Oikonomou N, Thanasopoulou A, Tzouvelekis A, Harokopos V, Paparountas T, Nikitopoulou I, Witke W, Karameris A, Kotanidou A, Bouros D, Aidinis V
Dr VInstitute of Immunology, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece.
Thorax. 2009 Jun;64(6):467-75. doi: 10.1136/thx.2008.107946. Epub 2009 Feb 12.
Despite intense research efforts, the aetiology and pathogenesis of idiopathic pulmonary fibrosis remain poorly understood. Gelsolin, an actin-binding protein that modulates cytoskeletal dynamics, was recently highlighted as a likely disease modifier through comparative expression profiling and target prioritisation.
To decipher the possible role of gelsolin in pulmonary inflammation and fibrosis, immunocytochemistry on tissue microarrays of human patient samples was performed followed by computerised image analysis. The results were validated in the bleomycin-induced animal model of pulmonary inflammation and fibrosis using genetically-modified mice lacking gelsolin expression. Moreover, to gain mechanistic insights into the mode of gelsolin activity, a series of biochemical analyses was performed ex vivo in mouse embryonic fibroblasts.
Increased gelsolin expression was detected in lung samples of patients with idiopathic interstitial pneumonia as well as in modelled pulmonary inflammation and fibrosis. Genetic ablation of gelsolin protected mice from the development of modelled pulmonary inflammation and fibrosis attributed to attenuated epithelial apoptosis.
Gelsolin expression is necessary for the development of modelled pulmonary inflammation and fibrosis, while the caspase-3-mediated gelsolin fragmentation was shown to be an apoptotic effector mechanism in disease pathogenesis and a marker of lung injury.
尽管进行了大量研究，但特发性肺纤维化的病因和发病机制仍知之甚少。凝溶胶蛋白是一种调节细胞骨架动力学的肌动蛋白结合蛋白，最近通过比较表达谱分析和靶点优先级确定，它被认为是一种可能的疾病调节因子。
为了解凝溶胶蛋白在肺部炎症和纤维化中的可能作用，对人类患者样本的组织微阵列进行免疫细胞化学分析，随后进行计算机图像分析。使用缺乏凝溶胶蛋白表达的基因修饰小鼠，在博来霉素诱导的肺部炎症和纤维化动物模型中验证了结果。此外，为了深入了解凝溶胶蛋白的活性模式，在小鼠胚胎成纤维细胞中进行了一系列体外生化分析。
在特发性间质性肺炎患者的肺样本以及模拟的肺部炎症和纤维化中，检测到凝溶胶蛋白表达增加。凝溶胶蛋白的基因缺失保护小鼠免受模拟的肺部炎症和纤维化的发展，这归因于上皮细胞凋亡的减弱。
凝溶胶蛋白表达对于模拟的肺部炎症和纤维化的发展是必要的，而半胱天冬酶-3介导的凝溶胶蛋白片段化被证明是疾病发病机制中的一种凋亡效应机制和肺损伤的标志物。
