OBJECTIVE The beneficial role of Cystic fibrosis transmembrane conductance regulator (CFTR) was reported in acute lung injury (ALI), however, there was no direct evidence supporting the relationship between CFTR and cell autophagy in ALI. Here, this study is to analyze the protective role of CFTR on autophagy in lipopolysaccharide (LPS)-induced ALI mice and its special mechanism. METHODS ALI mouse models were established by the stimulation of LPS. ALI mice were subjected to tail vein injection of Lv-CFTR, intraperitoneal injection of autophagy activator RAPA or tail vein injection of Lv-sh-HMGB1 before lung tissues and bronchoalveolar lavage fluid (BALF) were collected. The expression levels of CFTR, HMGB1, Beclin-1, p62, p-AKT, p-mTOR, and LC3-II/LC3-I ratio were estimated by qRT-PCR and Western blot. The lung edema in ALI mice was inspected by wet/dry weight (W/D) ratio. Hematoxylin and eosin (H&E) staining was utilized to observe pathological features of lung tissue. Immunofluorescence was applied to determine the expression intensity of LC-3. The superoxidase dismutase (SOD) and myeloperoxidase (MPO) activity and malondialdehyde (MDA) content were assayed, and inflammatory response in ALI mice was measured. RESULTS ALI mouse models were successfully induced by LPS, evidenced by an enhanced inflammatory response in lung tissues, heightened W/D ratio and cell autophagy markers. ALI mice had suppressed expression of CFTR, while injection of CFTR overexpression in ALI mice attenuated inflammation, autophagy, MPO activity and MDA content in addition to elevating SOD activity. Moreover, CFTR overexpression could increase the p-AKT, and p-mTOR. Overexpression of HMGB1 could reverse the expression pattern in mice injected with CFTR overexpression. CONCLUSION CFTR could inhibit cell autophagy by enhancing PI3K/AKT/mTOR signaling pathway, thereby playing a protective role in LPS-induced ALI in mice.

中文翻译：

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囊性纤维化跨膜电导调节剂可通过抑制小鼠PI3K / AKT / mTOR途径的自噬来减轻脂多糖诱导的急性肺损伤。

目的报道囊性纤维化跨膜电导调节剂（CFTR）在急性肺损伤（ALI）中的有益作用，但尚无直接证据支持CFTR与ALI中细胞自噬之间的关系。在这里，本研究旨在分析CFTR对脂多糖（LPS）诱导的ALI小鼠自噬的保护作用及其特殊机制。方法通过LPS刺激建立ALI小鼠模型。在收集肺组织和支气管肺泡灌洗液（BALF）之前，对ALI小鼠进行尾静脉注射Lv-CFTR，腹膜内注射自噬激活剂RAPA或尾静脉注射Lv-sh-HMGB1。通过qRT-PCR和Western印迹估计CFTR，HMGB1，Beclin-1，p62，p-AKT，p-mTOR和LC3-II / LC3-I的表达水平。通过干/湿重（W / D）比检查ALI小鼠的肺水肿。苏木精和曙红（H＆E）染色用于观察肺组织的病理特征。应用免疫荧光测定LC-3的表达强度。测定了超氧化物酶歧化酶（SOD）和髓过氧化物酶（MPO）的活性以及丙二醛（MDA）的含量，并测量了ALI小鼠的炎症反应。结果LPS成功诱导ALI小鼠模型，肺组织炎症反应增强，W / D比升高和细胞自噬标记物证明了这一点。ALI小鼠抑制了CFTR的表达，而ALI小鼠注射CFTR的过表达除了提高SOD活性外，还减轻了炎症，自噬，MPO活性和MDA含量。此外，CFTR过度表达可能会增加p-AKT，和p-mTOR。HMGB1的过表达可以逆转注射CFTR过表达的小鼠的表达模式。结论CFTR可以通过增强PI3K / AKT / mTOR信号通路抑制细胞自噬，从而在LPS诱导的小鼠ALI中起保护作用。