Aortic Carboxypeptidase-Like Protein Is Expressed in Fibrotic Human Lung and its Absence Protects against Bleomycin-Induced Lung Fibrosis
Aortic Carboxypeptidase-Like Protein Is Expressed in Fibrotic Human Lung and its Absence Protects against Bleomycin-Induced Lung Fibrosis
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DOI：
10.2353/ajpath.2009.080856
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发表时间：
2009-03-01
影响因子：
6
通讯作者：
Layne, Matthew D.
中科院分区：
文献类型：
--
作者：
Schissel, Scott L.;Dunsmore, Sarah E.;Layne, Matthew D.
特发性肺纤维化的病理特征包括增殖的成纤维细胞和肌成纤维细胞，以及过度的胶原基质沉积。此外，肌成纤维细胞收缩和富含胶原的基质的重塑都有助于纤维化肺的异常结构和功能。知之甚少。然而，关于促进成纤维细胞和肌成纤维细胞保留的胶原相关蛋白，以及这些细胞在细胞外基质上的增殖。在这项研究中，我们证明了主动脉羧肽酶样蛋白（ACLP），一种具有盘状蛋白样结构域的胶原相关蛋白，在人类纤维化肺组织和人类成纤维细胞中以高水平表达，并且其表达在博来霉素损伤的小鼠的肺中显著增加。重要的是，与野生型对照组相比，尽管博莱霉素诱导的炎症水平相当，但博莱霉素损伤后，ACLP缺陷小鼠肺中肌成纤维细胞和胶原蛋白的积累显著减少。由肺成纤维细胞分泌的ACLP保留在纤维状胶原上，并且在胶原上培养的ACLP缺陷的肺成纤维细胞表现出细胞铺展、增殖和胶原基质收缩的变化。最后，添加重组的ACLP盘状结构域培养的ACLP缺陷的肺成纤维细胞恢复细胞的扩展和增加胶原凝胶的收缩。因此，ACLP及其盘状蛋白样结构域可能是基于抗肌成纤维细胞的治疗肺纤维化的新靶点。(Am J Pathol 2009，174：818-828; DOI：10.2353/ajpath.2009.080856）
The pathological hallmarks of idiopathic pulmonary fibrosis include proliferating fibroblasts and myofibroblasts, as well as excessive collagen matrix deposition. In addition, both myofibroblast contraction and remodeling of the collagen-rich matrix contribute to the abnormal structure and function of the fibrotic lung. Little is known., however, about collagen-associated proteins that promote fibroblast and myofibroblast retention, as well as the proliferation of these cells on the extracellular matrix. in this study, we demonstrate that aortic carboxypeptidase-like protein (ACLP), a collagen-associated protein with a discoidin-like domain, is expressed at high levels in human fibrotic lung tissue and human fibroblasts, and that its expression increases markedly in the lungs of bleomycin-injured mice.]Importantly, ACLP-deficient mice accumulated significantly fewer myofibroblasts and less collagen in the lung after bleomycin injury, as compared with wild-type controls, despite equivalent levels of bleomycin-induced inflammation. ACLP that is secreted by lung fibroblasts was retained on fibrillar collagen, and ACLP-deficient lung fibroblasts that were cultured on collagen exhibited changes in cell spreading, proliferation, and contraction of the collagen matrix. Finally, the addition of recombinant discoidin-like domain of ACLP to cultured ACLP-deficient lung fibroblasts restored cell spreading and increased the contraction of collagen gels. Therefore, both ACLP and its discoidin-like domain may be novel targets for anti-myofibroblast-based therapies for the treatment of pulmonary fibrosis. (Am J Pathol 2009,174:818-828; DOI: 10.2353/ajpath.2009.080856)