Mechanism Of Acute Lung Injury Caused By H5N1 Avian Influenza Virus And Nanomaterials And Screening Of Drugs For Control

The mechanisms of and candidate drugs to treat Acute Lung Injury induced by H5N1 avian influenza virusSince avian influenza H5N1 virus was first found to be able to infect human beings in 2003, there are a total of 784 human cases of H5N1 infection reported by WHO. Among them,429 patients were died of this disease from 2003 to 2014 worldwide, with a morbidity rate of 54.7% among infected patients. In addition, recent researches on influenza virus transmission have proven that only a few amino acid mutations on the HA and PB2 of H5N1 influenza virus can make it transmissible among ferrets, an animal model that has the most similar response to human beings after infection with influenza virus. Thus, we want to focus on the mechanisms of host desease induced by H5N1 influenza virus and then further find some novel candidate drugs or methods to treat H5N1 influenza virus infection.Our previous researches have proved the important function of RAS in H5N1 induced acute lung injury. We found that Ang II of RAS was significantly upregulated and helped to induce the acute lung injury, while ACE2 protein, which can protect host from lung injury, was down-regulated. We further testified that prophylacticly and therapeuticly administration of ACE2 protein could help to alleviate the symptoms of acute lung injury and to rescue the death infected by H5N1 influenza virus in mouse models. In this project, we further found out that AngⅡ was up-regulated in human patients infected by H5N1 influenza virus. Through analysis on Ang II levels in series serum samples from both human patients and mouse models, we found Ang Ⅱ’s changes and final concentrations can be taken as a candidate biomarker to reflect the final result after H5N1 infection. We then found out the mechanisms under ACE2 protein’s protection, which included downregulation of AngⅡ, inhibited virus replication and downregulated virus titer et al.With the theory of "repurposing of old drugs", we tested several clinical used drugs and finally found that anti-hypertension drug named Losartan and anti-malaria drug called Chloroquine could efficiently treat H5N1-induced acute lung injury through different mechanisms. We also tested some other anti-hypertension drugs including Captopril and Enalapril, anti-cholesterol drug including Pravastatin and Simvastatin, but no protections of these drugs were discovered. Our research provides some candidate clinical drugs which can be directly used to treat H5N1 influenza virus infection.Copper Oxide Nanoparticles can induce autophgic cell death in A549 cells.Metal oxide nanoparticles (NPs) are among the most highly produced nanomaterials, and have many diverse functions in catalysis, environmental remediation as sensors, and in the production of personal care products. Our previous research has found that among the toxicity of several widely used metal oxide NPs such as copper oxide, silica, titanium oxide and ferric oxide NPs, only CuO NPs can induce significant cell death in cell lines from respiratory system.In this study, we further tried to elucidate the potential mechanisms under CuO NPs induced cell death. The classical indexes of autophagy, including autophagsomes observed by electron microscope, LC3 puncta-positive cells counted by confocal and autophagy flux detected after treatment of Bafilomycin A1, were all upregulated after infection with CuO NPs. It proved that CuO NPs can induce severe autophagy in cells. Administration of siRNA targeting ATG5 or autophagy inhibitors can significantly rescue the cell death inducedy by CuO NPs, which proved the autophagic cell death induced by CuO NPs.