Fibrosis is characterized by fibroblast activation, leading to matrix remodeling culminating in a stiff, type I collagen–rich fibrotic matrix. Alveolar epithelial cell (AEC) apoptosis is also a major feature of fibrogenesis, and AEC apoptosis is sufficient to initiate a robust lung fibrotic response. TGF-β (transforming growth factor-β) is a major driver of fibrosis and can induce both AEC apoptosis and fibroblast activation. We and others have previously shown that changes in extracellular matrix stiffness and composition can regulate the cellular response to TGF-β. In the present study, we find that type I collagen signaling promotes TGF-β–mediated fibroblast activation and inhibits TGF-β–induced AEC death. Fibroblasts cultured on type I collagen or fibrotic decellularized lung matrix had augmented activation in response to TGF-β, whereas AECs on cultured on type I collagen or fibrotic lung matrix were more resistant to TGF-β–induced apoptosis. Both of these responses were mediated by integrin α₂β₁, a major collagen receptor. AECs treated with an α₂ integrin inhibitor or with deletion of α₂ integrin had loss of collagen-mediated protection from apoptosis. We found that mice with fibroblast-specific deletion of α₂ integrin were protected from fibrosis whereas mice with AEC-specific deletion of α₂ integrin had more lung injury and a greater fibrotic response to bleomycin. Intrapulmonary delivery of an α₂ integrin–activating collagen peptide inhibited AEC apoptosis in vitro and in vivo and attenuated the fibrotic response. These studies underscore the need for a thorough understanding of the divergent response to matrix signaling.

纤维化的特征是成纤维细胞活化，导致基质重塑，最终形成坚硬的富含 I 型胶原蛋白的纤维化基质。肺泡上皮细胞 (AEC) 细胞凋亡也是纤维化的主要特征，AEC 细胞凋亡足以启动强大的肺纤维化反应。TGF-β（转化生长因子-β）是纤维化的主要驱动因素，可诱导 AEC 细胞凋亡和成纤维细胞活化。我们和其他人之前已经表明，细胞外基质硬度和组成的变化可以调节细胞对 TGF-β 的反应。在本研究中，我们发现 I 型胶原信号促进 TGF-β 介导的成纤维细胞活化并抑制 TGF-β 诱导的 AEC 死亡。在 I 型胶原蛋白或纤维化脱细胞肺基质上培养的成纤维细胞对 TGF-β 的反应增强了激活，而在 I 型胶原蛋白或纤维化肺基质上培养的 AECs 对 TGF-β 诱导的细胞凋亡具有更强的抵抗力。这两种反应都是由整合素 α 介导的₂ β ₁，一种主要的胶原受体。用 α ₂整联蛋白抑制剂或缺失 α ₂整联蛋白处理的 AEC失去了胶原介导的细胞凋亡保护。我们发现具有成纤维细胞特异性 α ₂整联蛋白缺失的小鼠免受纤维化的影响，而具有 AEC 特异性 α ₂整联蛋白缺失的小鼠具有更多的肺损伤和对博来霉素的更大的纤维化反应。肺内递送α ₂整合素激活胶原肽在体外和体内抑制 AEC 细胞凋亡并减弱纤维化反应。这些研究强调需要彻底了解对基质信号的不同反应。