發(fā)布時(shí)間：2018-02-01 13:00

  本文關(guān)鍵詞： 凋亡 呼吸 豬源甲型H1N1流感 納米材料 PAMAM ACE2 急性肺損傷　出處：《北京協(xié)和醫(yī)學(xué)院》2011年博士論文　論文類型：學(xué)位論文

【摘要】：2009年4月,在墨西哥首次檢測(cè)并發(fā)現(xiàn)了一種新型的甲型流感病毒(Novel Swine-Origin Influenza A)在人群中傳播,并造成感染人群的發(fā)病。這種新型的甲型H1N1流感病毒(S-OIV H1N1)迅速傳播至全球許多國(guó)家和地區(qū)。2009年6月11日,世界衛(wèi)生組織(WHO)發(fā)布公告,甲型流感病毒的全球警戒水平提升至6級(jí),這也預(yù)示著全球流感大流行的爆發(fā)。 盡管此次流行的甲型H1N1流感病毒感染多為散在的個(gè)體,且感染癥狀一般比較輕微,但對(duì)于青年人以及那些本來(lái)有基礎(chǔ)病的人群(其中包括哮喘、糖尿病、病態(tài)肥胖癥以及孕婦)而言,導(dǎo)致更為嚴(yán)重疾病的病程的情況將會(huì)大大增加。2010年8月10日,WHO甲型H1N1流感病毒大流行結(jié)束,但地區(qū)性流感爆發(fā)仍在延續(xù)。根據(jù)WHO最新統(tǒng)計(jì)結(jié)果,而一般情況下,因季節(jié)性流感病毒感染,每年死亡人數(shù)在250,000-500,000之間。此次甲型H1N1流感大流行共導(dǎo)致18,000人死亡,死亡率占4%,健康保護(hù)機(jī)構(gòu)(HPA)報(bào)道,最近在英國(guó)確證因感染流感病毒導(dǎo)致214人死亡,其中195人確證感染了2009年的甲型H1N1流感病毒株。該機(jī)構(gòu)由此提出,甲型H1N1(S-OIV H1N1)可能會(huì)卷土重來(lái)。 2009年大流行的甲型H1N1病毒可能來(lái)源于典型的豬甲型H1N1流感病毒、可能與1918年“西班牙大流感”流行的人甲型H1N1流感病毒以及禽甲型流感病毒北歐世系有同源性。研究人員對(duì)分離到的病毒進(jìn)行全基因序列測(cè)定,但沒(méi)有發(fā)現(xiàn)任何已經(jīng)確定的毒力標(biāo)記物。動(dòng)物實(shí)驗(yàn)表明,造成2009年大流行的甲型H1N1病毒比人季節(jié)性甲型H1N1流感病毒具有明顯的致病力。動(dòng)物模型研究顯示,與季節(jié)性甲型流感病毒相比,2009年的甲型H1N1病毒可以更有效地在宿主細(xì)胞內(nèi)進(jìn)行病毒復(fù)制,并導(dǎo)致更為嚴(yán)重的發(fā)病率和致死率。 對(duì)許多生理過(guò)程,包括組織萎縮、發(fā)展以及腫瘤生物學(xué)等而言,進(jìn)程性細(xì)胞死亡、或凋亡是至關(guān)重要,在眾多包括疾病性感染的病理過(guò)程中,細(xì)胞凋亡發(fā)揮重要的作用。許多病毒感染均可導(dǎo)致宿主細(xì)胞凋亡,流感病毒可在體內(nèi)和體外造成許多種類的細(xì)胞凋亡。 有報(bào)道,感染H5N1-AVI患者和禽的肺泡上皮細(xì)胞或血感管內(nèi)皮細(xì)胞出現(xiàn)細(xì)胞凋亡。還有其他一些研究報(bào)道提出,感染H5N1-AVI的人類患者,細(xì)胞發(fā)生凋亡是導(dǎo)致發(fā)展成為急性呼吸窘迫癥(acute respiratory distress syndrome, ARDS)所必須的。 通過(guò)進(jìn)行細(xì)胞培養(yǎng)和感染小鼠的研究實(shí)驗(yàn)證明,導(dǎo)致1918-1919年爆發(fā)的“西班牙大流感”的甲型H1N1流感病毒以及流感H9N2病毒均能夠?qū)е滤拗骷?xì)胞凋亡。然而至今,尚未有2009年造成全球流感大流行的甲型H1N1流感病毒有關(guān)可產(chǎn)生細(xì)胞凋亡的報(bào)道。 有研究發(fā)現(xiàn),感染豬源性甲型H1N1流感死亡患者的肺部發(fā)現(xiàn)有肺泡的損傷,支氣管壞死和組織出血。并在支氣管上皮細(xì)胞以及肺泡細(xì)胞出現(xiàn)病變。 我們?cè)谘芯恐?對(duì)2009年流感大流行期間在國(guó)內(nèi)分離到的一些豬源性甲型H1N1流感病毒株,發(fā)現(xiàn)其中甲型H1N1病毒文山株(A/Wenshan/01/2009H1N1)能夠?qū)е氯撕粑郎掀ぜ?xì)胞A549株和CNE-2Z株細(xì)胞的凋亡。 我們還發(fā)現(xiàn),對(duì)于感染文山株病毒(A/Wenshan/01/2009H1N1),來(lái)源于上呼吸道的CNE-2Z細(xì)胞比下呼吸道的A549更為敏感,與人季節(jié)性甲型流感病毒相比,文山株顯示出更高的侵入能力和病毒復(fù)制能力。 我們通過(guò)研究還證實(shí)了,流感病毒是利用clathrin-依賴的和dynamin依賴的進(jìn)入通路進(jìn)入宿主細(xì)胞。 在人類邁入二十一世紀(jì)的今天,納米技術(shù)在醫(yī)藥、信息以及通訊技術(shù)產(chǎn)業(yè)領(lǐng)域里被認(rèn)為是極為重要的新興技術(shù)。 納米材料半徑微小,其特殊的小尺寸效應(yīng)、量子效應(yīng)和巨大比表面積。樹狀分子材料(PAMAM)為單分散結(jié)構(gòu),且高度分枝化的納米材料,這種結(jié)構(gòu)能夠設(shè)計(jì)成單分散膠體、封閉的金屬簇、結(jié)合組織液、或具有生物活性的成分,并且能夠在適宜的介質(zhì)中溶解,并可與某些成分的表面結(jié)合。由于PAMAM的這一結(jié)構(gòu)特性,因此,PAMAM可用于開發(fā)成各種功能性材料用于眾多領(lǐng)域,包括化學(xué)物質(zhì)的分離、富集、醫(yī)療影像以及DNA或藥物的釋放等。 樹狀分子材料是由重復(fù)的分支組成的球型大分子,圍繞核心形成三維對(duì)稱結(jié)構(gòu)。樹狀分子呈單分散對(duì)稱性球型結(jié)構(gòu)的結(jié)構(gòu)決定了其特性。樹狀分子材料可分為低分子量和高分子量。前者一般指樹狀分支,后者包括樹枝狀多聚體、超枝化聚合物多聚體等。樹狀分枝納米材料的特性取決于分子表面的功能基團(tuán)。同時(shí),也是的樹狀分子納米材料與其他聚合材料不同,可成為水溶性材料,樹狀結(jié)構(gòu)包裹的功能分子結(jié)構(gòu)可以成為行使活性功能的場(chǎng)所。樹狀分子納米材料可由于合成過(guò)程中重復(fù)的分支循環(huán)數(shù)量的不同分成不同的代。每新合成一代其分子量比上一代增加一倍。PAMAM G5樹狀分子材料是和一定數(shù)量的乙酰酐乙�；磻�(yīng)的產(chǎn)物。高分子量的樹狀納米材料具有更多的功能基團(tuán),用于商業(yè)化的樹狀分子納米材料可以有更為廣泛的應(yīng)用。 聚酰胺納米材料(PAMAM)是目前研究比較成熟的樹狀分子納米材料。PAMAM的核心為是乙二胺,和另外一個(gè)乙二胺經(jīng)胺化反應(yīng)形成G-0代。PAMAM納米材料的表面功能基團(tuán)被認(rèn)為是鏈接化學(xué),具有許多潛在的應(yīng)用價(jià)值。PAMAM樹枝狀大分子被用廣泛應(yīng)用于藥物研究,用于抗感染,抑制細(xì)胞、病毒、細(xì)菌、蛋白間的多價(jià)結(jié)合等。納米材料在醫(yī)學(xué)領(lǐng)域具有極大的應(yīng)用前景。 但隨著納米技術(shù)的廣泛應(yīng)用,納米材料可能存在的安全性問(wèn)題越來(lái)越引起廣泛的關(guān)注。當(dāng)前,納米材料對(duì)機(jī)體可能會(huì)機(jī)體造成肺損傷已成為研究的熱點(diǎn),由此導(dǎo)致全世界都在呼吁在納米材料的安全性問(wèn)題徹底解決前應(yīng)暫停納米材料的使用,特別是在醫(yī)藥領(lǐng)域的呼聲更為強(qiáng)烈。美國(guó)環(huán)境保護(hù)機(jī)構(gòu)開始評(píng)價(jià)納米技術(shù)對(duì)人類健康產(chǎn)生的影響,這對(duì)PAMAM納米材料的毒性以及對(duì)環(huán)境的安全性發(fā)揮重要作用的資料。 目前,關(guān)于對(duì)納米顆粒毒性的研究的重點(diǎn)是導(dǎo)致肺部疾病。我們?cè)?jīng)開展過(guò)相關(guān)研究顯示,血管緊張素轉(zhuǎn)化酶2(angiotensin I converting enzyme2,ACE2)能夠保護(hù)肺部酸吸入綜合征、敗血癥以及感染SARS冠狀病毒的小鼠避免導(dǎo)致嚴(yán)重的就急性肺損傷。由以前的研究,我們?cè)O(shè)想,是否ACE2也能夠保護(hù)小鼠抵抗因納米顆粒產(chǎn)生的肺損傷。 目前,可供商業(yè)化提供的全代(陽(yáng)離子)或半代(陰離子)的PAMAM納米材料。由于PAMAM納米材料正越來(lái)越廣泛地在應(yīng)用于醫(yī)藥領(lǐng)域,PAMAM陽(yáng)離子納米材料也即將完成臨床試驗(yàn),獲得美國(guó)食品藥品管理局(FDA)的批準(zhǔn)。我們對(duì)陽(yáng)性PAMAM納米材料進(jìn)行了深入的研究,闡明通過(guò)實(shí)驗(yàn)觀察到的PAMAM導(dǎo)致肺損傷的毒性機(jī)理。 我們的研究顯示,給小鼠注射PAMAM,能夠上調(diào)小鼠肺組織的ACE2表達(dá),下調(diào)血管緊張素Ⅱ的產(chǎn)生,從而避免嚴(yán)重肺損傷的產(chǎn)生。注射ACE2基因敲除小鼠,導(dǎo)致動(dòng)物肺損傷的發(fā)生。我們的研究解釋可使納米顆粒不能夠?qū)е路螕p傷的原因,并建議為日益關(guān)注的納米技術(shù)的安全性問(wèn)題提供了可能的治療策略。
[Abstract]:In April 2009, the first detection and discovery of a novel influenza A virus in Mexico (Novel Swine-Origin Influenza A) spread in the population, the incidence of infection and cause. The new H1N1 influenza virus (S-OIV H1N1) quickly spread to the world in many countries and regions in.2009 June 11th, WHO (WHO) announced influenza A virus, the global alert level raised to 6, which also indicates that the global influenza pandemic outbreak.
Although the H1N1 influenza virus infection of the epidemic is more scattered in the individual, and the symptoms of infection is generally mild, but for young people and people who have underlying diseases (including asthma, diabetes, morbid obesity and pregnant women), which is a serious disease course situation will greatly increase.2010 in August 10th WHO, H1N1 influenza virus pandemic is over, but regional flu outbreak continues. According to the results of the latest statistics WHO, under normal circumstances, due to seasonal influenza virus infection, the annual death toll in 250000-500000. The H1N1 flu pandemic caused a total of 18000 deaths, mortality accounted for 4%, the Health Protection Agency (HPA) reported recently in the UK was due to a flu virus that killed 214 people, including 195 people were infected with influenza a H1N1 influenza virus strain in 2009. The agency which provided A H1N1 (S-OIV H1N1) may come back again.
The 2009 pandemic influenza H1N1 virus may be derived from classical swine H1N1 influenza virus may have homology with the 1918 "Spanish flu" epidemic H1N1 human influenza virus and avian influenza virus. The researchers determined the Nordic descent from the virus genome sequence has been determined, but found no toxicity marker. Animal experiments show that caused the 2009 pandemic influenza a H1N1 virus has obvious pathogenicity than human seasonal influenza a H1N1 influenza virus. Animal model studies show that compared with the seasonal influenza virus, 2009 H1N1 influenza virus can be more effective for virus replication in host cells, and lead to more morbidity and the fatality rate of serious.
In many physiological processes, including tissue atrophy, development and tumor biology, the process of cell death, or apoptosis is critical in many pathological processes, including disease infection, cell apoptosis play an important role in host cells. Apoptosis can be many viral infections, influenza viruses can cause apoptosis in many types of in vivo and in vitro.
Reported that patients infected with H5N1-AVI and avian alveolar epithelial cells or blood vascular endothelial cells appeared apoptosis sense. Some research reports suggested that H5N1-AVI infection in human patients, cell apoptosis is lead to the development of acute respiratory distress syndrome (acute respiratory distress syndrome, ARDS) must be.
Through the study of cell culture and experimental infection of mice that led to 1918-1919 years of the outbreak of the "Spanish flu" influenza a H1N1 influenza virus and influenza H9N2 virus can cause the host cell apoptosis. However, so far, has not yet been reported in 2009 caused a global influenza pandemic influenza a H1N1 virus can produce cell apoptosis.
It has been found that alveolar injury, bronchial necrosis and tissue bleeding are found in the lungs of patients infected with swine influenza a H1N1 influenza, and there are lesions in bronchial epithelial cells and alveolar cells.
In our research, we detected some swine influenza A virus strains isolated from China during the 2009 influenza pandemic. We found that the H1N1 strain of Wenshan virus (A/Wenshan/01/2009H1N1) can induce apoptosis of A549 and CNE-2Z cells of human respiratory epithelial cells, H1N1.
We also found that for infected strains of Wenshan virus (A/Wenshan/01/2009H1N1), CNE-2Z cells from the upper respiratory tract were more sensitive than A549 in the lower respiratory tract. Compared with the seasonal influenza A virus, Wenshan strains showed higher invasion ability and virus replication ability.
We have also demonstrated that influenza viruses are entering the host cells using clathrin- dependent and dynamin dependent access pathways.
As mankind enters the twenty-first Century, nanotechnology is regarded as a very important new technology in the fields of medicine, information and communication technology industry.
Nano materials and its special radius of small, small size effect, quantum effect and large specific surface area. Dendrimer material (PAMAM) for monodisperse and highly branched structure, nano materials of this structure can be designed into monodisperse colloidal metal clusters, closed, combined with tissue fluid, or biologically active ingredients. And can be dissolved in a suitable medium, and can be combined with certain surface components. Due to the structural characteristics of PAMAM, therefore, PAMAM can be used to develop into various functional materials used in many fields, including separation, chemical enrichment, medical imaging and DNA or drug release.
Dendrimer material is spherical macromolecules composed of repeated branches, around the core to form a three-dimensional symmetric structure. A monodisperse dendrimer structure symmetry spherical structure determines its characteristics. Dendrimer materials can be divided into low and high molecular weight. The former refers to the tree branch, the latter including dendritic poly dimers, super branched polymer polymer. Functional groups dependent on dendritic nano materials on the molecular surface. At the same time, but also the dendrimers of different nano materials and other polymeric materials, can be water soluble material, tree structure package molecular structure can become active functional exercise in place. The tree molecular nano materials may be due to the synthesis process of repeated cycles of different number of branches into different generations. Each new generation of synthetic molecular weight than the previous generation of double.PAMAM G5 dendrimer material The products of acetylation reaction with a certain number of acetyl anhydride. High molecular weight dendrimers have more functional groups. The commercialized dendrimer nano materials can be widely applied.
Polyamide nano material (PAMAM) is the core of the dendrimer nanoparticles.PAMAM mature as ethylenediamine, and another ethylenediamine by amination of functional groups formed on the surface of G-0 generation of.PAMAM nano material is considered to be the link to chemistry, with many potential applications of.PAMAM dendrimers are widely used in medicine study for anti infection, inhibiting cell, virus, bacteria, protein between multivalent binding. Nano material has great application prospect in the field of medicine.
But with the wide application of nanotechnology, safety of nanomaterials may exist more and more attention. At present, nano materials may cause body lung injury has become a research hotspot in the body, resulting in the world calls for the problem of nano materials should be used to solve an before suspension of nano materials especially in the field of medicine, more and more applause. The U.S. Environmental Protection Agency began to impact assessment of nanotechnology to human health, the toxicity of PAMAM nano materials and environmental security play an important role.
At present, the focus on research of nanoparticle toxicity is the cause of lung disease. We have carried out relevant studies show that angiotensin converting enzyme 2 (angiotensin I converting enzyme2, ACE2) can protect the lung acid aspiration syndrome, sepsis and infection of SARS coronavirus in mice to avoid severity of acute lung injury. From previous studies, we assume that whether ACE2 can protect mice from nanoparticles due to lung injury.
At present, for commercial whole generation (cationic) or half generation (anionic) PAMAM nano materials. Because PAMAM nano materials are becoming more and more widely applied in the field of medicine, PAMAM cationic nano materials will also be completed clinical trials, the U.S. Food and Drug Administration (FDA) to obtain approval. We are a further study on the positive PAMAM nano materials, clarify the experimentally observed PAMAM induced toxicity mechanism of lung injury.
Our study shows that mice injected with PAMAM can increase the ACE2 expression in lung tissue of mice, decreased the production of angiotensin II, so as to avoid serious lung injury. Injection of ACE2 gene knockout mice, resulting in animal lung injury. Our study can make the interpretation of nanoparticles can cause lung injury the security problem and suggest more attention nanotechnology provides possible therapeutic strategies.

【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】：2011
【分類號(hào)】：R373.13;R318.08

【共引文獻(xiàn)】

相關(guān)期刊論文 前10條

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