Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease of indeterminate etiology and limited therapeutic options. The initiation, development, and progression of IPF are influenced by genetic predisposition, aging, and host and environmental factors, but the magnitude of the contribution of each of them and the sequence of the pathogenic events are uncertain. Current evidence indicates that accumulated environmental exposures in a genetically predisposed individual, usually over 60 years of age, leads to phenotypic and functional alterations of the lung epithelium. Aberrant activation of epithelial cells results, through a complex release of numerous mediators, in the local expansion of peculiar subsets of aggressive fibroblasts and myofibroblasts, which are crucial effector cells of fibrotic remodeling and loss of the normal lung architecture and function. Progressive increase of the mechanical stiffness activates cell-autonomous and matrix-dependent processes contributing to the perpetuation of the fibrotic response. This Perspective provides an integral overview of the major risk factors underpinning the pathogenesis of IPF, including gene variants, aging alterations, environmental factors, host risk factors, and epigenetic reprogramming.

特发性肺纤维化（IPF）是病因不明且治疗选择有限的慢性纤维化肺部疾病。IPF的启动，发展和进程受遗传易感性，衰老以及宿主和环境因素的影响，但是它们各自的贡献程度和致病事件的顺序尚不确定。目前的证据表明，通常在60岁以上的遗传易感人群中累积的环境暴露会导致肺上皮的表型和功能改变。上皮细胞的异常激活通过大量介质的复杂释放导致侵袭性成纤维细胞和成肌纤维细胞的特殊亚群的局部扩展，它们是纤维化重构和正常肺结构和功能丧失的关键效应细胞。机械刚度的逐渐提高激活了细胞自主和依赖于基质的过程，从而促进了纤维化反应的持续。该观点提供了IPF发病机理的主要风险因素的完整概述，包括基因变异，衰老变化，环境因素，宿主风险因素和表观遗传重编程。