E-cigarette Inhalation and Cardiopulmonary Dysfunction

电子烟吸入与心肺功能障碍

• 批准号: 10701661
• 负责人: Anna Kathryn Whitehead
• 金额: $ 3.95万
• 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/10701661
• 关键词: Acetylcholine; Angiotensin II; Angiotensin Receptor; Angiotensins; Antihypertensive Agents; Blood Vessels; Cardiopulmonary; Cardiovascular Diseases; Cause of Death; Chemicals; Chronic; Data; Disease; Electronic Nicotine Delivery Systems; Electronic cigarette; Ensure; Exhibits; Fellowship; Fibrosis; Flavoring; Fostering; Functional disorder; Future; Homeostasis; Impairment; Inflammation; Inhalation; Investigation; Lead; Losartan; Lung; Lung diseases; Mediating; Medical Research; Medicine; Mentors; Modeling; Molecular; Mus; NOS3 gene; National Research Service Awards; Nicotine; Operative Surgical Procedures; Oral Ingestion; Patients; Peptidyl-Dipeptidase A; Perception; Phosphorylation; Physicians; Propylene Glycols; Pulmonary Heart Disease; Pulmonary Hypertension; Receptor Signaling; Renin-Angiotensin System; Research; Right Ventricular Hypertrophy; Risk Factors; Role; Safety; Scientist; Signal Transduction; Systolic Pressure; Techniques; Testing; Training; United States Food and Drug Administration; Vascular Diseases; Vasodilation; Ventricular; Work; antagonist; cardiopulmonary system; career; career development; cigarette smoking; combustible cigarette; e-cigarette aerosols; electronic cigarette use; electronic vape; experimental study; interest; lung injury; mouse model; multidisciplinary; new therapeutic target; nicotine exposure; nicotine inhalation; nicotine vapor; pre-clinical research; prevent; receptor; right ventricular remodeling; smoking prevalence; tool; training opportunity; vaping; vaping associated lung injury; vegetable glycerin

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.

摘要 这个Ruth L的主要目的。Kirschstein NRSA F30应用程序提供的框架将 准备申请人成功的职业生涯作为一个医生科学家。申请人的大部分职业发展 将来自电子烟（eCig）吸入引起的心肺功能障碍研究， 她将获得一个宝贵的机会，利用小鼠模型进行高质量的研究， 间歇性电子烟蒸汽暴露。心脏病是全世界死亡的主要原因， 吸烟仍然是最重要和可预防的危险因素。虽然吸烟率 自1950年以来一直稳步下降，最近电子烟或电子烟的普及率急剧上升。 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，最近的eCig或vaping产品使用相关的肺损伤病例，表示EVALI，表明 潜在危害很大。电子烟对心肺功能的影响尚未完全阐明;然而， 申请人的指导小组证明，单独慢性尼古丁蒸汽吸入可诱导 肾素-血管紧张素系统（RAS）和肺动脉高压（PH）。此外，初步数据 这一建议表明尼古丁诱导血管功能障碍。虽然先前的研究表明， 尼古丁具有有害的心肺影响，尚不清楚添加其他电子烟组分（例如， 丙二醇/植物甘油）将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的可能的协同活性是有保证的。本提案的目的是 评估长期eCig蒸汽吸入对心肺功能的影响，这可能有助于 EVALI，在慢性eCig蒸气吸入的鼠模型中。提出的假设是，慢性电子烟 蒸汽吸入破坏RAS稳态，导致血管功能障碍、PH和右心室 (RV)重塑拟议的研究将采用各种最先进的工具和技术来测试 该假设使用两个特定目的：（1）长期eCig蒸气吸入促进血管功能障碍，PH， 和RV重塑，以及（2）慢性eCig蒸汽吸入诱导的心肺功能障碍的机制 依赖于RAS激活和血管紧张素I型受体（AT 1 R）介导的血管紧张素信号传导。在 此外，本研究还将研究用氯沙坦阻断血管紧张素受体信号传导是否能保护 eCig蒸汽吸入引起的心肺功能障碍。这项研究的结果将推动我们的 了解电子烟对心肺系统的有害影响，并可能发现新的 用于治疗eCig相关的心血管和肺部疾病（CVPD）的治疗靶点。与 在一个强有力的多学科指导小组的支持下，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事业。