Bridges James P, Vladar Eszter K, Kurche Jonathan S, Krivoi Andrei, Stancil Ian T, Dobrinskikh Evgenia, Hu Yan, Sasse Sarah K, Lee Joyce S, Blumhagen Rachel Z, Yang Ivana V, Gerber Anthony N, Peljto Anna L, Evans Christopher M, Redente Elizabeth F, Riches David Wh, Schwartz David A
Department of Medicine, National Jewish Health, Denver, Colorado, USA.
Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
J Clin Invest. 2025 Jan 2;135(1):e183836. doi: 10.1172/JCI183836.
Idiopathic pulmonary fibrosis (IPF) is etiologically complex, with well-documented genetic and nongenetic origins. In this Review, we speculate that the development of IPF requires two hits: the first establishes a vulnerable bronchoalveolar epithelium, and the second triggers mechanisms that reprogram distal epithelia to initiate and perpetuate a profibrotic phenotype. While vulnerability of the bronchoalveolar epithelia is most often driven by common or rare genetic variants, subsequent injury of the bronchoalveolar epithelia results in persistent changes in cell biology that disrupt tissue homeostasis and activate fibroblasts. The dynamic biology of IPF can best be contextualized etiologically and temporally, including stages of vulnerability, early disease, and persistent and progressive lung fibrosis. These dimensions of IPF highlight critical mechanisms that adversely disrupt epithelial function, activate fibroblasts, and lead to lung remodeling. Together with better recognition of early disease, this conceptual approach should lead to the development of novel therapeutics directed at the etiologic and temporal drivers of lung fibrosis that will ultimately transform the care of patients with IPF from palliative to curative.
特发性肺纤维化（IPF）病因复杂，其遗传和非遗传起源均有充分记录。在本综述中，我们推测IPF的发展需要两次打击：第一次打击使支气管肺泡上皮处于易损状态，第二次打击触发相关机制，使远端上皮细胞重编程，从而启动并维持促纤维化表型。虽然支气管肺泡上皮的易损性通常由常见或罕见的基因变异驱动，但随后支气管肺泡上皮的损伤会导致细胞生物学的持续变化，进而破坏组织稳态并激活成纤维细胞。IPF的动态生物学过程可以从病因学和时间维度进行最佳阐释，包括易损阶段、疾病早期以及持续性和进行性肺纤维化阶段。IPF的这些方面突出了对上皮功能产生不利影响、激活成纤维细胞并导致肺重塑的关键机制。随着对疾病早期的更好识别，这种概念性方法应能推动针对肺纤维化病因和时间驱动因素的新型治疗方法的开发，最终将IPF患者的治疗从姑息性转变为治愈性。
