K. Kuwano et al., P21(WAF1 CIP1/SDI1) AND P53 EXPRESSION IN ASSOCIATION WITH DNA STRANDBREAKS IN IDIOPATHIC PULMONARY FIBROSIS/, American journal of respiratory and critical care medicine, 154(2), 1996, pp. 477-483
Citations number
35
Categorie Soggetti
Emergency Medicine & Critical Care","Respiratory System
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.