Chilosi Marco, Poletti Venerino, Murer Bruno, Lestani Maurizio, Cancellieri Alessandra, Montagna Licia, Piccoli Paola, Cangi Giulia, Semenzato Gianpietro, Doglioni Claudio
Department of Pathology, University of Verona, Verona, Italy.
Lab Invest. 2002 Oct;82(10):1335-45. doi: 10.1097/01.lab.0000032380.82232.67.
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.
p63基因是p53家族中最近被描述的成员，其产物在人类支气管和细支气管的基底细胞中持续表达。p63基因的截短异构体（δN-p63蛋白）在DNA损伤后可抵消p53的凋亡和细胞周期抑制功能，这一特性可能在分层上皮组织的细胞更新策略中起核心作用。为了研究特发性肺纤维化/普通型间质性肺炎（IPF/UIP）所特有的功能失调的修复过程，我们采用免疫组织化学方法分析了从患有这种疾病的患者身上获取的16份组织样本中p63基因的反式激活和显性负性异构体的表达情况。在本文所研究的大多数IPF病例中，在细支气管-肺泡连接处异常增殖的部位观察到表达δN-p63的上皮细胞，其特征为上皮增生、鳞状化生、细支气管化生以及p53核内异常积聚。在正常肺组织以及取自用作对照的其他肺部疾病（包括急性间质性肺炎、特发性闭塞性细支气管炎伴机化性肺炎、非特异性间质性肺炎和脱屑性间质性肺炎）的样本中未观察到类似特征。基于这些发现，我们可以推测UIP发病机制的一个新模型，该模型涉及细胞损伤后间充质-上皮相互作用的失调发展以及细支气管-肺泡连接处上皮细胞的异常增殖。我们认为，IPF/UIP损伤后肺泡组织的逐渐丧失和肺重塑一方面是由肺细胞丧失和肺泡塌陷造成的，另一方面是由细支气管的逐渐增殖和结构扭曲造成的。
