Department of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Thorax. 2012 Feb;67(2):139-46. doi: 10.1136/thoraxjnl-2011-200717. Epub 2011 Sep 15.
The development of organ fibrosis after injury requires activation of transforming growth factor β(1) 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-β(1)-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-β(1)-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.
损伤后器官纤维化的发展需要转化生长因子β(1)的激活，该因子调节致纤维化基因的转录。据报道，蛋白酶体抑制剂的全身给药可预防肝、肾和骨髓纤维化的发展。据推测，蛋白酶体抑制通过抑制 TGF-β(1)介导的转录，可防止肺和皮肤损伤后的纤维化。
硼替佐米是一种广泛应用于临床的小分子蛋白酶体抑制剂，在博来霉素气管内或皮内给药后 7 天开始给小鼠给药，并分别在 21 或 40 天后测量肺和皮肤纤维化。为了研究这种保护的机制，给原代正常肺成纤维细胞以及分别来自特发性肺纤维化和硬皮病患者的原代肺和皮肤成纤维细胞给予硼替佐米。
硼替佐米在博来霉素起始后 7 天开始给药时可促进正常修复并预防肺和皮肤纤维化。在来自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来自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-β(1)介导的靶基因表达。核激素受体 PPARγ（Smad 介导的转录抑制剂）的丰度和活性增加促成了这种反应。
蛋白酶体抑制通过增加 PPARγ 的丰度和活性部分预防损伤后肺和皮肤纤维化。蛋白酶体抑制可能为调节组织修复和纤维化的患者提供一种新的治疗选择。
