The role of Clara cell senescence in the pathogenesis of COPD

Background: COPD is a chronic inflammatory disease caused by long-term inhalation of noxious particles and gases, such as cigarette smoke. The prevalence of COPD is age dependent, and the link between aging and COPD pathogenesis is strongly supported by numerous studies.One emerging hypothesis suggests that alveolar- and airway- cell senescence is a key factor linking aging lung to COPD, since cellular senescence limits the proliferative capacity necessary for tissue repair and promotes chronic inflammation.Clara cells are progenitor cells of the peripheral airways involved in airway regeneration and immune responses following injury, and have been suggested to play a critical role in COPD progression.However, the specific contribution of Clara cells senescence to this process has been largely overlooked. Objective and Methods: To investigate the role of Clara cell senescence in the pathogenesis of COPD we have used a genetic approach based on transgenic mice in which p53, a pivotal senescence regulator was specifically knocked-out in Clara cells. Subsequently, these mice were exposed to chronic LPS inhalation and evaluated for senescence induction, lung inflammation and alveolar destruction. Results: Chronic LPS exposure induced Clara cell senescence as assessed by increased SA-β-GAL activity, whereas the p53 transgenic mice showed an attenuated Clara cell senescence. Attenuated Clara cell senescence resulted in dramatically reduced innate and adaptive immune responses, and in decrease in emphysematous changes. Conclusions: Clara-cell senescence plays an important role in the pathogenesis of COPD and its impairment by p53 deletion, protects lungs from progressive alveolar destruction, a hallmark of COPD.