Divisions of Molecular Medicine & Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109-2216, USA.
Am J Physiol Lung Cell Mol Physiol. 2011 Nov;301(5):L683-92. doi: 10.1152/ajplung.00187.2011. Epub 2011 Aug 12.
In acute and chronic lung disease, widespread disruption of tissue architecture underlies compromised pulmonary function. Pulmonary fibroblasts have been implicated as critical effectors of tissue-destructive extracellular matrix (ECM) remodeling by mobilizing a spectrum of proteolytic enzymes. Although efforts to date have focused on the catabolism of type I collagen, the predominant component of the lung interstitial matrix, the key collagenolytic enzymes employed by pulmonary fibroblasts remain unidentified. Herein, membrane type-1 matrix metalloprotease (MT1-MMP) is identified as the dominant and direct-acting protease responsible for the type I collagenolytic activity mediated by both mouse and human pulmonary fibroblasts. Furthermore, MT1-MMP is shown to be essential for pulmonary fibroblast migration within three-dimensional (3-D) hydrogels of cross-linked type I collagen that recapitulate ECM barriers encountered in the in vivo environment. Together, these findings demonstrate that MT1-MMP serves as a key effector of type I collagenolytic activity in pulmonary fibroblasts and earmark this pericellular collagenase as a potential target for therapeutic intervention.
在急性和慢性肺部疾病中，组织结构的广泛破坏是肺功能受损的基础。肺部成纤维细胞通过动员一系列蛋白水解酶，被认为是破坏细胞外基质（ECM）重塑的关键效应因子。尽管迄今为止的研究重点都放在了Ⅰ型胶原的降解上，而Ⅰ型胶原又是肺间质基质的主要成分，但肺部成纤维细胞所采用的关键胶原水解酶仍未确定。本文中，膜型 1 基质金属蛋白酶（MT1-MMP）被鉴定为负责介导小鼠和人肺部成纤维细胞Ⅰ型胶原降解的主要和直接作用的蛋白酶。此外，MT1-MMP 对于肺部成纤维细胞在交联Ⅰ型胶原的三维（3-D）水凝胶中的迁移是必需的，该水凝胶可模拟体内环境中遇到的 ECM 屏障。综上所述，这些发现表明 MT1-MMP 是肺部成纤维细胞Ⅰ型胶原降解活性的关键效应因子，并将这种细胞周胶原酶标记为潜在的治疗干预靶点。
