van den Brûle Sybille, Misson Pierre, Bühling Frank, Lison Dominique, Huaux François
Université Catholique de Louvain, Clos Chapelle-aux-Champs, 30.54, 1200 Brussels, Brussels, Belgium.
Respir Res. 2005 Jul 27;6(1):84. doi: 10.1186/1465-9921-6-84.
Lung fibrosis is characterized by tissue remodeling resulting from an imbalance between synthesis and degradation of extracellular organic matrices. To examine whether cathepsin(s) (Cat) are important in the development of pulmonary fibrosis, we assessed the expression of four Cat known for their collagenolytic activity in a model of silica-induced lung fibrosis.
Different strains of mice were transorally instilled with 2.5 mg crystalline silica or other particles. Cat expression (Cat K, S, L and B) was quantified in lung tissue and isolated pulmonary cells by quantitative RT-PCR. In vitro, we assessed the effect of different cytokines, involved in lung inflammatory and fibrotic responses, on the expression of Cat K by alveolar macrophages and fibroblasts.
In lung tissue, Cat K transcript was the most strongly upregulated in response to silica, and this upregulation was intimately related to the fibrotic process. In mouse strains known for their differential response to silica, we showed that the level of Cat K expression following silica treatment was inversely related to the level of TGF-beta expression and the susceptibility of these strains to develop fibrosis. Pulmonary macrophages and fibroblasts were identified as Cat K overproducing cells in the lung of silicotic mice. In vitro, Cat K was downregulated in mouse and human lung fibroblasts by the profibrotic growth factor TGF-beta1.
Altogether, these data suggest that while Cat K may contribute to control lung fibrosis, TGF-beta appears to limit its overexpression in response to silica particles.
肺纤维化的特征是细胞外有机基质合成与降解失衡导致的组织重塑。为了研究组织蛋白酶是否在肺纤维化发展过程中起重要作用，我们在二氧化硅诱导的肺纤维化模型中评估了四种已知具有胶原酶活性的组织蛋白酶的表达。
给不同品系的小鼠经口灌胃2.5mg结晶二氧化硅或其他颗粒。通过定量逆转录聚合酶链反应（qRT-PCR）对肺组织和分离的肺细胞中的组织蛋白酶表达（组织蛋白酶K、S、L和B）进行定量。在体外，我们评估了参与肺部炎症和纤维化反应的不同细胞因子对肺泡巨噬细胞和成纤维细胞中组织蛋白酶K表达的影响。
在肺组织中，组织蛋白酶K转录本对二氧化硅反应上调最为强烈，且这种上调与纤维化过程密切相关。在对二氧化硅反应不同的小鼠品系中，我们发现二氧化硅处理后组织蛋白酶K的表达水平与转化生长因子-β（TGF-β）的表达水平以及这些品系发生纤维化的易感性呈负相关。肺巨噬细胞和成纤维细胞被确定为矽肺小鼠肺中过度产生组织蛋白酶K的细胞。在体外，促纤维化生长因子TGF-β1可下调小鼠和人肺成纤维细胞中组织蛋白酶K的表达。
总之，这些数据表明，虽然组织蛋白酶K可能有助于控制肺纤维化，但TGF-β似乎会限制其对二氧化硅颗粒反应的过度表达。
