The Interplay of the Genetic Architecture, Aging, and Environmental Factors in the Pathogenesis of Idiopathic Pulmonary Fibrosis

Am J Respir Cell Mol Biol. 2021 Feb;64(2):163-172. doi: 10.1165/rcmb.2020-0373PS.


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.

Keywords: aging; epigenetic reprogramming; gene variants; genetic predisposition; smoking.

Publication types

  • Review

MeSH terms

  • Aging / genetics*
  • Aging / pathology*
  • Disease Progression
  • Epigenesis, Genetic / genetics
  • Epithelial Cells / pathology
  • Epithelium / pathology
  • Fibroblasts / pathology
  • Humans
  • Idiopathic Pulmonary Fibrosis / genetics*
  • Idiopathic Pulmonary Fibrosis / pathology*
  • Lung / pathology
  • Myofibroblasts / pathology
  • Risk Factors