本文選題：急性肺損傷 + 豬流感病毒�。� 參考：《北京協(xié)和醫(yī)學(xué)院》2015年博士論文

【摘要】：2009年4月,一種新型的H1N1豬流感病毒在墨西哥爆發(fā)并迅速地在全球范圍內(nèi)廣泛流行和傳播,引起了人的感染和死亡[1]。人感染該新型豬流感病毒后的主要臨床表現(xiàn)為急性呼吸道感染癥狀,部分患者會(huì)發(fā)展成急性肺損傷(Acute Lung Injury, ALI),甚至是更為嚴(yán)重的急性呼吸窘迫綜合征(Acute Respiratory Distress Syndrome, ARDS),出現(xiàn)呼吸衰竭和多器官損傷,并最終死亡[2]。其死亡率顯著高于普通的季節(jié)性H1N1流感,據(jù)世界衛(wèi)生組織(World Health Organization, WHO)統(tǒng)計(jì),從2009年4月到2010年8月期間,此次甲型H1N1流感大流行造成了至少18,449人的死亡,對(duì)人類健康和社會(huì)經(jīng)濟(jì)造成了嚴(yán)重的影響,引發(fā)了極大的恐慌。而2009年甲型H1N1流感病毒感染導(dǎo)致急性肺損傷的分子致病機(jī)制尚不清楚。我們的研究發(fā)現(xiàn),在感染甲型H1N1流感病毒的病人血清和小鼠的肺泡灌洗液當(dāng)中都出現(xiàn)了典型的細(xì)胞因子風(fēng)暴[3]。而IP-10這種CXCL家族的趨化因子在所有被檢測的細(xì)胞因子和趨化因子中,升高是最為顯著異常的。而敲除Ip-10基因后會(huì)顯著地緩解甲型H1N1流感病毒感染誘導(dǎo)的小鼠急性肺損傷。我們隨后證明了PI3K-Akt-p38-ATF2和JNK/MAPK兩條信號(hào)通路,在甲型H1N1流感病毒感染誘導(dǎo)的小鼠急性肺損傷模型中,位于IP-10的下游并發(fā)揮了重要的生物學(xué)功能。我們進(jìn)一步研究發(fā)現(xiàn),通過靜脈給予外源性的IP-10單克隆抗體可以有效地緩解甲型H1N1流感病毒導(dǎo)致的小鼠急性肺損傷癥狀。上述結(jié)果表明,IP-10在甲型H1N1流感病毒感染誘導(dǎo)的小鼠急性肺損傷中發(fā)揮了重要作用,針對(duì)IP-10的單克隆抗體或許可以作為未來預(yù)防和控制甲型流感爆發(fā)的候選藥物。2013年3月末,在我國長江三角洲一帶的城市陸續(xù)發(fā)現(xiàn)了人感染甲型H7N9禽流感病毒的病例[36]。大多數(shù)患者主要的臨床癥狀表現(xiàn)為發(fā)熱,咳嗽和氣促,部分患者會(huì)發(fā)展成重癥肺炎,出現(xiàn)呼吸困難,可快速進(jìn)展成急性肺損傷或更嚴(yán)重的急性呼吸窘迫綜合征,并最終死亡[37,38]。截至2014年4月22日,中國共確診病例414例,其中81人死亡。雖然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流感病毒的感染都會(huì)導(dǎo)致過度的細(xì)胞因子反應(yīng),產(chǎn)生細(xì)胞因子風(fēng)暴[3,10,11],但到目前為止,還沒有直接的證據(jù)將細(xì)胞因子風(fēng)暴的動(dòng)態(tài)變化與病人的臨床癥狀和病程聯(lián)系起來。因此,現(xiàn)在就迫切的需要找到這樣的一些細(xì)胞因子和趨化因子,來作為預(yù)測病人預(yù)后的生物標(biāo)志物,為病人不同階段的臨床治療提供實(shí)時(shí)的指導(dǎo)和幫助。在2013年H7N9禽流感疫情爆發(fā)期間,我們聯(lián)合浙江大學(xué)第一附屬醫(yī)院等多家單位從浙江、江蘇和上海等地招募了47名甲型H7N9禽流感病毒感染患者,檢測了他們血漿中48種細(xì)胞因子和趨化因子的濃度,發(fā)現(xiàn)有34種都顯著異常升高。進(jìn)一步的統(tǒng)計(jì)學(xué)分析發(fā)現(xiàn),血漿中HGF、SCF、IL-18、IP-10、MIG、IL-6、SCGF-β和MIF的水平與病人不同時(shí)期的臨床打分APACHE Ⅱ呈正相關(guān)。在發(fā)病第二周,死亡病人中HGF、SCF、IL-18、IP-10、MIG、SCGF-β和MIF的血漿水平比康復(fù)病人的顯著升高,而二者在發(fā)病第一周內(nèi)無統(tǒng)計(jì)學(xué)差異,進(jìn)一步的統(tǒng)計(jì)學(xué)分析證明,在發(fā)病第二周這7種細(xì)胞因子的水平與病人的死亡相關(guān)。在未來可能爆發(fā)的流感大流行中,本研究的發(fā)現(xiàn)有望為流感患者的臨床診斷和治療提供實(shí)時(shí)的參考。
[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.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R511.7

【共引文獻(xiàn)】

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本文編號(hào)：1918447