ATP binding cassette class A3 (ABCA3) is a lipid transporter that plays a critical role in pulmonary surfactant function. The substitution of valine for glutamic acid at codon 292 (E292V) produces a hypomorphic variant that accounts for a significant portion of ABCA3 mutations associated with lung disorders spanning from neonatal respiratory distress syndrome and childhood interstitial lung disease to diffuse parenchymal lung disease (DPLD) in adults including pulmonary fibrosis. The mechanisms by which this and similar ABCA3 mutations disrupt alveolar type 2 (AT2) cell homeostasis and cause DPLD are largely unclear. The present study, informed by a patient homozygous for the E292V variant, used an in vitro and a preclinical murine model to evaluate the mechanisms by which E292V expression promotes aberrant lung injury and parenchymal remodeling. Cell lines stably expressing EGFP-tagged ABCA3 isoforms show a functional deficiency of the ABCA3^E292V variant as a lipid transporter. AT2 cells isolated from mice constitutively homozygous for ABCA3^E292V demonstrate the presence of small electron-dense lamellar bodies, time dependent alterations in macroautophagy, and induction of apoptosis. These changes in AT2 cell homeostasis are accompanied by a spontaneous lung phenotype consisting of both age dependent inflammation and fibrillary collagen deposition in alveolar septae. Older ABCA3^E292V mice exhibit increased vulnerability to exogenous lung injury by bleomycin. Collectively, these findings support the hypothesis that the ABCA3^E292V variant is a susceptibility factor for lung injury through effects on surfactant deficiency and impaired AT2 autophagy.

中文翻译：

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常见的 ABCA3E292V 变体破坏 AT2 细胞质量控制并增加对肺损伤和异常重塑的易感性

ATP 结合盒 A3 类 (ABCA3) 是一种脂质转运蛋白，在肺表面活性剂功能中起关键作用。在密码子 292 (E292V) 处用缬氨酸取代谷氨酸产生了一个亚型变异，该变异占与肺部疾病相关的大部分 ABCA3 突变，从新生儿呼吸窘迫综合征和儿童间质性肺病到弥漫性实质肺病 (DPLD)成人包括肺纤维化。这种和类似的 ABCA3 突变破坏肺泡 2 型 (AT2) 细胞稳态并导致 DPLD 的机制在很大程度上尚不清楚。本研究由一名 E292V 变异纯合子患者告知，使用体外和临床前鼠模型来评估 E292V 表达促进异常肺损伤和肺实质重塑的机制。^E292V变体作为脂质转运蛋白。^{从 ABCA3 E292V}组成型纯合小鼠中分离的 AT2 细胞表明存在小的电子致密层状体、巨自噬的时间依赖性改变和细胞凋亡的诱导。AT2 细胞稳态的这些变化伴随着自发的肺表型，包括年龄依赖性炎症和肺泡间隔中的纤维胶原沉积。较年长的 ABCA3 ^E292V小鼠表现出对博莱霉素外源性肺损伤的易感性增加。总的来说，这些发现支持这样的假设，即 ABCA3 ^E292V变体是通过对表面活性剂缺乏和 AT2 自噬受损的影响而成为肺损伤的易感因素。