本文選題：急性肺損傷　切入點：地塞米松　出處：《北京協(xié)和醫(yī)學(xué)院》2012年博士論文

【摘要】：納米技術(shù)已經(jīng)是當(dāng)今最重要及新興的科技發(fā)展之一,但因為它的發(fā)展而導(dǎo)致的安全問題也引起了越來越多的關(guān)注。在它們的發(fā)展過程中對納米材料在人體暴露和引起的環(huán)境問題方面的危害評估對于納米材料將來的發(fā)展至關(guān)重要。 本文所研究的納米材料是具有可溶性的修飾化單壁碳納米管(functionalized single-walled carbon nanotubes,f-SWCNTs)。碳納米管(Carbon NanoTubes,CNT)是一種特殊形式的碳分子,是碳原子之間形成化學(xué)鍵組成的管狀結(jié)構(gòu)。單壁碳管(single-walled carbon nanotubes, SWCNT),由一層碳原子網(wǎng)組成,直徑范圍0.6～2.4nm；由于其特有的理化性質(zhì)(重量較輕,較好的延伸性能,熱力學(xué)/化學(xué)穩(wěn)定性以及導(dǎo)電能力),碳納米管被大量用于制造組織支架。同時,由于具有較大的表面積,表面可以被各種功能基團修飾而具有不同的功能,碳納米管被廣泛用于遞送肽段、蛋白質(zhì)、基因、藥物或疫苗等[4]。 本研究針對表面功能基團為AMIDE, COOH, PABS, PEG的單壁碳管在小鼠中的肺毒性做了評估并闡述了相關(guān)的分子機制,進一步檢測了修飾化單壁碳納米管處理后小鼠的自我修復(fù)能力和小鼠肺纖維化程度。在氣管注射修飾化單壁碳納米管18h或14d后,檢測了小鼠肺組織病理、肺泡支氣管灌洗液(Bronchial Alveolar Lavage Fluid, BALF)中細胞因子、肺血管通透性以及血氧分壓,另外也做了免疫組化檢測。我們發(fā)現(xiàn)部分修飾化單壁碳納米管能在小鼠中通過MyD88-NF-κB信號通路能引起促炎性細胞因子風(fēng)暴而造成急性肺損傷(Acute Lung Injury, ALI)。 本研究中,我們也證實了皮質(zhì)類固醇類藥物能減輕修飾化單壁碳納米管在小鼠中誘導(dǎo)的急性肺損傷。另外,單次給藥14d后,小鼠的急性肺損傷幾乎完全恢復(fù)正常,而同時輕度至中度的肺纖維化、肉芽腫、DNA損失在14d時仍然存在。 綜上所述,我們的研究為將來處理隨著應(yīng)用而不斷增長的納米材料安全性問題提供了可能的參考。 背景：2009年在北美爆發(fā)了以一株新的豬源性甲型H1N1流感病毒造成的的流行性感冒[1,2,3],該病毒隨后在人類中流行并短時間內(nèi)傳播至全世界大部分地區(qū)。然而此病毒在人呼吸道上皮細胞和哺乳動物中的致病機制仍然不清晰。 實驗方法及實驗結(jié)果：在本研究中,我們發(fā)現(xiàn)一株從病人身上分離的2009年甲型H1N1流感病毒,A/Beijing/501/2009,能在雪貂中引起典型的流行性感冒癥狀,包括體重減輕、體溫波動、肺組織病理變化。我們的研究也證實了人肺腺癌上皮細胞A549細胞對甲型H1N1流感病毒易感,同時被感染的細胞在早期即發(fā)生了凋亡。與季節(jié)性H1N1流感病毒相比,甲型H1N1流感病毒株A/Beijing/501/2009能在A549細胞中引起更多的細胞死亡,且細胞死亡方式是依賴caspase-3信號通路的凋亡。另外,感染了甲型流感A/Beijing/501/2009H1N1病毒株的雪貂表現(xiàn)出體溫上升、體重下降更厲害、肺組織中病毒滴度更高等癥狀。因此,A/Beijing/501/2009型甲型H1N1流感病毒株能成功感染雪貂肺組織,并能造成比季節(jié)性流感病毒更嚴重的病理損傷。 結(jié)論：本研究發(fā)現(xiàn)2009年甲型H1N1流感病毒與季節(jié)性H1N1流感病毒在體內(nèi)和體外表現(xiàn)出不同的毒力,可能是通過不同的機制導(dǎo)致的。細胞凋亡參與甲型H1N1流感病毒造成的體外細胞病變、甲型H1N1流感病毒感染的雪貂肺組織中病理變化比季節(jié)性流感病毒更嚴重的這些發(fā)現(xiàn)拓寬了人類對甲型H1N1流感病毒在感染人類和動物的致病機制方面的知識。
[Abstract]:Nanotechnology is one of the most important and emerging scientific and technological developments in the present day , but the security problems caused by its development have attracted more and more attention . In the course of their development , the damage assessment of nanomaterials in human exposure and environmental problems is essential to the future development of nanomaterials .

Nanomaterials studied in this paper are soluble modified single - walled carbon nanotubes ( f - SWCNTs ) . Carbon NanoTubes ( CNT ) is a special form of carbon molecule , which is a tubular structure composed of chemical bonds between carbon atoms . Single - walled carbon nanotubes ( SWCNT ) are composed of a layer of carbon network with a diameter ranging from 0.6 to 2.4 nm .
The carbon nanotubes are widely used to deliver peptide segments , proteins , genes , drugs or vaccines because of their specific physical and chemical properties ( lighter weight , better elongation properties , thermodynamic / chemical stability , and conductivity ) .

In this study , the lung toxicity of single - walled carbon nanotubes in mice was assessed and the relative molecular mechanism was assessed and the self - healing ability and the degree of pulmonary fibrosis in mice were also described . After tracheal injection - modified single - walled carbon nanotubes for 18 h or 14 d , the expression of cytokines , pulmonary vascular permeability and oxygen partial pressure in lung tissues of mice were examined .

In this study , we also demonstrated that corticosteroids can alleviate acute lung injury induced by modified single - walled carbon nanotubes in mice . In addition , after a single dose of 14 days , acute lung injury in mice is almost completely normal , while mild to moderate pulmonary fibrosis , granuloma , DNA loss still exist at 14d .

In conclusion , our research provides a potential reference for future handling of the safety of nanomaterials with growing applications .

Background : In 2009 , a new swine - derived influenza A ( H1N1 ) virus , caused by a new swine - derived influenza A ( H1N1 ) virus , was outbreak in North America , which was then prevalent in humans and disseminated in a short period of time to most parts of the world . However , the pathogenic mechanism of the virus in human respiratory epithelial cells and mammals remains unclear .

In this study , we found that influenza A / A / Beijing / 501 / 2009 , isolated from a patient , can cause typical influenza symptoms , including weight loss , body temperature fluctuation and pathological changes in lung tissues . In addition , the influenza A / Beijing / 501 / 2009 H1N1 virus strain can cause more cell death in A549 cells . In addition , A / Beijing / 501 / 2009 H1N1 virus strain can successfully infect ferret lung tissue , and can cause more serious pathological damage than seasonal influenza virus .

Conclusion : This study shows that influenza A ( H1N1 ) virus and seasonal H1N1 influenza virus exhibit different virulence in vivo and in vitro , which may be caused by different mechanisms . Apoptosis is involved in the in vitro cellular pathological changes caused by influenza A H1N1 virus , and the pathological changes in mink lung tissues infected by influenza A H1N1 influenza virus are more serious than those of seasonal influenza virus . These findings broaden the knowledge of influenza A ( H1N1 ) virus in infection of human and animal pathogenic mechanisms .

【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2012
【分類號】：R114

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2 楊保華;吳純啟;廖明陽;;碳納米管的生物安全性研究進展[J];毒理學(xué)雜志;2007年04期

3 張水華;梅其炳;馬t，

本文編號：1707112