Kuwano K, Kunitake R, Kawasaki M, Nomoto Y, Hagimoto N, Nakanishi Y, Hara N
Research Institute for Diseases of the Chest, Faculty of Medicine, Kyushu University, Higashiku, Fukuoka, Japan.
Am J Respir Crit Care Med. 1996 Aug;154(2 Pt 1):477-83. doi: 10.1164/ajrccm.154.2.8756825.
The tumor suppressor p53 protein is a transcription factor that plays a central role in the cellular response to DNA damage, and it can cause either G1 arrest or apoptosis. Recently, it was shown to induce the tumor suppressor p21Waf1/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 with an initial inflammatory lesion localized to the alveolus and progresses 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 strand breaks or apoptosis (TUNEL) in the tissues as well as immunohistochemistry (IHC) for p53 and p21. Positive signals by TUNEL were detected mainly in the bronchiolar and alveolar epithelial cells in 10 of 14 lung specimens from patients with IPF. On the other hand, no positive signal by TUNEL was detected in normal lung parenchyma or in specimens 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 specimens for p21. These results are consistent with those obtained by TUNEL. In normal lung parenchyma and specimens of pulmonary emphysema, p53 and p21 were not detected except in scattered alveolar macrophages and in the epithelial cells within localized fibrotic regions. These results suggest that p53 and p21 are upregulated in association with chronic DNA damage, resulting in either G1 arrest or apoptosis so that the DNA 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.
肿瘤抑制蛋白p53是一种转录因子，在细胞对DNA损伤的反应中起核心作用，它可导致G1期阻滞或细胞凋亡。最近研究表明，它能诱导肿瘤抑制蛋白p21Waf1/Cip1/Sdi1（p21），后者可抑制细胞周期蛋白 - CDK复合物激酶活性。尽管特发性肺纤维化（IPF）的病因仍不明确，但据推测，IPF始于局限于肺泡的初始炎症病变，并进展为伴有肺泡炎的慢性炎症。我们研究了IPF患者支气管和肺泡上皮细胞中p53和p21是否与慢性DNA损伤相关上调，以尝试修复损伤。我们对组织进行了DNA链断裂或凋亡的原位检测（TUNEL法）以及p53和p21的免疫组织化学（IHC）检测。在14例IPF患者的肺标本中，有10例TUNEL阳性信号主要在细支气管和肺泡上皮细胞中检测到。另一方面，在正常肺实质或肺气肿标本中未检测到TUNEL阳性信号。免疫组织化学显示，除5例p21标本外，所有IPF患者肺组织增生的支气管和肺泡上皮细胞中均有p53和p21表达。这些结果与TUNEL法获得的结果一致。在正常肺实质和肺气肿标本中，除散在的肺泡巨噬细胞和局部纤维化区域内的上皮细胞外，未检测到p53和p21。这些结果表明，在IPF中，p53和p21与慢性DNA损伤相关上调，导致G1期阻滞或细胞凋亡，从而使DNA损伤得以修复。我们推测，慢性DNA损伤和修复可能导致IPF中p53基因的突变和肿瘤发生。
