Extracellular Histones Play an Inflammatory Role in Acid Aspiration-induced Acute Respiratory Distress Syndrome
Extracellular Histones Play an Inflammatory Role in Acid Aspiration-induced Acute Respiratory Distress Syndrome
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细胞外组蛋白在酸吸入引起的急性呼吸窘迫综合征中发挥炎症作用
DOI：
10.1097/aln.0000000000000429
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发表时间：
2015-01-01
期刊：
影响因子：
8.8
通讯作者：
Wen, Tao
中科院分区：
文献类型：
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作者：
Zhang, Yanlin;Wen, Zongmei;Wen, Tao
背景：全身炎症是酸吸入诱导的急性呼吸窘迫综合征（ARDS）的一个重要特征，但引发炎症的因素尚不清楚。作者推测，细胞外组蛋白，一种新发现的炎症介质，在ARDS的发病机制中发挥重要作用。方法：作者使用盐酸吸入诱导的ARDS模型来研究细胞外组蛋白是否是致病性的以及靶向组蛋白是否是保护性的。将外源性组蛋白和抗组蛋白抗体给予小鼠。肝素可以与组蛋白结合，因此作者研究了肝素是否可以使用细胞和小鼠模型来预防ARDS。此外，作者还分析了细胞外组蛋白是否参与了胃吸入性ARDS患者的临床研究。结果：伤后3 h，酸处理组小鼠支气管肺泡灌洗液中细胞外组蛋白含量（1.832 ± 0.698）显著高于假处理组（0.63 ± 0.153; P = 0.0252，n = 5/组）。升高的组蛋白可能来源于受损的肺细胞和中性粒细胞浸润。外源性组蛋白可加重肺损伤，而抗组蛋白抗体可明显减轻ARDS的程度。值得注意的是，肝素对ARDS提供了类似的保护作用。对21例ARDS患者血浆组蛋白水平的分析显示，组蛋白水平升高与ARDS程度显著相关，死亡组（2.723 ± 0.2933，n = 7）高于存活组（1.725 ± 0.1787，P = 0.006，n = 14）。结论：细胞外组蛋白可能通过促进组织损伤和全身炎症反应在ARDS中发挥作用，并可能成为反映疾病活动性的新指标。通过中和抗体或肝素靶向组蛋白显示出强有力的保护作用，提示了潜在的治疗策略。
Background:Systemic inflammation is a key feature in acid aspiration-induced acute respiratory distress syndrome (ARDS), but the factors that trigger inflammation are unclear. The authors hypothesize that extracellular histones, a newly identified inflammatory mediator, play important roles in the pathogenesis of ARDS. Methods:The authors used a hydrochloric acid aspiration-induced ARDS model to investigate whether extracellular histones are pathogenic and whether targeting histones are protective. Exogenous histones and antihistone antibody were administered to mice. Heparin can bind to histones, so the authors studied whether heparin could protect from ARDS using cell and mouse models. Furthermore, the authors analyzed whether extracellular histones are clinically involved in ARDS patients caused by gastric aspiration. Results:Extracellular histones in bronchoalveolar lavage fluid of acid-treated mice were significantly higher (1.832 ± 0.698) at 3 h after injury than in sham-treated group (0.63 ± 0.153; P = 0.0252, n = 5 per group). Elevated histones may originate from damaged lung cells and neutrophil infiltration. Exogenous histones aggravated lung injury, whereas antihistone antibody markedly attenuated the intensity of ARDS. Notably, heparin provided a similar protective effect against ARDS. Analysis of plasma from ARDS patients (n = 21) showed elevated histones were significantly correlated with the degree of ARDS and were higher in nonsurvivors (2.723 ± 0.2933, n = 7) than in survivors (1.725 ± 0.1787, P = 0.006, n = 14). Conclusion:Extracellular histones may play a contributory role toward ARDS by promoting tissue damage and systemic inflammation and may become a novel marker reflecting disease activity. Targeting histones by neutralizing antibody or heparin shows potent protective effects, suggesting a potentially therapeutic strategy.