Pivotal role of cathepsin K in lung fibrosis
Pivotal role of cathepsin K in lung fibrosis
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DOI：
10.1016/s0002-9440(10)63777-7
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发表时间：
2004-06-01
影响因子：
6
通讯作者：
Welte, T
中科院分区：
文献类型：
--
作者：
Bühling, F;Röcken, C;Welte, T
细胞外基质的动态平衡对肺功能的至高无上的重要性体现在两个截然相反的极端：肺气肿和肺纤维化。本研究探讨了组织蛋白酶K(CatK)在小鼠肺纤维化病理中的作用及其与人类疾病活动性的关系。我们比较了博莱霉素对肺纤维化的诱导作用。CTSK-/-小鼠沉积的细胞外基质明显多于对照组小鼠。CTSK-/-小鼠来源的原代肺成纤维细胞的胶原酶活性降低，提示CatK在胶原蛋白降解中起作用。有趣的是，CTSK+/+对照组小鼠在纤维化的肺区显示CatK的表达增加，这表明CatK具有保护作用，以对抗病变肺中胶原基质的过度沉积。同样，在肺纤维化患者的肺标本中，成纤维细胞表达的CatK比从正常肺获得的更多。人肺成纤维细胞在原代细胞培养中被激活，通过增强基因转录和蛋白表达，导致CatK活性增加，并增加细胞内胶原酶的分解活性。我们认为，这是第一个研究表明在生理和病理条件下，CatK在肺基质动态平衡中起关键作用。
The paramount importance of the homeostasis of the extracellular matrix for pulmonary function is exemplified by two opposing extremes: emphysema and pulmonary fibrosis. This study examined the putative role of cathepsin K (catK) in the pathology of lung fibrosis in mice and its relevance to the human disease activity. We compared the induction of lung fibrosis by administration of bleomycin. CTSK-/- mice deposited significantly more extracellular matrix than control mice. Primary lung fibroblasts derived from CTSK-/- mice showed a decreased collagenolytic activity indicating the role of catK in collagen degradation. Interestingly, CTSK+/+ control mice revealed an increased expression of catK in fibrotic lung regions suggesting a protective role of catK to counter the excessive deposition of collagen matrix in the diseased lung. Similarly, in lung specimens obtained from patients with lung fibrosis fibroblasts expressed larger amounts of catK than those obtained from normal lungs. Activation of human pulmonary fibroblasts in primary cell cultures led to an increased activity of catK through enhanced gene transcription and protein expression and to increased intracellular collagenolytic activity. We believe that this is the first study to show that catK plays a pivotal role in lung matrix homeostasis under physiological and pathological conditions.