p53-Dependent Senescence in Bronchial Club Cells Promotes Chronic Lung Inflammation

Purpose

Chronic obstructive pulmonary disease (COPD) is an age-related disorder of the lungs which is currently estimated as the third leading cause of death worldwide. Chronic lung inflammation is the main component of COPD. p53 limits tumorigenesis by inducing apoptosis, cell cycle arrest and senescence. At present, the role of senescence of bronchial cells and of p53 in regulation of chronic inflammation is not understood.

Methods

To understand the role of p53 in chronic lung inflammation we have constructed a mouse model where p53 is specifically knocked out in bronchial epithelia Club cells and subjected these mice to repetitive lipopolysaccharide (LPS) inhalations.

Results

This chronic exposure resulted in severe bronchitis within weeks. Surprisingly, lungs deficient in p53 in their Club cells were significantly protected from the chronic inflammatory processes, as reflected in reduced accumulation of neutrophils, macrophages as well as CD3, CD4 and CD8 T cells, in both bronchio-alveolar space and lung interstitium. LPS stimulated Club cell p53 dependent accumulation of bronchus associated lymphoid tissue (BALT). Chronically inflamed bronchioles expressed senescence, but not apoptosis markers, which were significantly attenuated in Club cell specific p53 knockout mice as well as in mice knockout for one of the senescence regulators - p21(Cdkn1a). Moreover, pharmacological elimination of senescent cells protected wild type mice from chronic LPS induced bronchitis and BALT generation nearby bronchioles. We propose that p53 is necessary for the induction of cellular senescence in Club cells exposed to repeated LPS induced injury.

Conclusions

Our data therefore provides the first positive link between p53 induced Club cell senescence and progression of airway inflammation. We suggest that senescence in bronchial epithelial cells drives COPD progression. Our current research focuses on the mechanisms that mediate this dramatic effect. Understanding of these mechanisms will eventually lead to identification of novel strategies for treatment of COPD.