| In April2009, a new strain of influenza virus that caused disease and transmitted in humans (Novel Swine-Origin Influenza A, H1N1) was detected. This new swine-origin H1N1influenza A virus (S-OIV H1N1) spread efficiently around the world, leading to the World Health Organization (WHO) declaring that the outbreak a pandemic on11June2009. Although the infection was mild for most individuals, the young and those with certain underlying conditions (including asthma, diabetes, morbid obesity, and pregnancy) seem to at great risk of severe disease progression. On10August2010, the WHO announced the H1N1influenza virus has moved into the post-pandemic period. However, localized outbreaks of various magnitudes are likely to continue. According to the latest WHO statistics, the virus has killed more than18,000people, approximately4%of the250,000to500,000annual influenza deaths. The Health Protection Agency (HPA) reported that of the recent214confirmed deaths in the UK,195has been infected with the2009H1N1strain, suggesting this S-OIV H1N1may return.The2009pandemic H1N1derived from two unrelated swine H1N1viruses, one of them a "classic" swine derivative of the1918human virus and the other the European avian-like H1N1lineage. Sequence analysis of its whole genome has failed to identify any virulence markers previously recognized. Animal studies have indicated that2009pandemic H1N1is slightly more pathogenic than contemporary human seasonal H1N1viruses. In a mouse model, the2009H1N1virus also replicated more efficiently and caused greater morbidity and mortality than seasonal influenza virus.Programmed cell death, or apoptosis is critical for many physiological processes, including tissue atrophy, development, and tumor biology. Apoptosis also plays an important role in the pathogenesis of many infectious diseases, including those caused by virus. Many virus infections cause apoptosis in host cells, and the influenza virus induces apoptosis in numerous cell types, both in vivo and in vitro. The alveolar epithelial cells or vascular endothelial cells of human patients and chickens infected by H5N1-AVI were reported to undergo apoptosis Other reports suggest that apoptosis of those cells is essential for the development of acute respiratory distress syndrome (ARDS) in humans which is observed in H5N1-AVI-infected patients.1918H1N1influenza virus and H9N2also have been shown to induce apoptosis in infected mouse and cell culture. But until now, there has been no report on the apoptosis induced by2009pandemic H1N1.The other study shows that diffuse alveolar damage was present in the patients confirmed (S-OIV) infection. The diffuse alveolar damage was associated with necrotizing bronchiolitis and in five with extensive hemorrhage. There was also a cytopathic effect in the bronchial and alveolar epithelial cells, as well as necrosis, epithelial hyperplasia, and squamous metaplasia of the large airways.In this study, we have screened a few2009pandemic S-OIV H1N1isolated in China and found A/Wenshan/01/2009H1N1could cause apoptotic cell death in both human airway epithelial cell lines-A549and CNE-2Z. We also found that CNE-2Z cells from upper respiratory tract are more susceptible to A/Wenshan H1N1infection than A549cells that originate in the lower respiratory tract. While compared with contemporary seasonal H1N1A/Jinnan virus, the A/Wenshan H1N1displayed higher entry efficiency and virus replication.We also found that the influenza virus can enter into the host cells via clathrin-dependent and dynamin-dependent pathway endocytosis. Nanotechnologies are thought to be potentially important for a number of different industries particularly the pharmaceutical industry, information and communication technology, and other areas that require stronger and lighter materials.Nano-materials have some features in a special small size, quantum effects and large surface area due to very small radius. Dendrimers are relatively monodisperseand highly branched nanoparticles that can be designed to chelate metal ions; encapsulate metal clusters; bind organic solutes or bioactive compounds; and become soluble in appropriate media or bind onto appropriate surfaces. Because of these unique properties, dendrimers are providing unprecedented opportunities to develop functional nanomaterials for a variety of applications, including chemical separations, chemical sensing, medical imaging, DNA/drug delivery.Dendrimers are repeatedly branched, roughly spherical large molecules. A dendrimer is typically symmetric around the core, and often adopts a spherical three-dimensional morphology. Dendritic molecules are characterized by structural perfection. Dendrimers are monodisperse and usually highly symmetric, spherical compounds. The field of dendritic molecules can be roughly divided into low-molecular weight and high-molecular weight species. The first category includes dendrimers and dendrons, and the latter includes dendronized polymers and hyperbranched polymers.The properties of dendrimers are dominated by the functional groups on the molecular surface. Dendritic encapsulation of functional molecules allows for the isolation of the active site, also, it is possible to make dendrimers water soluble, unlike most polymers, by functionalizing their outer shell with charged species or other hydrophilic groups.Dendrimers are also classified by generation, which refers to the number of repeated branching cycles that are performed during its synthesis. Each successive generation results in a dendrimer roughly twice the molecular weight of the previous generation. The primary amines of generation5(G5) PAMAM dendrimers were acetylated by reaction with prescribed amounts of acetic anhydride. Higher generation dendrimers also have more exposed functional groups on the surface, which can later be used to customize the dendrimer for a given application.Poly(amidoamine), or PAMAM, is perhaps the most well known dendrimer. The core of PAMAM is a diamine (commonly ethylenediamine), which is reacted with methyl acrylate, and then another ethylenediamine to make the generation-0(G-0) PAMAM. The functional group on the surface of PAMAM dendrimers is ideal for click chemistry, which gives rise to many potential applications.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, several issues have been raised that threaten the potential widespread utility of nanotechnologies. Of these concerns, the toxicities of nanoparticles in humans are among the most distressing; nanomaterials have been reported to be potentially harmful at the cellular, subcellular, and protein level, and have been found to evoke injurious responses in various organisms.Many of these studies have focused on lung diseases and a worldwide moratorium on nanomaterials has been called until the safety issues have been resolved. Therefore, it is of critical importance to elucidate the molecular mechanisms by which nanoparticles induce lung injury. As the U.S. Environmental Protection Agency (EPA) begins its assessment of the impact of nanotechnology on human health and the environment, there is a critical need of data and quantitative tools for assessing the environmental fate and toxicity of engineered nanomaterials such as dendrimers。Most studies on nanoparticle toxicity have focused on lung diseases. We previously showed that angiotensin I converting enzyme2(ACE2) protects mice from severe acute lung injury induced by acid aspiration, sepsis and the SARS coronavirus, and in this study we sought to determine whether ACE2also protects against nanoparticle-induced lung injury.PAMAM dendrimers are commercially available as either whole (cationic) or half (anionic) generation polymers. Because PAMAM dendrimer nanomaterials are widely used in the pharmaceutical industry-a cationic species was just being completed in clinical trials, as approved by US FDA.we further examined the toxicity of the cationic PAMAM dendrimers to investigate the underlying molecular mechanism that leads to the observed lung injury. Moreover, the in vivo tissue distribution of G5has been reported to show high concentrations in lung tissue.Here we show that administration of specific cationic Starburst polyamidoamine dendrimers, but not functional carbon nanotubes, to mice downregulated ACE2expression in lung tissues, upregulated angiotensin II production, and precipitated acute lung failure.Administration of recombinant ACE2ameliorated nanoparticle-induced lung injury. Our data provide a molecular explanation for nanoparticle-induced acute lung failure, and suggest potential therapeutic strategies to address the growing concerns over the safety of nanotechnology. |
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