Zhu Qingteng, Wang Hui, Wang Hairong, Luo Yong, Yu Yang, Du Qirong, Fei Aihua, Pan Shuming
Department of Emergency Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China.
Department of Respiratory Medicine, Putuo Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.
Mol Med Rep. 2017 Mar;15(3):1272-1278. doi: 10.3892/mmr.2017.6118. Epub 2017 Jan 13.
Among a number of clinical factors, bacterial infection is one of the most common causes of acute lung injury (ALI), a serious complication that carries a high risk of mortality (~40%). During the process of ALI, intense local and systemic inflammation is elicited, which exacerbates the injury. Neutrophil infiltration into airspace is observed in early stage of ALI, and is required for the full development of ALI through an array of mechanisms, including the release of granule contents and the production of pro‑inflammatory cytokines, due to the overactivation of complement and cytokines. The present study noted that ethyl pyruvate alleviated ALI in lipopolysaccharide (LPS)‑induced ALI mice. Increased autophagy in neutrophils from ALI mice was observed, while ethyl pyruvate diminished autophagy in neutrophils and constrained granule release, and therefore myeloperoxidase (MPO) in bronchoalveolar lavage fluid and the production of proinflammatory cytokines. Using neutrophil cells, it was identified that autophagy was required for neutrophil activation and granule release, and that ethyl pyruvate caused neutrophil autophagy, leading to the restriction of granule release, and thus contributing to the mitigation of ALI. If autophagy was obviated through knockdown of key regulator of autophagy Atg5, the effects of ethyl pyruvate on granule release by neutrophils disappeared. Taken together, the results demonstrated that ethyl pyruvate alleviates ALI through inhibition of autophagy‑induced granule release by neutrophils, and this mechanism suggested a novel potential therapeutic target in autophagy regulation for ALI.
在众多临床因素中，细菌感染是急性肺损伤（ALI）最常见的病因之一，ALI是一种严重并发症，死亡率很高（约40%）。在ALI过程中，会引发强烈的局部和全身炎症，从而加重损伤。在ALI早期可观察到中性粒细胞浸润到肺泡腔，并且由于补体和细胞因子的过度激活，中性粒细胞通过一系列机制（包括颗粒内容物的释放和促炎细胞因子的产生）参与ALI的充分发展。本研究指出，丙酮酸乙酯可减轻脂多糖（LPS）诱导的ALI小鼠的ALI。观察到ALI小鼠中性粒细胞中的自噬增加，而丙酮酸乙酯可减少中性粒细胞中的自噬并抑制颗粒释放，进而减少支气管肺泡灌洗液中的髓过氧化物酶（MPO）和促炎细胞因子的产生。利用中性粒细胞，研究发现自噬是中性粒细胞激活和颗粒释放所必需的，并且丙酮酸乙酯可引起中性粒细胞自噬，导致颗粒释放受限，从而有助于减轻ALI。如果通过敲除自噬关键调节因子Atg5消除自噬，丙酮酸乙酯对中性粒细胞颗粒释放的影响就会消失。综上所述，结果表明丙酮酸乙酯通过抑制中性粒细胞自噬诱导的颗粒释放来减轻ALI，这一机制提示了自噬调节在ALI治疗中的一个新的潜在靶点。
