Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Am J Respir Crit Care Med. 2013 Feb 1;187(3):262-75. doi: 10.1164/rccm.201205-0851OC. Epub 2012 Dec 13.
Injury to alveolar epithelial cells (AECs) and to their repair process is integral to the pathogenesis of acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF). The mechanisms regulating the integrity of AECs and their intrinsic regulators remain unclear. Pten is a tumor suppressor, and its function in epithelial cells during organ fibrosis is unknown.
To determine the role of epithelial Pten in ALI and lung fibrosis.
Bronchioalveolar epithelium-specific Pten-deleted SP-C-rtTA/(tetO)(7)-Cre/Pten(Δ/Δ) (SOPten(Δ/Δ)) mice were studied by structural, biochemical, and physiologic analyses and compared with wild-type mice. Further mechanistic studies were performed in vivo, in vitro, and on samples from patients with IPF.
SOPten(Δ/Δ) mice demonstrated exacerbated alveolar flooding and subsequent augmented lung scarring with enhanced disassembly of tight junctions (TJs) of AECs and degradation of basement membranes. The induction of dominant negative PTEN gene in lung epithelial cells led to augmented transforming growth factor-1-induced disruptions of TJs. Epithelial-derived myofibroblasts were increased in the epithelium-specific Pten-deficient mice. The lungs of bleomycin-treated SOPten(Δ/Δ) mice showed increased pAkt, pS6K, Snail, and matrix metalloproteinase expressions and decreased claudin-4, E-cadherin, and laminin-β1 expressions. Akt inactivation definitively saved SOPten(Δ/Δ) mice through amelioration of ALI and retention of AEC integrity. We detected a reduction of PTEN expression and AKT hyperactivation in the AECs of human IPF lungs.
Our results highlight epithelial Pten as a crucial gatekeeper controlling ALI and lung fibrosis by modulating AEC integrity, and the Pten/PI3K/Akt pathway as a potential therapeutic target in these intractable diseases.
肺泡上皮细胞（AECs）的损伤及其修复过程是急性肺损伤（ALI）和特发性肺纤维化（IPF）发病机制的重要组成部分。调节 AEC 完整性及其内在调节因子的机制尚不清楚。Pten 是一种肿瘤抑制因子，但其在器官纤维化过程中上皮细胞的功能尚不清楚。
确定上皮细胞 Pten 在 ALI 和肺纤维化中的作用。
通过结构、生化和生理分析研究了支气管肺泡上皮细胞特异性 Pten 缺失的 SP-C-rtTA/（tetO）（7）-Cre/Pten（Δ/Δ）（SOPten（Δ/Δ））小鼠，并与野生型小鼠进行了比较。进一步的机制研究在体内、体外和特发性肺纤维化患者的样本中进行。
SOPten（Δ/Δ）小鼠表现出更严重的肺泡积水，随后出现更严重的肺瘢痕形成，AEC 紧密连接（TJ）解体和基底膜降解增强。在肺上皮细胞中诱导显性失活的 PTEN 基因导致转化生长因子-1 诱导的 TJ 破坏加剧。上皮细胞特异性 Pten 缺陷小鼠中上皮源性肌成纤维细胞增加。博莱霉素处理的 SOPten（Δ/Δ）小鼠的肺中 pAkt、pS6K、Snail 和基质金属蛋白酶表达增加，Claudin-4、E-钙黏蛋白和层粘连蛋白-β1 表达减少。Akt 失活通过改善 ALI 和保留 AEC 完整性，明确挽救了 SOPten（Δ/Δ）小鼠。我们在人特发性肺纤维化肺上皮细胞中检测到 PTEN 表达减少和 AKT 过度激活。
我们的研究结果强调了上皮细胞 Pten 通过调节 AEC 完整性作为控制 ALI 和肺纤维化的关键守门员的作用，以及 Pten/PI3K/Akt 途径作为这些难治性疾病的潜在治疗靶点。
