细胞因子风暴在流感病毒诱导的急性肺损伤中作用机制的研究

发布时间：2018-05-21 08:20

本文选题：急性肺损伤 + 猪流感病毒　；参考：《北京协和医学院》2015年博士论文

【摘要】：2009年4月,一种新型的H1N1猪流感病毒在墨西哥爆发并迅速地在全球范围内广泛流行和传播,引起了人的感染和死亡[1]。人感染该新型猪流感病毒后的主要临床表现为急性呼吸道感染症状,部分患者会发展成急性肺损伤(Acute Lung Injury, ALI),甚至是更为严重的急性呼吸窘迫综合征(Acute Respiratory Distress Syndrome, ARDS),出现呼吸衰竭和多器官损伤,并最终死亡[2]。其死亡率显著高于普通的季节性H1N1流感,据世界卫生组织(World Health Organization, WHO)统计,从2009年4月到2010年8月期间,此次甲型H1N1流感大流行造成了至少18,449人的死亡,对人类健康和社会经济造成了严重的影响,引发了极大的恐慌。而2009年甲型H1N1流感病毒感染导致急性肺损伤的分子致病机制尚不清楚。我们的研究发现,在感染甲型H1N1流感病毒的病人血清和小鼠的肺泡灌洗液当中都出现了典型的细胞因子风暴[3]。而IP-10这种CXCL家族的趋化因子在所有被检测的细胞因子和趋化因子中,升高是最为显著异常的。而敲除Ip-10基因后会显著地缓解甲型H1N1流感病毒感染诱导的小鼠急性肺损伤。我们随后证明了PI3K-Akt-p38-ATF2和JNK/MAPK两条信号通路,在甲型H1N1流感病毒感染诱导的小鼠急性肺损伤模型中,位于IP-10的下游并发挥了重要的生物学功能。我们进一步研究发现,通过静脉给予外源性的IP-10单克隆抗体可以有效地缓解甲型H1N1流感病毒导致的小鼠急性肺损伤症状。上述结果表明,IP-10在甲型H1N1流感病毒感染诱导的小鼠急性肺损伤中发挥了重要作用,针对IP-10的单克隆抗体或许可以作为未来预防和控制甲型流感爆发的候选药物。2013年3月末,在我国长江三角洲一带的城市陆续发现了人感染甲型H7N9禽流感病毒的病例[36]。大多数患者主要的临床症状表现为发热,咳嗽和气促,部分患者会发展成重症肺炎,出现呼吸困难,可快速进展成急性肺损伤或更严重的急性呼吸窘迫综合征,并最终死亡[37,38]。截至2014年4月22日,中国共确诊病例414例,其中81人死亡。虽然1918年西班牙流感病毒、高致病性H5N1禽流感病毒和2009年甲型H1N1流感病毒的感染都会导致过度的细胞因子反应,产生细胞因子风暴[3,10,11],但到目前为止,还没有直接的证据将细胞因子风暴的动态变化与病人的临床症状和病程联系起来。因此,现在就迫切的需要找到这样的一些细胞因子和趋化因子,来作为预测病人预后的生物标志物,为病人不同阶段的临床治疗提供实时的指导和帮助。在2013年H7N9禽流感疫情爆发期间,我们联合浙江大学第一附属医院等多家单位从浙江、江苏和上海等地招募了47名甲型H7N9禽流感病毒感染患者,检测了他们血浆中48种细胞因子和趋化因子的浓度,发现有34种都显著异常升高。进一步的统计学分析发现,血浆中HGF、SCF、IL-18、IP-10、MIG、IL-6、SCGF-β和MIF的水平与病人不同时期的临床打分APACHE Ⅱ呈正相关。在发病第二周,死亡病人中HGF、SCF、IL-18、IP-10、MIG、SCGF-β和MIF的血浆水平比康复病人的显著升高,而二者在发病第一周内无统计学差异,进一步的统计学分析证明,在发病第二周这7种细胞因子的水平与病人的死亡相关。在未来可能爆发的流感大流行中,本研究的发现有望为流感患者的临床诊断和治疗提供实时的参考。
[Abstract]:In April 2009, a new type of H1N1 swine influenza virus broke out in Mexico and was widely spread worldwide, causing human infection and death of [1]. people to infect the new type of swine influenza virus, the main clinical manifestation was acute respiratory infection symptoms, and some patients developed acute lung injury (Acute Lung Injury, AL). I), even more severe acute respiratory distress syndrome (Acute Respiratory Distress Syndrome, ARDS), respiratory failure and multiple organ damage, and eventual death of [2]. is significantly higher than the common seasonal H1N1 influenza, according to the WHO (World Health Organization, WHO) statistics from April 2009 to August 2010. In the meantime, the H1N1 influenza pandemic caused at least 18449 deaths, a serious impact on human health and social economy, causing great panic. In 2009, the molecular pathogenesis of acute lung injury caused by influenza a H1N1 virus infection was not clear. Our study found that the infection of the H1N1 influenza A virus was found. A typical cytokine storm [3]. appeared in both the patient's sera and the mice's alveolar lavage, and the chemokines of the CXCL family of IP-10, the CXCL family, were most significantly abnormal in all detected cytokines and chemokines. The knockout of the Ip-10 gene could significantly alleviate the acute H1N1 virus infection induced in mice. We subsequently demonstrated that the two signal pathways of PI3K-Akt-p38-ATF2 and JNK/MAPK, in the model of acute lung injury induced by influenza a H1N1 virus infection in mice, are downstream of IP-10 and play important biological functions. We further found that the intravenous administration of exogenous IP-10 monoclonal antibodies can be effective. The results suggest that IP-10 plays an important role in acute lung injury induced by influenza A (H1N1) virus infection in mice, and the monoclonal antibodies against IP-10 may be used as a candidate for the future prevention and control of influenza A (H1N1) outbreak at the end of 3 month, at the end of 3 months. The cases of human infection with H7N9 avian influenza A virus in the cities of the Yangtze River Delta have been found in China [36].. Most of the patients' main clinical symptoms are fever, coughing and shortness of breath. Some patients develop into severe pneumonia and dyspnea, which can quickly develop into acute lung injury or more severe acute respiratory distress syndrome. And final death [37,38]. as of April 22, 2014, a total of 414 cases were confirmed in China, of which 81 were dead. Although the 1918 Spanish influenza virus, the highly pathogenic H5N1 avian influenza virus and the 2009 H1N1 influenza virus infection could cause excessive cytokine response and the cytokine storm [3,10,11], but so far, no There is direct evidence to link the dynamic changes of the cytokine storm with the clinical symptoms and course of the patient. Therefore, it is urgent to find such cytokines and chemokines as biomarkers for predicting the prognosis of the patients and to provide real-time guidance and help for clinical treatment at different stages of the patient. 201 During the 3 year outbreak of H7N9 avian influenza, we recruited 47 patients with avian influenza A (H7N9) virus infection from Zhejiang, Jiangsu and Shanghai, the First Affiliated Hospital of Zhejiang University, and other places. The concentrations of 48 cytokines and chemokines in their plasma were detected, and the 34 species were significantly increased. It was found that the levels of HGF, SCF, IL-18, IP-10, MIG, IL-6, SCGF- beta and MIF in the plasma were positively correlated with the clinical score of the patients at different periods. In the second week, the plasma levels of HGF, SCF, IL-18, and plasma were significantly higher than those of the rehabilitation, but the two were not statistically different during the first week of the onset of the disease. Further statistical analysis shows that the level of the 7 cytokines at second weeks is related to the patient's death. In the future possible outbreak of influenza pandemic, the findings of this study are expected to provide a real time reference for the clinical diagnosis and treatment of influenza patients.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R511.7

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