Cigarette Smoke Disrupted Lung Endothelial Barrier Integrity and Increased Susceptibility to Acute Lung Injury via Histone Deacetylase 6
Cigarette Smoke Disrupted Lung Endothelial Barrier Integrity and Increased Susceptibility to Acute Lung Injury via Histone Deacetylase 6
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DOI：
10.1165/rcmb.2015-0149oc
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发表时间：
2016-05-01
影响因子：
6.4
通讯作者：
Lu, Qing
中科院分区：
文献类型：
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作者：
Borgas, Diana;Chambers, Eboni;Lu, Qing
流行病学证据表明，香烟烟雾（CS）与急性肺损伤（ALI）的发生有关。我们之前已经表明，短暂的CS暴露会加剧体内脂多糖（LPS）诱导的ALI和体外内皮屏障功能障碍。在这项研究中，我们发现 CS 还会加剧假单胞菌诱导的小鼠 ALI。我们证明，从暴露于 CS 的小鼠中分离出的肺微血管内皮细胞 (EC) 在受到 LPS 和凝血酶攻击后具有更大的通透性或不完全恢复。组蛋白脱乙酰酶 (HDAC) 6 使维持内皮屏障功能所必需的蛋白质脱乙酰。我们发现，在暴露于 CS 的小鼠肺组织和暴露于香烟烟雾提取物 (CSE) 的肺 EC 中，HDAC6 丝氨酸 22 磷酸化增加。 HDAC6 的抑制减弱了 CSE 诱导的 EC 通透性增加和 ALI 的 CS 启动。微管稳定剂紫杉醇提供了类似的屏障保护，它保留了α-微管蛋白乙酰化。 CSE 降低α-微管蛋白乙酰化并引起微管解聚。与 HDAC6 磷酸化增加相协调，CSE 抑制 Akt 并激活糖原合酶激酶 (GSK)-3 beta；抗氧化剂 N-乙酰半胱氨酸可以改善这些影响。我们的结果表明，CS 可能通过氧化应激诱导的 Akt 失活和随后的 GSK-3 beta 激活，增加肺 EC 通透性，从而增强对 ALI 的易感性。激活的 GSK-3 beta 可能通过丝氨酸 22 的磷酸化激活 HDAC6，导致 α-微管蛋白脱乙酰化和微管解体。 HDAC6 的抑制可能是吸烟者 ALI 的一种新的治疗选择。
Epidemiologic evidence indicates that cigarette smoke (CS) is associated with the development of acute lung injury (ALI). We have previously shown that brief CS exposure exacerbates lipopolysaccharide (LPS)-induced ALI in vivo and endothelial barrier dysfunction in vitro. In this study, we found that CS also exacerbated Pseudomonas-induced ALI in mice. We demonstrated that lung microvascular endothelial cells (ECs) isolated from mice exposed to CS had a greater permeability or incomplete recovery after challenges by LPS and thrombin. Histone deacetylase (HDAC) 6 deacetylates proteins essential for maintenance of endothelial barrier function. We found that HDAC6 phosphorylation at serine-22 was increased in lung tissues of mice exposed to CS and in lung ECs exposed to cigarette smoke extract (CSE). Inhibition of HDAC6 attenuated CSE-induced increases in EC permeability and CS priming of ALI. Similar barrier protection was provided by the microtubule stabilizer taxol, which preserved alpha-tubulin acetylation. CSE decreased a-tubulin acetylation and caused microtubule depolymerization. In coordination with increased HDAC6 phosphorylation, CSE inhibited Akt and activated glycogen synthase kinase (GSK)-3 beta; these effects were ameliorated by the antioxidant N-acetyl cysteine. Our results suggest that CS increases lung EC permeability, thereby enhancing susceptibility to ALI, likely through oxidative stress-induced Akt inactivation and subsequent GSK-3 beta activation. Activated GSK-3 beta may activate HDAC6 via phosphorylation of serine-22, leading to alpha-tubulin deacetylation and microtubule disassembly. Inhibition of HDAC6 may be a novel therapeutic option for ALI in cigarette smokers.