Smad3 deficiency ameliorates experimental obliterative bronchiolitis in a heterotopic tracheal transplantation model
Smad3 deficiency ameliorates experimental obliterative bronchiolitis in a heterotopic tracheal transplantation model
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DOI：
10.1016/s0002-9440(10)63382-2
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发表时间：
2004-10-01
影响因子：
6
通讯作者：
Roman, J
中科院分区：
文献类型：
--
作者：
Ramirez, AM;Takagawa, S;Roman, J
慢性同种异体移植排斥反应表现为闭塞性细支气管炎（OB）仍然是肺移植后长期生存的最大障碍。转化生长因子-β 1（TGF-β 1）与OB相关的组织重塑反应有关。因此，其细胞内信号转导子Smad 3是研究的主要目标。在此，我们研究TGF-β 1的作用，通过Smad 3，在OB的发展中使用异位气管移植在野生型和Smad 3-null小鼠。TGF-β 1在移植后早期浸润的单核细胞内可检测到。后来，在移植同种异体移植物的管腔和气道壁内的成纤维细胞和结缔组织中检测到。结缔组织生长因子的时间和组织分布相似。核检测Smad 3和磷酸化Smads内管腔成纤维细胞与增加管腔内沉积的纤维连接蛋白和胶原蛋白。当移植到Smad 3-null小鼠，同种异体移植物，未能组织管腔内渗出物，尽管成纤维细胞积累，并显示减少纤连蛋白和胶原蛋白沉积。在培养中，与野生型细胞相比，Smad 3缺陷型成纤维细胞对TGF-β 1的反应中表达减少的纤连蛋白。总之，这些研究表明，TGF-β信号转导，Smad 3，需要在移植气管实验OB的发展。
Chronic allograft rejection manifested as obliterative bronchiolitis (OB) remains the single greatest impediment to long-term survival after lung transplantation. Transforming growth factor-beta1 (TGF-beta1) has been implicated in the tissue remodeling response associated with OB. Therefore, its intracellular signal transducer, Smad3, is a prime target of investigation. Herein, we examine the role of TGF-beta1, through Smad3, in the development of OB using heterotopic tracheal transplantation in wild-type and Smad3-null mice. TGF-beta1 was detectable within infiltrating mononuclear cells early after transplantation. Later it was detected in fibroblasts and in the connective tissue accumulating within the lumen and the airway wall of the transplanted allografts. Connective tissue growth factor had a similar time and tissue distribution. Nuclear detection of Smad3 and phosphorylated Smads within intraluminal fibroblasts coincided with increased intraluminal deposition of fibronectin and collagen. When transplanted into Smad3-null mice, allografts; failed to organize the intraluminal exudates despite fibroblast accumulation and showed reduced fibronectin and collagen deposition. in culture, Smad3-deficient fibroblasts expressed reduced fibronectin in response to TGF-beta1 compared to wildtype cells. Together, these studies suggest that the TGF-beta signal transducer, Smad3, is required for the development of experimental OB in transplanted tracheas.