Differences in the fibrogenic response after transfer of active transforming growth factor-β1 gene to lungs of "fibrosis-prone" and "fibrosis-resistant" mouse strains
Differences in the fibrogenic response after transfer of active transforming growth factor-β1 gene to lungs of "fibrosis-prone" and "fibrosis-resistant" mouse strains
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DOI：
10.1165/ajrcmb.27.2.4674
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发表时间：
2002-08-01
影响因子：
6.4
通讯作者：
Gauldie, J
中科院分区：
文献类型：
--
作者：
Kolb, M;Bonniaud, P;Gauldie, J
肺纤维化的特征是细胞外基质在间质中过度沉积，导致肺功能受损和呼吸衰竭。研究个体对纤维化发生的易感性的差异可能有助于发现当暴露于纤维化刺激时有纤维化风险的患者。在这项研究中，我们使用腺病毒基因转移将纤维化倾向(C57BL/6)和纤维化抵抗(BALB/c)小鼠品系瞬时暴露于高水平的活性转化生长因子(TGF)-β1，一种关键的促纤维化细胞因子。与C57BL/6小鼠相比，BALB/c小鼠在对活性的转化生长因子-β1的反应中发生的纤维化明显较少，尽管肺中转基因蛋白的水平更高。这不是因为细胞对转化生长因子-β1普遍无反应，因为两种菌株的原代成纤维细胞在体外对转化生长因子-β1刺激的胶原合成都有相同程度的增加。然而，转化生长因子-β1诱导C57BL/6小鼠肺成纤维细胞和肺组织金属蛋白酶组织抑制因子-1基因的表达明显上调，而对Balb/c小鼠的诱导作用较弱。这些发现表明，肺纤维化易感性的差异是在转化生长因子-β1的下游，纤维化倾向于肺内的胶原蛋白代谢可能发生了改变，这种变化趋向于“非降解性”环境。
Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix in the interstitium, resulting in impaired lung function and respiratory failure. Investigation of the differences in individual susceptibility to the development of fibrosis may help to detect patients that are at risk to fibrosis when exposed to fibrogenic stimuli. In this study we used adenoviral gene transfer to transiently expose a fibrosis-prone (C57BL/6) and a fibrosis-resistant (Balb/c) mouse strain to high levels of active transforming growth factor (TGF)-beta1, a key profibrotic cytokine. Balb/c mice developed significantly less fibrosis compared with C57BL/6 mice in response to active TGF-beta1 despite higher, levels of the transgene protein in the lung. This was not due to, a general unresponsiveness of cells to TGF-beta1, because primary fibroblasts of both strains increased collagen synthesis upon stimulation with TGF-beta1 in vitro to the same degree. However, TGF-beta1 induced a strong upregulation of tissue inhibitor of metalloprotease-1 gene in pulmonary fibroblasts as well as in lungs of C57BL/6 mice, in contrast to a weak induction in Balb/c mice. These findings suggest that the differences in susceptibility to pulmonary fibrosis are downstream from TGF-beta1 and that fibrosis-prone individuals may have an altered collagen metabolism in the lungs that is balanced toward a "nondegrading" environment.