Abstract：
Damage and repair are recurring processes in tissues, with fibroblasts playing key roles by remodeling extracellular matrices (ECM) through protein synthesis, proteolysis, and cell contractility. Dysregulation of fibroblasts can lead to fibrosis and tissue damage, as seen in idiopathic pulmonary fibrosis (IPF). In advanced IPF, tissue damage manifests as honeycombing, or voids in the lungs. This study explores how transforming growth factor-beta (TGF-β), a crucial factor in IPF, induces lung fibroblast spheroids to create voids in reconstituted collagen through proteolysis and cell contractility, a process is termed as hole formation. These voids reduce when proteases are blocked. Spheroids mimic fibroblast foci observed in IPF. Results indicate that cell contractility mediates tissue opening by stretching fractures in the collagen meshwork. Matrix metalloproteinases (MMPs), including MMP1 and MT1-MMP, are essential for hole formation, with invadopodia playing a significant role. Blocking MMPs reduces hole size and promotes wound healing. This study shows how TGF-β induces excessive tissue destruction and how blocking proteolysis can reverse damage, offering insights into IPF pathology and potential therapeutic interventions.
摘要：
损伤和修复是组织中反复出现的过程，成纤维细胞通过蛋白质合成重塑细胞外基质（ECM）发挥关键作用，蛋白水解，和细胞收缩性。成纤维细胞的失调可导致纤维化和组织损伤，如特发性肺纤维化（IPF）所示。在高级IPF中，组织损伤表现为蜂窝状，或者肺部的空隙。本研究探讨了转化生长因子-β(TGF-β)IPF中的一个关键因素，通过蛋白水解和细胞收缩性诱导肺成纤维细胞球状体在重建的胶原蛋白中产生空隙，一个过程被称为孔形成。当蛋白酶被阻断时,这些空隙减少。在IPF中观察到球体模拟成纤维细胞病灶。结果表明，细胞收缩性通过拉伸胶原网中的骨折来介导组织开放。基质金属蛋白酶（MMPs），包括MMP1和MT1-MMP，对洞的形成至关重要，invadopodia发挥了重要作用。阻断MMP减小孔尺寸并促进伤口愈合。这项研究显示了TGF-β如何诱导过度的组织破坏，以及阻断蛋白水解如何逆转损伤，提供对IPF病理学和潜在治疗干预的见解。
