Immunosuppressive injurious effects of e-cigarettes on human lung parenchyma

项目摘要/摘要 这两项PI研究计划的目的是确定e-P的免疫抑制和损伤作用。 香烟对人远端肺结构细胞(即小气道上皮细胞和肺微血管)的影响 内皮细胞)对慢性阻塞性肺疾病(COPD)的发病机制至关重要，通常 烟草烟雾暴露所致。电子烟在美国年轻人中的使用正在迅速增加 但其对远端肺的健康影响尚未调查。我们发现吸入电子烟- 香烟蒸气(ECVap)可到达小气道，导致远端肺损伤。具体地说，我们已经证明了 暴露于ECVap成分，包括尼古丁，显著削弱远端肺(例如小气道) 先天免疫对抗甲型流感病毒感染和微血管内皮细胞屏障功能，并增强 肺部发炎。我们将测试电子烟损害抗病毒免疫力的假设，导致 中性粒细胞炎症和远端肺结构细胞(小气道和微血管内皮细胞)损伤 通过提出三个具体目标。在目标1中，我们将确定ECVap损害抗病毒的机制 精密切割人(15~25岁)肺组织RNA测序对人远端肺免疫功能的影响 ECVap和A型流感病毒(IAV)暴露的切片，并进行人原代小气道上皮 细胞气液界面培养在ECVap和IAV存在或不存在的情况下。在目标2中，我们将确定如何 ECVap增强人远端肺组织对IAV感染的中性粒细胞炎症反应 人肺切片及人微血管内皮细胞与中性粒细胞共培养体系。在AIM 3，我们将通过测试ECVap暴露是否会增加IAV感染后远端肺损伤来确定ECVap如何增加远端肺损伤 减少鞘磷脂促生存信号，从而增加小气道上皮细胞的易损性 和内皮细胞对病毒诱导的损伤。我们拟议研究的研究结果将显著 提高我们对青少年使用电子烟对远端肺部健康影响的了解，并向政策提供信息 电子烟法规。

Project Summary/Abstract The goal of this two PI research proposal is to determine the immunosuppressive and injurious effects of e- cigarettes on human distal lung structural cells (i.e. small airway epithelial cells and lung microvascular endothelial cells) that are critical to the pathogenesis of chronic obstructive pulmonary disease (COPD), typically induced by tobacco cigarette smoke exposure. The use of e-cigarettes is rapidly increasing in the US youth population, but its health effects on distal lungs have not been investigated. We have found that inhaling e- cigarette vapor (ECVap) can reach small airways to cause distal lung injury. Specifically, we have demonstrated that exposures to ECVap constituents, including nicotine, significantly weaken distal lung (e.g. small airway) innate immunity against influenza A virus infection and microvascular endothelial barrier function, and enhance lung inflammation. We will test the hypothesis that e-cigarettes impair the antiviral immunity, causing increased neutrophilic inflammation and distal lung structural cell (small airway and microvascular endothelial cell) injury by proposing three specific aims. In Aim 1, we will identify the mechanisms whereby ECVap impairs the antiviral immunity of human distal lungs by performing RNA sequencing in precision-cut human (15 to 25 years old) lung slices exposed to ECVap and influenza A viruses (IAV), and carrying out human primary small airway epithelial cell air-liquid interface culture in the presence or absence of ECVap and IAV. In Aim 2, we will determine how ECVap enhances neutrophilic inflammatory response to IAV infection of the human distal lung by using the human lung slices and the co-culture system of human microvascular endothelial cells and neutrophils. In Aim 3, we will determine how ECVap increases distal lung injury following IAV infection by testing if ECVap exposure reduces sphingolipid pro-survival signaling and subsequently increases the vulnerability of small airway epithelial and endothelial cells to virus-induced injury. Research findings from our proposed studies will significantly improve our understanding about the distal lung health effects of e-cigarette use in youth, and inform policies of e-cigarette regulation.