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

项目摘要/摘要 随着“热不烧”(HNB)烟草产品的推出，烟草市场的格局已经 又变了一次。新兴的HNB产品声称与以下产品相比可以减少接触有毒物质 可燃尼古丁产品，如烟草香烟，避免直接燃烧烟草，而是 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 作为经修改的危险烟草产品(MRTP)获得授权。关于降低iQOS(不可燃)风险的索赔 烟草产品)与传统卷烟(可燃烟草产品)相比几乎都是基于 仅限于行业资助的研究，而关于其对健康影响的可靠独立研究并不是 可用于支持这些索赔。因此，迫切需要独立研究，以提供 平衡地看待HNB产品对健康的潜在影响。有一个关键的知识缺口，在 HNB气雾剂对肺部炎症和对呼吸道病原体免疫的潜在影响 疾病。我们的提案寻求利用两名首席调查人员和我们的投资组合的综合专业知识 首次证明慢性暴露于HNB气雾剂是否有可能 导致肺部炎症改变，肺组织形态发生改变，从而改变免疫功能 回应。这项应用的总体目标是确定吸入HNB气雾剂是否有可能 导致肺损伤，抑制接种疫苗的免疫反应。在并排比较中 格式，我们将比较HNB气雾剂的影响与烟草、香烟烟雾或电子烟造成的影响 香烟喷雾剂。我们的假设将在已建立的小鼠模型中进行测试，并将同时使用雄性和雌性 评估宿主性别对小鼠的潜在影响。因为吸烟者可能倾向于改用HNB 产品假设它们比传统香烟危害小，因此这一点 前提将由我们在“转换”实验中检验。在具体目标1中，我们将检验假设 慢性吸入暴露于HNB气雾剂有可能引起肺部炎症并导致改变 肺部炎症细胞数量和细胞因子水平，这种环境改变了先天免疫 回应。在具体目标2中，我们建议检验长期吸入HNB气雾剂会产生 可能损害对疫苗的适应性免疫反应的肺部环境，我们将 检查引起的反应清除急性肺部感染的能力。最后，在具体目标3中， 我们将测试这一假设，即烟草烟雾暴露后过渡到使用HNB可能会阻碍 通过真正的停药可以达到的炎症消退。这项提案的结果将会是 直接的监管影响和现实世界的相关性，因为它们将提供关于绝对和 HNB产品的相对健康风险(与烟草和电子烟相比)。

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.