Analyses of alveolar epithelial injury via lipid-related stress in mammalian target of rapamycin inhibitor-induced lung disease.
Analyses of alveolar epithelial injury via lipid-related stress in mammalian target of rapamycin inhibitor-induced lung disease.
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雷帕霉素抑制剂诱导的肺病哺乳动物靶标中脂质相关应激所致肺泡上皮损伤的分析。
DOI：
10.1038/s41374-018-0158-9
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发表时间：
2019
影响因子：
5
通讯作者：
Shimizu A.
中科院分区：
文献类型：
--
作者：
Kokuho N;Terasaki Y;Kunugi S;Saito Y;Urushiyama H;Terasaki M;Hayashi H;Gemma A;Shimizu A.
尽管哺乳动物雷帕霉素靶点抑制剂（mTORi）被用于治疗各种恶性肿瘤，但它们经常诱导活动性肺泡炎和血脂异常。脂质代谢异常影响肺泡表面活性物质的功能，导致肺部疾病;然而，肺损伤的病理生理及其与脂质代谢的关系仍然未知。我们研究了脂质代谢与肺泡上皮损伤之间的关系，重点是过氧化物酶体增殖物激活受体-γ（PPAR-γ）作为mTORi诱导的肺损伤中的脂质应激相关因子。我们对三名mTORi诱导的肺损伤患者进行了临床病理学检查。我们在小鼠中使用替西罗莫司（30 mg/kg/天）构建了mTORi损伤小鼠模型，其中具有媒介物对照组和博来霉素损伤组。我们还使用替西罗莫司（0-40 μM）在小鼠肺上皮细胞系MLE-12中构建了培养的肺泡上皮细胞损伤模型，并在有或无吡格列酮（PPAR-γ激动剂）治疗的情况下进行了分析。所有3例患者均存在血脂异常和肺组织增生性肺泡细胞病变，伴有泡沫样和扩大的改变。在小鼠模型中，与对照组相比，替西罗莫司诱导血清中总胆固醇和游离脂肪酸水平显著升高，血清和BAL液中表面活性蛋白D水平升高，肺中炎性细胞因子增加。在显微镜分析中，与对照组或博来霉素组相比，替西罗莫司还诱导了增生的泡沫状肺细胞，脂质相关斑点增加，圆形电子透明体更大。在MLE-12细胞中，替西罗莫司给药也诱导了细胞质内的多个脂质相关斑点。替西罗莫司下调小鼠肺和MLE-12细胞中的PPAR-γ表达，但上调MLE-12细胞中的裂解型caspase-3。吡格列酮阻断了MLE-12细胞中上调的裂解型caspase-3表达。mTORi诱导的肺疾病的发病机制可能涉及肺泡上皮损伤，通过脂质代谢应激与下调的PPAR-γ表达相关。关注脂质代谢应激与肺泡上皮细胞损伤的关系是研究肺损伤的一个潜在的新途径。
Although mammalian target of rapamycin inhibitors (mTORi) are used to treat various malignancies, they frequently induce active alveolitis and dyslipidemia. Abnormal lipid metabolism affects alveolar surfactant function and results in pulmonary disorders; however, the pathophysiology of lung injury and its relationship with lipid metabolism remain unknown. We investigated the relationship between lipid metabolism and alveolar epithelial injury, focusing on peroxisome proliferator-activated receptor-γ (PPAR-γ) as a lipid stress-related factor in mTORi-induced lung injury. We clinicopathologically examined three patients with mTORi-induced lung injury. We constructed an mTORi injury mouse model using temsirolimus in mice (30 mg/kg/day), with the vehicle control and bleomycin injury groups. We also constructed a cultured alveolar epithelial cell injury model using temsirolimus (0–40 μM) in the mouse lung epithelial cell line MLE-12 and performed analysis with or without pioglitazone (PPAR-γ agonist) treatment. All three patients had dyslipidemia and lung lesions of hyperplastic pneumocytes with foamy and enlarged changes. In the mouse model, temsirolimus induced significantly higher levels of total cholesterol and free fatty acids in serum and higher levels of surfactant protein D in serum and BAL fluid with an increase in inflammatory cytokines in the lung compared to control. Temsirolimus also induced hyperplastic foamy pneumocytes with increased lipid-associated spots and larger round electron-lucent bodies compared to the control or bleomycin groups in microscopic analyses. Multiple lipid-associated spots within the cytoplasm were also induced by temsirolimus administration in MLE-12 cells. Temsirolimus downregulated PPAR-γ expression in mouse lung and MLE-12 cells but upregulated cleaved caspase-3 in MLE-12 cells. Pioglitazone blocked the upregulated cleaved caspase-3 expression in MLE-12 cells. The pathogenesis of mTORi-induced lung disease may be involved in alveolar epithelial injury, via lipid metabolic stress associated with downregulated PPAR-γ expression. Focusing on the relationship between lipid metabolic stress and alveolar epithelial injury represents a potentially novel approach to the study of pulmonary damage.