Idiopathic pulmonary fibrosis (IPF) is a chronic scarring disease in which aging, environmental exposure(s) and genetic susceptibility have been implicated in disease pathogenesis, however, the causes and mechanisms of the progressive fibrotic cascade are still poorly understood. As epithelial–mesenchymal interactions are essential for normal wound healing, through human 2D and 3D in vitro studies, we tested the hypothesis that IPF fibroblasts (IPFFs) dysregulate alveolar epithelial homeostasis. Conditioned media from IPFFs exaggerated the wound-healing response of primary human Type II alveolar epithelial cells (AECs). Furthermore, AECs co-cultured with IPFFs exhibited irregular epithelialization compared with those co-cultured with control fibroblasts (NHLFs) or AECs alone, suggesting that epithelial homeostasis is dysregulated in IPF as a consequence of the abnormal secretory phenotype of IPFFs. Secretome analysis of IPFF conditioned media and functional studies identified the matricellular protein, SPARC, as a key mediator in the epithelial–mesenchymal paracrine signaling, with increased secretion of SPARC by IPFFs promoting persistent activation of alveolar epithelium via an integrin/focal adhesion/cellular-junction axis resulting in disruption of epithelial barrier integrity and increased macromolecular permeability. These findings suggest that in IPF fibroblast paracrine signaling promotes persistent alveolar epithelial activation, so preventing normal epithelial repair responses and restoration of tissue homeostasis. Furthermore, they identify SPARC-mediated paracrine signaling as a potential therapeutic target to promote the restoration of lung epithelial homoestasis in IPF patients.

特发性肺纤维化（IPF）是一种慢性疤痕疾病，其中衰老、环境暴露和遗传易感性与疾病发病机制有关，然而，进行性纤维化级联的原因和机制仍知之甚少。由于上皮-间质相互作用对于正常伤口愈合至关重要，通过人体 2D 和 3D 体外研究，我们测试了 IPF 成纤维细胞 (IPFF) 调节肺泡上皮稳态的假设。来自 IPFF 的条件培养基夸大了原代人 II 型肺泡上皮细胞 (AEC) 的伤口愈合反应。此外，与与对照成纤维细胞（NHLF）或单独 AEC 共培养的 AEC 相比，与 IPFF 共培养的 AEC 表现出不规则的上皮化，表明由于 IPFF 的异常分泌表型，IPF 中上皮稳态失调。IPFF 条件培养基的分泌组分析和功能研究确定了基质细胞蛋白 SPARC 是上皮-间质旁分泌信号传导的关键介质，IPFF 分泌的 SPARC 增加，通过整合素/粘着斑/细胞-促进肺泡上皮的持续激活。连接轴导致上皮屏障完整性破坏和大分子通透性增加。这些发现表明，在 IPF 中，成纤维细胞旁分泌信号传导促进持续的肺泡上皮活化，从而阻止正常的上皮修复反应和组织稳态的恢复。此外，他们将 SPARC 介导的旁分泌信号传导确定为促进 IPF 患者肺上皮稳态恢复的潜在治疗靶点。