Fukumoto Jutaro, Leung Joseph, Cox Ruan, Czachor Alexander, Parthasarathy Prasanna Tamarapu, Lagishetty Venu, Mandry Maria, Hosseinian Nima, Patel Priyanshi, Perry Brittany, Breitzig Mason T, Alleyn Matthew, Failla Athena, Cho Young, Cooke Andrew J, Galam Lakshmi, Soundararajan Ramani, Sharma Nirmal, Lockey Richard F, Kolliputi Narasaiah
Division of Allergy and Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
Aging (Albany NY). 2019 Jan 13;11(1):209-229. doi: 10.18632/aging.101742.
Atp8b1 (ATPase, aminophospholipid transporter, class I, type 8B, member 1) is a cardiolipin transporter in the apical membrane of lung epithelial cells. While the role of Atp8b1 in pneumonia-induced acute lung injury (ALI) has been well studied, its potential role in oxidative stress-induced ALI is poorly understood. We herein show that Atp8b1 mice under hyperoxic conditions display exacerbated cell apoptosis at alveolar epithelium and aberrant proliferation of club cells at bronchiolar epithelium. This hyperoxia-induced ambivalent response in Atp8b1 lungs was followed by patchy distribution of non-uniform interstitial fibrosis at late recovery phase under normoxia. Since this club cell abnormality is commonly observed between Atp8b1 lungs under hyperoxic conditions and IPF lungs, we characterized this mouse fibrosis model focusing on club cells. Intriguingly, subcellular morphological analysis of IPF lungs, using transmission electron microscopy (TEM), revealed that metaplastic bronchiolar epithelial cells in fibrotic lesions and deformed type II alveolar epithelial cells (AECs) in alveoli with mild fibrosis, have common morphological features including cytoplasmic vacuolation and dysmorphic lamellar bodies. In conclusion, the combination of Atp8b1 mutation and hyperoxic insult serves as a novel platform to study unfocused role of club cells in IPF.
Atp8b1（ATP酶，氨基磷脂转运蛋白，I类，8B型，成员1）是肺上皮细胞顶端膜中的一种心磷脂转运蛋白。虽然Atp8b1在肺炎诱导的急性肺损伤（ALI）中的作用已得到充分研究，但其在氧化应激诱导的ALI中的潜在作用却知之甚少。我们在此表明，在高氧条件下的Atp8b1基因敲除小鼠在肺泡上皮表现出加剧的细胞凋亡，在细支气管上皮表现出俱乐部细胞的异常增殖。在高氧条件下，Atp8b1基因敲除小鼠肺部的这种高氧诱导的矛盾反应，在常氧下的晚期恢复阶段之后，伴随着不均匀的间质纤维化的斑片状分布。由于在高氧条件下的Atp8b1基因敲除小鼠肺部和特发性肺纤维化（IPF）肺部之间普遍观察到这种俱乐部细胞异常，我们以俱乐部细胞为重点对这种小鼠纤维化模型进行了表征。有趣的是，使用透射电子显微镜（TEM）对IPF肺部进行亚细胞形态学分析发现，纤维化病变中的化生细支气管上皮细胞和轻度纤维化肺泡中的变形II型肺泡上皮细胞（AEC）具有共同的形态学特征，包括细胞质空泡化和畸形板层小体。总之，Atp8b1突变和高氧损伤的组合为研究俱乐部细胞在IPF中的未聚焦作用提供了一个新的平台。
