Abnormal re-epithelialization and lung remodeling in idiopathic pulmonary fibrosis:: The role of ΔN-p63
Abnormal re-epithelialization and lung remodeling in idiopathic pulmonary fibrosis:: The role of ΔN-p63
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DOI：
10.1097/01.lab.0000032380.82232.67
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发表时间：
2002-10-01
影响因子：
5
通讯作者：
Doglioni, C
中科院分区：
文献类型：
--
作者：
Chilosi, M;Poletti, V;Doglioni, C
p63基因的产物，最近被描述为p53家族的成员，在人类支气管和细支的基底细胞中组成性表达。p63基因的截断异构体（DeltaN-p63蛋白）抵消了细胞凋亡和细胞凋亡。DNA损伤后p53的细胞周期抑制功能，这种特性可能是分层上皮组织细胞更新策略的核心。为了研究特发性肺纤维化/通常间质性肺炎（IPF/UIP）的功能失调修复过程，我们用免疫组织化学方法分析了从患有这种疾病的患者获得的16个组织样本中p63基因的反激活和显性阴性亚型的表达。在本文研究的大多数IPF病例中，在细支气管-肺泡连接处的异常增生部位观察到表达DeltaN-p63的上皮细胞，其特征是上皮增生、鳞状化生、细支气管化和p53核异常积聚。在正常肺和其他肺部疾病（包括急性间质性肺炎、特发性闭塞性细支气管炎组织性肺炎、非特异性间质性肺炎和脱屑性间质性肺炎）作为对照的样本中未观察到类似的特征。基于这些发现，我们可以假设一种新的UIP发病模型，涉及细胞损伤后细支气管-肺泡连接处间充质-上皮相互作用的失调发展和上皮细胞的异常增殖。我们认为，IPF/UIP损伤后肺泡组织的进行性损失和肺重塑，一方面是肺细胞损失和肺泡塌陷，另一方面是进行性细支气管增生和结构扭曲。
Products of the p63 gene, a recently described member of the p53 family, are constitutively expressed in the basal cells of human bronchi and bronchioli. The truncated isoforms of the p63 gene (DeltaN-p63 proteins) counteract the apoptotic and. cell cycle inhibitory functions of p53 after DNA damage, and this property is likely to be central in the cell renewal strategy of stratified epithelial tissues. To investigate the dysfunctional repair processes that characterize idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), we immunohistochemically analyzed the expression of the transactivating and dominant-negative isoforms of the p63 gene on 16 tissue samples obtained from patients suffering from this disorder. In most IPF cases herein investigated, epithelial cells expressing DeltaN-p63 were observed at sites of abnormal proliferation at the bronchiolo-alveolar junctions, characterized by epithelial hyperplasia, squamous metaplasia, bronchiolization, and abnormal p53 nuclear accumulation. Similar features were not observed in normal lung and in samples taken from other pulmonary diseases used as controls, including acute interstitial pneumonia, idiopathic bronchiolitis obliterans organizing pneumonia, nonspecific interstitial pneumonia, and desquamative interstitial pneumonia. On the basis of these findings, we can hypothesize a new model for UIP pathogenesis, involving a deregulated development of mesenchymal-epithelial interactions and abnormal proliferation of epithelial cells at the bronchiolo-alveolar junction after cell injury. In our view, the progressive loss of alveolar tissue and lung remodeling after injury in IPF/UIP is concomitantly produced by pneumocyte loss and alveolar collapse on one hand and by progressive bronchiolar proliferation and architectural distortion on the other.