Ramirez A M, Shen Z, Ritzenthaler J D, Roman J
Andrew J. McKelvey Lung Transplantation Center, Emory University School of Medicine, Atlanta, Georgia, USA.
Am J Transplant. 2006 Sep;6(9):2080-8. doi: 10.1111/j.1600-6143.2006.01430.x. Epub 2006 Jun 22.
We have shown that Smad3, an intracellular signal transducer for transforming growth factor-beta1 (TGF-beta1), 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-beta1-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-beta1, evidenced by increased alpha-smooth muscle actin mRNA and protein expression. In Smad3-null fibroblasts, TGF-beta1 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-beta1 in Smad3-deficient fibroblasts. Together, these studies suggest that in chronic allograft rejection, TGF-beta1 stimulates myofibroblast transdifferentiation through Smad3-dependent and -independent signals, contributing to the excessive matrix deposition that characterizes obliterative bronchiolitis.
我们已经表明，Smad3作为转化生长因子-β1（TGF-β1）的细胞内信号转导分子，在气管移植模型中引发闭塞性气道疾病的全部组织学表现是必需的。这表明慢性同种异体移植排斥反应导致TGF-β1诱导的Smad3激活，进而通过纤维增殖和基质沉积增加导致气道闭塞。在其他系统中，这些后期事件与成纤维细胞向肌成纤维细胞的转分化存在因果关系，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。我们使用免疫组织化学证实了与实验性OB相关的受影响气道内存在肌成纤维细胞。在体外研究气道成纤维细胞时，我们观察到TGF-β1可诱导肌成纤维细胞转分化增加，α-平滑肌肌动蛋白mRNA和蛋白表达增加证明了这一点。在Smad3基因缺失的成纤维细胞中，TGF-β1诱导的肌成纤维细胞转分化大大减弱但并未消除，这表明存在不依赖Smad3的途径。进一步的研究表明，p38（SB203580）和MEK/ERK（U1026）的小分子抑制剂可进一步降低TGF-β1在Smad3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-β1通过依赖Smad3和不依赖Smad3的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。
