E-cigarette Inhalation and Cardiopulmonary Dysfunction

电子烟吸入与心肺功能障碍

• 批准号: 10313665
• 负责人: Anna Kathryn Whitehead
• 金额: $ 3.79万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-02 至 2027-01-01
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10313665
• 关键词: cigarette; Inhalation; Cardiopulmonary; Dysfunction

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.

抽象的 Ruth L. Kirschstein NRSA F30 应用程序的主要目的是提供一个框架，该框架将 为申请人作为医师科学家的成功职业生涯做好准备。申请人职业发展的大部分 将来自电子烟（eCig）吸入引起的心肺功能障碍研究工作，并且 她将获得宝贵的机会，利用慢性病小鼠模型进行高质量的研究。 间歇性电子烟蒸汽暴露。心肺疾病是全世界死亡的主要原因， 吸烟仍然是最重要且可预防的危险因素。虽然吸烟流行率 自 1950 年以来一直在稳步下降，最近 eCig 或电子产品的普及度急剧增加 尼古丁输送系统（ENDS）。尽管人们认为这些产品是香烟的“更安全”替代品 吸烟，最近发生的电子烟或电子烟产品使用相关肺损伤（称为 EVALI）的病例表明， 潜在的危害性很大。电子烟对心肺功能的影响尚未完全阐明；然而， 申请人的指导团队证明，仅长期吸入尼古丁蒸气就会诱导激活 小鼠肾素-血管紧张素系统（RAS）和肺动脉高压（PH）。此外，初步数据 该提案表明尼古丁会导致血管功能障碍。虽然之前的研究表明 尼古丁对心肺有不利影响，目前尚不清楚添加其他电子烟成分（例如尼古丁）是否会对心肺产生不利影响。 丙二醇/植物甘油）也会产生相同或更大的有害影响。因此，调查 电子烟添加剂与尼古丁可能具有协同活性是有道理的。该提案的目标是 评估长期吸入电子烟蒸气对心肺功能的影响，这可能有助于 EVALI，在慢性电子烟蒸气吸入的小鼠模型中。所提出的假设是，长期电子烟 蒸气吸入破坏 RAS 稳态，导致血管功能障碍、PH 和右心室功能障碍 （RV）改造。拟议的研究将采用各种最先进的工具和技术来测试 该假设有两个具体目标：(1) 长期吸入电子烟蒸气会促进血管功能障碍、PH、 和RV重塑，以及（2）慢性电子烟蒸气吸入诱发心肺功能障碍的机制 依赖于 RAS 激活和 I 型血管紧张素受体 (AT1R) 介导的血管紧张素信号传导。在 此外，本研究将调查用氯沙坦阻断血管紧张素受体信号传导是否可以预防 电子烟蒸气吸入引起的心肺功能障碍。这项研究的结果将推动我们 了解电子烟对心肺系统的有害影响，并可能识别新的 治疗电子烟相关心血管和肺部疾病（CVPD）的治疗靶点。随着 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 申请人已准备好从事学术医学职业。