smad 3激活，通过纤维增生和增加的基质沉积导致气道闭塞。在其他系统中，这些后一种事件与成纤维细胞转分化为肌成纤维细胞有因果关系，但它们在肺移植后闭塞性细支气管炎（OB）中的作用尚不清楚。我们证实了肌成纤维细胞内受影响的气道与实验OB使用免疫组化。研究体外气道成纤维细胞，我们观察到肌成纤维细胞转分化增加，对TGF-β 1的反应，证明增加α-平滑肌肌动蛋白mRNA和蛋白质表达。在Smad 3缺失的成纤维细胞中，TGF-β 1诱导的肌成纤维细胞转分化大大减少，但没有被消除，这表明存在Smad 3非依赖性途径。进一步的研究表明，p38（SB 203580）和MEK/ERK（U1026）的小分子抑制剂进一步降低了TGF-β 1在Smad 3缺陷成纤维细胞中的剩余作用。总之，这些研究表明，在慢性同种异体移植排斥反应中，TGF-β 1通过Smad 3依赖性和非依赖性信号刺激肌成纤维细胞转分化，导致闭塞性细支气管炎特征性的过度基质沉积。
We have shown that Smad3, an intracellular signal transducer for transforming growth factor-beta 1 (TGF-beta 1), is required to elicit the full histological manifestations of obliterative airway disease in a tracheal transplant model. This suggests that chronic allograft rejection results in TGF-beta 1-induced Smad3 activation that leads to airway obliteration through fibroproliferation and increased matrix deposition. In other systems, these latter events are causally related to the transdifferentiation of fibroblasts into myofibroblasts, but their role in obliterative bronchiolitis (OB) after lung transplantation is unknown. We confirmed the presence of myofibroblasts inside affected airways associated with experimental OB using immunohistochemistry. Studying airway fibroblasts in vitro, we observed increased myofibroblast transdifferentiation in response to TGF-beta 1, evidenced by increased alpha-smooth muscle actin mRNA and protein expression. In Smad3-null fibroblasts, TGF-beta 1 induction of myofibroblast transdifferentiation was greatly diminished but not abolished, suggesting the presence of Smad3-independent pathways. Further studies revealed that small molecule inhibitors of p38 (SB203580) and MEK/ERK (U1026) further reduced the remaining effect of TGF-beta 1 in Smad3-deficient fibroblasts. Together, these studies suggest that in chronic allograft rejection, TGF-beta 1 stimulates myofibroblast transdifferentiation through Smad3-dependent and -independent signals, contributing to the excessive matrix deposition that characterizes obliterative bronchiolitis.