Myofibroblast transdifferentiation in obliterative bronchiolitis:: TGF-β signaling through Smad3-dependent and -independent pathways

被引:58
作者
Ramirez, A. M. [1 ]
Shen, Z.
Ritzenthaler, J. D.
Roman, J.
机构
[1] Emory Univ, Sch Med, Andrew J McKelvey Lung Transplantat Ctr, Atlanta, GA 30322 USA
[2] Emory Univ, Sch Med, Div Pulm Allergy & Crit Care Med, Atlanta, GA 30322 USA
[3] Atlantic Vet Affairs Med Ctr, Atlanta, GA USA
关键词
lung transplantation; mitogen-activated protein kinase; myofibroblast; obliterative bronchiolitis; Smad3; transforming growth factor-beta;
D O I
10.1111/j.1600-6143.2006.01430.x
中图分类号
R61 [外科手术学];
学科分类号
摘要
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.
引用
收藏
页码:2080 / 2088
页数:9
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