Proteasomal inhibition after injury prevents fibrosis by modulating TGF-β(1) signalling.
Proteasomal inhibition after injury prevents fibrosis by modulating TGF-β(1) signalling.
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DOI：
10.1136/thoraxjnl-2011-200717
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发表时间：
2012-02
期刊：
影响因子：
10
通讯作者：
Jain M
中科院分区：
文献类型：
--
作者：
Mutlu GM;Budinger GR;Wu M;Lam AP;Zirk A;Rivera S;Urich D;Chiarella SE;Go LH;Ghosh AK;Selman M;Pardo A;Varga J;Kamp DW;Chandel NS;Sznajder JI;Jain M
损伤后器官纤维化的发展需要转化生长因子β1的活化，其调节促纤维化基因的转录。已报道蛋白酶体抑制剂的全身施用可预防肝、肾和骨髓中纤维化的发展。据推测，蛋白酶体抑制可通过抑制TGF-β1介导的转录来预防损伤后的肺和皮肤纤维化。博替佐米是一种广泛临床使用的小分子蛋白酶体抑制剂，在肺内或皮内施用博来霉素后7天开始向小鼠施用，分别在21或40天后测量肺和皮肤纤维化。为了检查这种保护的机制，将硼替佐米分别施用于从特发性肺纤维化和硬皮病患者获得的原代正常肺成纤维细胞和原代肺和皮肤成纤维细胞。博莱霉素开始治疗7天后开始给药，硼替佐米可促进正常修复并预防肺和皮肤纤维化。在正常个体和特发性肺纤维化患者的原代人肺成纤维细胞以及硬皮病患者的皮肤成纤维细胞中，硼替佐米通过抑制激活的Smads诱导的转录来抑制TGF-β1介导的靶基因表达。核激素受体PPARγ（Smad介导的转录的阻遏物）的丰度和活性的增加促成了这种反应。蛋白酶体抑制通过增加PPARγ的丰度和活性来防止损伤后的肺和皮肤纤维化。蛋白酶体抑制可能为组织修复失调和纤维化患者提供一种新的治疗选择。
The development of organ fibrosis after injury requires activation of transforming growth factor β1 which regulates the transcription of profibrotic genes. The systemic administration of a proteasomal inhibitor has been reported to prevent the development of fibrosis in the liver, kidney and bone marrow. It is hypothesised that proteasomal inhibition would prevent lung and skin fibrosis after injury by inhibiting TGF-β1-mediated transcription. Bortezomib, a small molecule proteasome inhibitor in widespread clinical use, was administered to mice beginning 7 days after the intratracheal or intradermal administration of bleomycin and lung and skin fibrosis was measured after 21 or 40 days, respectively. To examine the mechanism of this protection, bortezomib was administered to primary normal lung fibroblasts and primary lung and skin fibroblasts obtained from patients with idiopathic pulmonary fibrosis and scleroderma, respectively. Bortezomib promoted normal repair and prevented lung and skin fibrosis when administered beginning 7 days after the initiation of bleomycin. In primary human lung fibroblasts from normal individuals and patients with idiopathic pulmonary fibrosis and in skin fibroblasts from a patient with scleroderma, bortezomib inhibited TGF-β1-mediated target gene expression by inhibiting transcription induced by activated Smads. An increase in the abundance and activity of the nuclear hormone receptor PPARγ, a repressor of Smad-mediated transcription, contributed to this response. Proteasomal inhibition prevents lung and skin fibrosis after injury in part by increasing the abundance and activity of PPARγ. Proteasomal inhibition may offer a novel therapeutic alternative in patients with dysregulated tissue repair and fibrosis.
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DOI：
10.1164/rccm.200906-0964oc
发表时间：
2010-03-15
影响因子：
24.7
作者：
Daniels, Craig E.;Lasky, Joseph A.;Schroeder, Darrell R.
通讯作者：
Schroeder, Darrell R.
影响因子：
6
作者：
Lakos, G;Takagawa, S;Varga, J
通讯作者：
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影响因子：
6
作者：
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通讯作者：
Heller, RA
影响因子：
--
作者：
Ghosh, AK;Bhattacharyya, S;Varga, J
通讯作者：
Varga, J
影响因子：
13.5
作者：
Anan, A;Baskin-Bey, ES;Gores, GJ
通讯作者：
Gores, GJ