Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30032, USA.
Am J Med Sci. 2012 Jul;344(1):41-51. doi: 10.1097/MAJ.0b013e318234c132.
Idiopathic pulmonary fibrosis (IPF) is a devastating progressive lung disease with an average survival of only 3 to 5 years. The mechanisms underlying the initiation and progression of IPF are poorly understood, and treatments available have only modest effect on disease progression. Interestingly, the incidence of IPF is approximately 60 times more common in individuals aged 75 years and older, but the mechanism by which aging promotes fibrosis is unclear. The authors hypothesized that aged lungs have a profibrotic phenotype that render it susceptible to disrepair after injury.
Young and old mice were treated with bleomycin to examine disrepair in the aged lung. In addition, uninjured young and old mouse lungs were analyzed for transforming growth factor-beta 1 (TGF-β1) production, extracellular matrix composition and lung fibroblast phenotype. Lung fibroblasts were treated with a DNA methyltransferase inhibitor to examine the potential epigenetic mechanisms involved in age-associated phenotypic alterations.
The lungs of old mice showed worse fibrosis after bleomycin-induced injury compared with the lungs from young mice. At baseline, aged lungs expressed a profibrotic phenotype characterized by increased mRNA expression for fibronectin extracellular domain A (Fn-EDA) and the matrix metalloproteinases (MMPs) MMP-2 and MMP-9. Old lungs also expressed higher levels of TGF-β receptor 1 and TGF-β1 mRNA, protein and activity as determined by increased Smad3 expression, protein phosphorylation and DNA binding. Lung fibroblasts harvested from aged lungs showed reduced expression of the surface molecule Thy-1, a finding also implicated in lung fibrosis; the latter did not seem related to Thy-1 gene methylation.
Altogether, aged lungs manifest a profibrotic phenotype characterized by enhanced fibronectin extracellular domain A and MMP expression and increased TGF-β1 expression and signaling and are populated by Thy-1-negative fibroblasts, all implicated in the pathogenesis of lung fibrosis.
特发性肺纤维化（IPF）是一种破坏性的进行性肺部疾病，平均存活时间仅为 3 至 5 年。IPF 起始和进展的机制尚不清楚，可用的治疗方法对疾病进展的影响也很有限。有趣的是，75 岁及以上人群中 IPF 的发病率大约高出 60 倍，但尚不清楚衰老促进纤维化的机制。作者假设，衰老的肺部具有致纤维化表型，使其在受伤后容易出现修复失败。
用博来霉素处理年轻和老年小鼠，以研究老年肺部的修复失败情况。此外，还分析了未受伤的年轻和老年小鼠肺部的转化生长因子-β1（TGF-β1）产生、细胞外基质组成和肺成纤维细胞表型。用 DNA 甲基转移酶抑制剂处理肺成纤维细胞，以研究年龄相关表型改变涉及的潜在表观遗传机制。
与年轻小鼠相比，博来霉素诱导损伤后老年小鼠的肺部纤维化更严重。在基线时，老年肺部表现出一种致纤维化表型，其特征是纤维连接蛋白外显子 A（Fn-EDA）和基质金属蛋白酶（MMPs）MMP-2 和 MMP-9 的 mRNA 表达增加。老年肺还表达更高水平的 TGF-β受体 1 和 TGF-β1mRNA、蛋白和活性，这是通过增加 Smad3 表达、蛋白磷酸化和 DNA 结合来确定的。从老年肺部中分离出的成纤维细胞表达减少了表面分子 Thy-1，这一发现也与肺纤维化有关；而后者似乎与 Thy-1 基因甲基化无关。
总之，老年肺部表现出一种致纤维化表型，其特征是增强了纤维连接蛋白外显子 A 和 MMP 的表达以及 TGF-β1 的表达和信号转导，并由 Thy-1 阴性成纤维细胞组成，所有这些都与肺纤维化的发病机制有关。
