P21(WAF1 CIP1/SDI1) AND P53 EXPRESSION IN ASSOCIATION WITH DNA STRANDBREAKS IN IDIOPATHIC PULMONARY FIBROSIS/

The tumor suppressor p53 protein is a transcription factor that plays a central role in the cellular response to DNA damage, and it can caus e either G1 arrest or apoptosis. Recently, it was shown to induce the tumor suppressor p21(Waf1/Cip1/Sdi1) (p21), which inhibits cyclin-CDK complex kinase activity. Although the etiology of idiopathic pulmonary fibrosis (IPF) is still uncertain, it is postulated that IPF begins w ith an initial inflammatory lesion localized to the alveolus and progr esses on to chronic inflammation with alveolitis. We examined whether p53 and p21 are upregulated in association with chronic DNA damage in the bronchial and alveolar epithelial cells in patients with IPF in an attempt to repair the injury. We performed in situ detection of DNA s trand breaks or apoptosis (TUNEL) in the tissues as well as immunohist ochemistry (IHC) for p53 and p21. Positive signals by TUNEL were detec ted mainly in the bronchiolar and alveolar epithelial cells in 10 of 1 4 lung specimens from patients with IPF. On the other hand, no positiv e signal by TUNEL was detected in normal lung parenchyma or in specime ns of pulmonary emphysema. The IHC demonstrated that p53 and p21 were expressed especially in hyperplastic bronchial and alveolar epithelial cells of lung tissues from all patients with IPF, except five specime ns for p21. These results are consistent with those obtained by TUNEL. In normal lung parenchyma and specimens of pulmonary emphysema, p53 a nd p21 were not detected except in scattered alveolar macrophages and in the epithelial cells within localized fibrotic regions. These resul ts suggest that p53 and p21 are upregulated in association with chroni c DNA damage, resulting in either G1 arrest or apoptosis so that the D NA damage can be repaired in IPF. We speculate that chronic DNA damage and repair may lead to mutation of the p53 gene and tumorigenesis in IPF.