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Study on damage mechanism of acute respiratory induced by nano materials PAMAM toxicity study and the H5N1 avian influenza virus

Author: SunYang
Tutor: JiangChengYu
School: Beijing Union Medical College
Course: Biochemistry and Molecular Biology
Keywords: nano-materials PAMAM Toxicity Pathogenesis ACE2 Acuteung injury Liver damage H5N1 Avian influenza H1N1 Seasonal influenza. Autophagy Autophagic cell death
CLC: R318.08
Type: PhD thesis
Year: 2010
Downloads: 120
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Abstract

Mechanism of toxicity of nano-materials PAMAMNano-materials and conventional materials have different physical and chemical effects. Nano-materials have some features in a special small size, quantum effects and large surface area due to very small radius. Dendrimer is a new type of synthetic polymer materials, with drug delivery, medical imaging and clinical diagnosis, is of great significance.Polyamide dendrimer nano-materials (PAMAM dendrimer) are a macromolecule with branch of highly symmetric, radiating. It consists of the central core, the inner branch of repeated subunits and the surface functional groups. Whole generation of PAMAM nano-material has amino as surface functional groups, as with carboxyl surface for half-generation. Whole generation PAMAM dendrimers, with high-density surface of the amino, could be combined with DNA and other biological macromolecules highly compressed in space. As non-viral vectors, it could deliever some genetic material and drugs such as DNA or oligonucleotide to cell efficiently. Dendrimer itself is also used as a drug for eliminating infection, inhibiting multivalent binding among cell, virus, bacteria and proteins. It has great prospects in the medical field.However, we also observed that easy accesses to a variety of cells are different from other synthetic materials carrier. It is the advantage of dendrimers, but more potential risks exist. Therefore, compatibility between cells and dendrimers is particularly concerned by the researchers. It is reported that the PAMAM G3, G5, G7have been studied in toxicity in vivo, immunogenicity and biological distribution and it could be effected by particle size. But the research is in its infancy, needs a lot of follow-up study.In this study, we verified PAMAM G3, G5, G7is toxic to cells according to the early experiments. And we focus on the G5for further research. PAMAM G5was injected into mice then organs and tissues were obtained for pathological examination. It is showed lung and liver injury is induced by PAMAM G5. We do the research in the mechanism in detail.Since rapid death of mice could be induced by PAMAM G5, we first studied the mechanism of lung injury lead by PAMAM G5. We found that Angiotensin Ⅱ significantly increased and angiotensin converting enzyme2(ACE2) decreased, resulting in disorders of renin angiotensin system, with edema formation because of pulmonary hypertension. Further we used ACE2knockout mice to verify. It was clearly understood a major mechanism of acute lung injury is caused by expression of ACE2reduced, which changes its negative regulatory effect and leads to increased levels of Angiotensin Ⅱ. Excessive Angiotensin Ⅱ in the lung combined with its receptor eventually lead to acute lung injury due to formation of pulmonary hypertension.Next liver injury induced by PAMAM G5was found. The results show that PAMAM G5can activate TLR4receptor of blood monocytes. It can activate NF-κB signaling pathway of liver in transgenic mouse. Then levels of various pro-inflammatory factors in blood are increased. We tested liver function in mice and found that levels of transaminase was increased, blood coagulation time was elevated, total protein content in the blood was decreased and liver weight to body weight ratio was increased. Therefore, we believe that PAMAM G5may activate TLR4of hepatic Kupfer cells (macrophages), which activate TLR4-NF-κB signaling pathway. It results levels of various inflammatory factors elevated, ultimately lead acute inflammation in liver and then resulted in acute liver injury.Molecular mechanism of H5N1avian influenza induced acute lung injuryThe cases of ongoing H5N1highly pathogenic avian influenza virus in poultry and human have raised widespread concern in the world. As the virus spreads rapidly in poultry, it can cause large-scale poultry deaths. Although not break of the barriers between human being, but the patient’s mortality is very high. And the virus has a high variability, the outbreak of large-scale epidemic most likely happens. There is no effective prevention and treatment. Therefore, doing the research in H5N1avian influenza virus pathogenesis is very important.The high mortality rate of H5N1infection is due predominantly to respiratory failure caused by acute lung injury. It is unknown how viral infection of lung cells contributes to this disease pathology. Interaction between a variety of viruses and cell suggest existence of autophagy. We verify that the H5N1avian influenza virus whether can lead to autophagy first. Then we use cells and mice to study the acute lung injury caused by H5N1. It is vertified that acute lung injury could caused by autophagic cell death. Here, we show that H5N1induces alveolar epithelial autophagic cell death through the Akt-TSC2-mTOR pathway. Our results also show that the specific inhibitor of autophagy and autophagy-related knockout of specific molecules can alleviate acute lung injury caused by H5N1. Therefore, H5N1avian influenza virus pathogenesis use Akt-TSC2-mTOR signaling pathway in lung epithelial cells to induce autophagic cell death and ultimately lead to the occurrence of acute lung injury. The results clarify the understanding of pathogenesis of H5N1. It is theoretical basis for development of new antiviral drugs.

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CLC: > Medicine, health > Basic Medical > Medical science in general > Biomedical Engineering > General issues > Biomaterial
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