Role of p21 (WAF1/Cip1) in the remodelling of the airway epithelium in smoker +/- COPD subjects

The Cyclin-dependent kinase inhibitor p21 exerts different functions on the basis of its intracellular localization. Nuclear localization leads to cell cycle arrest. Cytoplasmatic localization leads to oncogenic events via anti-apoptotic mechanisms. Moreover, in a condition of abnormal proliferation, such as in the squamous metaplastic epithelium, ki67 proliferation index is increased. The aim of the study was to explore whether an altered expression of p21 is associated with an increased proliferation and/or reduced cell death (caspase-3) of the airway epithelial cells in Healthy Smokers and COPD Smokers. We selected central airways from surgical specimens of Healthy non Smokers (HNS), Healthy Smokers (HS) (Gold 0) and COPD Smokers (COPD-S) (Gold I, II) and evaluated, by immunohistochemistry technique, the cytoplasmatic and nuclear p21 (WAF1/Cip)1 expression, the caspase-3 and Ki67 expression as well as the squamous metaplasia areas. We found in HS and in COPD-S a higher expression of cytoplasmatic and of nuclear p21 as well as a higher expression of Ki67 in comparison with HNS. The caspase-3 expression in HS and in COPD-S was, similarly to HNS, low. Furthermore, increased areas of squamous metaplasia were present in HS and COPD-S in comparison with HNS and a positive and significant correlation between squamous metaplasia and cytoplasmic p21 expression was observed. In conclusion, smoking subjects show increased Ki67, increased cytoplasmatic and nuclear p21 expression. The increased expression of cytoplasmatic p21 correlates to squamous metaplasia. Therefore, in the epithelium of central airways, the cytoplasmic p21 expression may be an important pre-oncogenic hallmark