Revealing the pathogenic and ageing-related mechanisms of the enigmatic idiopathic pulmonary fibrosis (and chronic obstructive pulmonary disease).

Abstract

Growing evidence suggests that ageing-associated alterations occur in both idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Here, we review the most recent literature on dysregulated ageing pathways in IPF and COPD and discuss how they may contribute to disease pathogenesis. Recent studies have shown that alveolar epithelial type II (ATII) cells undergo premature senescence under stress and that senescent ATII cells promote lung fibrogenesis. Some studies have explored the role of mitochondrial dysfunction in IPF. They have provided evidence that dysfunctional mitochondria are important contributors to fibrogenesis through release of damaged DNA and excessive formation of reactive oxygen species, whereas restoration of mitochondrial homeostasis may attenuate lung fibrosis. Insufficient autophagy has been shown to promote epithelial-to-mesenchymal transition and aberrant epithelial-fibroblast crosstalk, suggesting that autophagy augmentation may represent a potential therapeutic strategy. A number of studies have also explored the role of cellular senescence, mitochondrial homeostasis and autophagy in COPD. Several ageing mechanisms are dysregulated in the lungs of patients with IPF and COPD, although how they contribute to disease development and progression remains elusive. Genetic or pharmacologic attenuation of senescence-related pathways and elimination of senescent cells may represent a promising therapeutic strategy.