Impact of novel Heat-not-Burn cigarettes on pulmonary inflammation and immunity

项目总结/摘要 随着“加热不燃烧”（HnB）烟草产品的推出，烟草市场的格局已经 再次改变。新兴的HnB产品声称，与 可燃尼古丁产品，如烟草香烟，避免直接燃烧烟草， 加热烟草菲利普莫里斯国际公司向美国FDA提交了其HnB产品iQOS的申请 被授权为改良风险烟草产品（MRTP）。iQOS（不可燃）风险降低的声明 与传统香烟（可燃烟草产品）相比， 完全依赖于行业资助的研究，而关于其健康影响的可靠独立研究 来支持这些主张。因此，迫切需要进行独立研究， 对HNB产品的潜在健康影响的平衡观点。有一个关键的知识差距， HnB气溶胶对肺部炎症和对引起呼吸道疾病的病原体的免疫力的潜在影响 疾病我们的建议旨在利用两名主要调查员的综合专长和我们的投资组合 标准化检测首次证明长期暴露于HnB气溶胶是否有可能 导致肺部炎症改变、肺形态学改变和免疫调节 反应本申请的总体目标是确定吸入HnB气雾剂是否有可能 导致肺损伤并抑制对疫苗接种的免疫反应。在并排比较中 格式，我们将比较HnB气溶胶的影响，由烟草香烟烟雾或电子 香烟气雾剂我们的前提将在已建立的小鼠模型中进行测试，并将使用雄性和雌性 小鼠，以评估宿主性别的潜在影响。由于吸烟者可能倾向于改用HnB， 假设它们比传统香烟的危害小，因此， 我们将在“转换”实验中检验这一前提。在具体目标1中，我们将检验以下假设： 慢性吸入暴露于HnB气溶胶有可能引起肺部炎症， 炎症细胞数量和细胞因子水平，这种环境改变了先天免疫， 反应在具体目标2中，我们建议检验慢性吸入HnB气雾剂会产生 肺内环境有可能损害对疫苗的适应性免疫反应，我们将 检查引起的反应清除急性肺部感染的能力。在第三个具体目标中， 我们将检验以下假设，即烟草烟雾暴露后过渡到HnB使用可能阻碍 通过真正的停止可以达到的炎症消退。这项提案的结果将 直接的监管影响和真实的世界的相关性，因为它们将提供关于绝对和 HnB产品的相对（与烟草和电子烟相比）健康风险。

PROJECT SUMMARY/ABSTRACT With the introduction of the `Heat-not-Burn' (HnB) tobacco products the landscape of tobacco market has changed yet again. Emerging HnB products purport to reduce exposure to toxicants compared with combustible nicotine products such as tobacco cigarettes by avoiding directly burning tobacco and instead heating tobacco. Philip Morris International submitted an application to the US FDA for their HnB product iQOS to be authorized as a modified risk tobacco product (MRTP). Claims of lowered risk of iQOS (non-combustible tobacco product) compared to conventional cigarettes (combustible tobacco product) are based almost exclusively on industry-funded research, and reliable independent research on their health effects is not available to support these claims. Independent research is therefore urgently needed to provide a balanced view on the potential health impact of HnB products. There is a critical knowledge gap in the potential impact of HnB aerosols on pulmonary inflammation and immunity to pathogens that cause respiratory diseases. Our proposal seeks to utilize the combined expertise of two principal investigators and our portfolio of standardized assays to demonstrate for the first time if chronic exposure to HnB aerosol has the potential to result in alteration of pulmonary inflammation, morphological changes in the lung and modify the immune response. The overall goal of this application is to determine if inhalation of HnB aerosol has the potential to result in pulmonary damage and suppress the immune response to vaccination. In a side–by-side comparison format, we will compare the effect of HnB aerosol to effects caused by tobacco cigarette smoke or electronic cigarette aerosol. Our premise will be tested in an established mouse model and will use both male and female mice to evaluate the potential effect of sex of the host. As cigarette smokers may be inclined to switch to HnB products under the assumption that they are less damaging than conventional cigarettes, therefore this premise will be tested by us in `switching' experiments. In Specific Aim 1 we will test the hypothesis that chronic inhalation exposure to HnB aerosol has the potential to cause lung inflammation and result in changes in inflammatory cell numbers and cytokines levels in the lung and this milieu alters the innate immune response. In Specific Aim 2 we propose to test the hypothesis that chronic inhalation of HnB aerosol creates a milieu in the lungs which has the potential to impair adaptive immune responses to a vaccine and we will examine the ability of the response elicited to clear an acute pulmonary infection. Finally, in Specific Aim 3, we will test the hypothesis that transition to HnB usage following tobacco smoke exposure could hinder resolution of inflammation that can be achieved by true cessation. The findings from this proposal would have direct regulatory implications and real world relevance as they will provide novel insights on absolute and relative (as compared to tobacco and electronic cigarettes) health risk of HnB products.