The ageing lung under stress

Abstract

Healthy ageing of the lung involves structural changes but also numerous cell-intrinsic and cell-extrinsic alterations. Among them are the age-related decline in central cellular quality control mechanisms such as redox and protein homeostasis. In this review, we would like to provide a conceptual framework of how impaired stress responses in the ageing lung, as exemplified by dysfunctional redox and protein homeostasis, may contribute to onset and progression of COPD and idiopathic pulmonary fibrosis (IPF). We propose that age-related imbalanced redox and protein homeostasis acts, amongst others (e.g. cellular senescence), as a "first hit" that challenges the adaptive stress-response pathways of the cell, increases the level of oxidative stress and renders the lung susceptible to subsequent injury and disease. In both COPD and IPF, additional environmental insults such as smoking, air pollution and/or infections then serve as "second hits" which contribute to persistently elevated oxidative stress that overwhelms the already weakened adaptive defence and repair pathways in the elderly towards non-adaptive, irremediable stress thereby promoting development and progression of respiratory diseases. COPD and IPF are thus distinct horns of the same devil, "lung ageing".

FIGURE 1

Lung histology of a) a 62-year-old patient with COPD, b) a 64-year-old patient with idiopathic pulmonary fibrosis and c) a 61-year-old organ donor. All patients are male and are (former) smokers. Shown is a representative immunohistochemistry for alpha-smooth-muscle-actin (α-SMA). Scale bar=1 mm.

FIGURE 2

Pathogenesis of lung ageing. The decline of major components of overall adaptive homeostasis capacity (e.g. antioxidant defences and proteostasis capacity) during ageing increases oxidative stress which further exerts detrimental effects on genomic integrity and proteostasis, leading to a progressive deterioration of pulmonary function and a pro-inflammatory shift. This is accompanied by a structural change designated “senile emphysema”, which is characterised by reduced proliferation of alveolar/septal wall cells and eminent enlargement of the alveolar airspaces without alveolar wall destruction.

FIGURE 3

Predisposition of the aged lung to chronic lung diseases such as COPD or idiopathic pulmonary fibrosis (IPF). The vulnerable aged lung is primed to oxidative stress, cell injury and disrepair, acting as the “first hit”. Environmental challenges such as cigarette smoking, air pollution or viral/bacterial infections may serve as “second hits” which worsen age-related events and contribute to persistently elevated oxidative stress levels, that overwhelms the (weakened) defence and repair pathways. Whereas increased demise of type-II alveolar epithelial cells (AECII) is a common feature in both diseases, in COPD, however, oxidative stress and its detrimental consequences also result in a loss of structural fibroblasts and septal endothelial cells, leading to an irreversible loss of lung tissue and progressive formation of emphysematous spaces. In IPF, death and loss of AECII triggers abnormal fibroblast proliferation, myofibroblast differentiation and irreversible scar tissue generation, with oxidative stress contributing to this process. The “origins” that predispose the ageing lung to develop either COPD or IPF after the decisive injury, remain elusive.