E-cigarette Inhalation and Cardiopulmonary Dysfunction

摘要 此Ruth L.Kirschstein NRSA F30应用程序的主要目的是提供以下框架 为申请者成为一名成功的内科科学家做好准备。申请人的大部分职业发展 将来自电子烟(ECig)吸入导致心肺功能障碍的研究工作，以及 她将获得宝贵的机会，利用慢性粒细胞白血病小鼠模型进行高质量的研究。 间歇性接触eCig蒸气。心肺疾病是全世界主要的死亡原因， 吸烟仍然是最重要和可预防的危险因素。虽然吸烟的流行率 自1950年以来一直在稳步下降，但最近eCig或电子产品的受欢迎程度急剧上升 尼古丁输送系统(完)。尽管人们认为这些产品是香烟的“更安全”替代品 吸烟，最近的eCig或蒸发产品使用相关的肺损伤案例，表示为EVALI，表明 极有可能造成伤害。ECig对心肺功能的影响尚未完全阐明；然而， 申请者的指导团队证明，慢性吸入尼古丁蒸气本身就会诱导激活 肾素-血管紧张素系统(RAS)与小鼠肺动脉高压(PH)此外，初步数据 这一建议表明尼古丁会导致血管功能障碍。虽然前一项研究表明 尼古丁对心肺有不利影响，目前尚不清楚是否添加其他eCig成分(如： 丙二醇/植物甘油)会产生相同或更大的有害影响。因此，对 ECig添加剂与尼古丁可能存在协同作用。这项提议的目标是 评估慢性吸入eCig对心肺功能的影响，这可能有助于 EVALI，在慢性eCig蒸汽吸入的小鼠模型中。提出的假设是慢性eCig 蒸汽吸入破坏RAS稳态，导致血管功能障碍、PH和右室 (RV)重塑。拟议的研究将使用各种最先进的工具和技术来测试 该假说基于两个特定的目的：(1)慢性吸入eCig蒸汽促进血管功能障碍，PH， 和右室重构，以及(2)慢性eCig蒸气吸入所致心肺功能障碍的机制 依赖RAS激活和血管紧张素I型受体(AT1R)介导的血管紧张素信号转导。在……里面 此外，这项研究还将调查用氯沙坦阻断血管紧张素受体信号是否有保护作用。 ECig蒸气吸入致心肺功能障碍。这项研究的发现将推动我们的 了解eCig对心肺系统的有害影响并可能识别新的 ECig相关心血管和肺部疾病(CVPD)的治疗靶点。与 在强大的多学科指导团队的支持下，完成拟议的培训计划将确保 申请者准备开始学术医学的职业生涯。

Abstract The primary purpose of this Ruth L. Kirschstein NRSA F30 application is to provide the framework that will prepare the applicant for a successful career as a physician scientist. Much of the applicant’s career development will come from work in electronic cigarette (eCig) inhalation-induced cardiopulmonary dysfunction research, and she will be provided the invaluable opportunity to carry out high quality research using a murine model of chronic intermittent eCig vapor exposure. Cardiopulmonary diseases are the leading causes of death worldwide, and cigarette smoking remains the most significant and preventable risk factor. While cigarette smoking prevalence has steadily declined since 1950, there has been a recent drastic increase in the popularity of eCig or electronic nicotine delivery systems (ENDS). Despite the perception that these products are “safer” alternatives to cigarette smoking, recent cases of eCig or vaping product use-associated lung injury, denoted EVALI, demonstrate a strong potential for harm. The impact of eCig on cardiopulmonary function has yet to be fully elucidated; however, the applicant’s mentoring team demonstrated that chronic nicotine vapor inhalation alone induces activation of the renin-angiotensin system (RAS) and pulmonary hypertension (PH) in mice. Furthermore, preliminary data for this proposal indicate nicotine induces vascular dysfunction. While the previous study demonstrates that nicotine has detrimental cardiopulmonary impacts, it is unknown if the addition of other eCig components (e.g. propylene glycol/vegetable glycerin) will produce the same or greater harmful effects. Thus, investigation into the possible synergistic activity of eCig additives with nicotine is warranted. The OBJECTIVE of this proposal is to evaluate the effects of chronic eCig vapor inhalation on cardiopulmonary function, which could contribute to EVALI, in a murine model of chronic eCig vapor inhalation. The proposed HYPOTHESIS is that chronic eCig vapor inhalation disrupts RAS homeostasis, leading to vascular dysfunction, PH, and right ventricular (RV) remodeling. The proposed study will employ a wide variety of state-of-the-art tools and techniques to test the hypothesis using two specific aims: (1) Chronic eCig vapor inhalation promotes vascular dysfunction, PH, and RV remodeling, and (2) Mechanisms of chronic eCig vapor inhalation-induced cardiopulmonary dysfunction depend on RAS activation and angiotensin signaling mediated by the angiotensin type I receptor (AT1R). In addition, this study will investigate if blocking angiotensin receptor signaling with Losartan will protect against eCig vapor inhalation-induced cardiopulmonary dysfunction. Findings from this study will advance our understanding of the detrimental effects of eCig on the cardiopulmonary system and may identify novel therapeutic targets for the treatment of eCig related cardiovascular and pulmonary diseases (CVPD). With the support of a strong multidisciplinary mentoring team, completion of the proposed training plan will ensure that the applicant is ready to embark on a career in academic medicine.