Pulmonary Epithelial TRPV3 and Wood Smoke Injury

肺上皮 TRPV3 和木材烟雾损伤

基本信息

批准号：
10112903
负责人：
Christopher A Reilly
金额：
$ 34.31万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112903
关键词：
Acute Adverse effects Affect Agonist Air Air Pollutants Apoptotic Asthma Biological Assay Biological Markers Biomass Cell Proliferation Cells Cessation of life Chemicals Chronic Chronic Obstructive Airway Disease Coupled Couples Coupling Cytokine Gene Data Development Disease Dose Environmental Air Pollutants Epidermal Growth Factor Receptor Epithelial Epithelial Cells Equilibrium Eukaryotic Initiation Factors Exposure to Gap Junctions Goals Health Homeostasis Human In Vitro Inflammatory Inhalation Injury Intervention Ion Channel Irritants Link Long-Term Effects Lung Mass Fragmentography Mechanics Mediating Mediator of activation protein Methods Modernization Molecular Morphology Mus PTGS2 gene Particulate Pathologic Pathway interactions Phosphotransferases Play Poison Predisposition Prevention Process Prokaryotic Initiation Factor-2 Prosopis juliflora Pulmonary Emphysema Pulmonary Pathology Reporting Research Respiration Disorders Respiratory Tract Infections Respiratory physiology Risk Role Scheme Seminal Signal Transduction Societies Stress Structure TRPV channel Testing Therapeutic Intervention Tissues Toxic effect Toxicology Toxin Vanilloid Wood material airway remodeling base biomass fuel biomass smoke bronchial epithelium celecoxib chemical property cigarette smoke cytotoxic cytotoxicity endoplasmic reticulum stress experimental study gene induction human morbidity improved inhibitor/antagonist injury and repair innovation lung injury metabolomics novel particle prevent pulmonary function receptor repaired respiratory response restoration screening wood smoke

项目摘要

Project Summary/Abstract: Combustion of wood and other forms of biomass releases enormous quantities of toxic materials into the air and is linked to multiple human morbidities and an estimated 3-4M excess deaths/year. Like many forms of particulate materials (PM), wood/biomass smoke PM (WBSPM) is pneumotoxic. WBSPM exposure increases people's susceptibility to respiratory infections, exacerbates asthma, and causes emphysema and COPD. Exposure to WBSPM is often unavoidable even in modern society and specific molecular and chemical interactions that link exposure to the established acute and long term effects of WBSPM are not fully understood. Accordingly, the ability to treat respiratory and other conditions resulting from exposure to WBSPM, and ways to effectively reduce risks to humans, are extremely limited. We propose a novel mechanistic paradigm for how WBSPM can cause deleterious effects in the lungs, through activation of the Ca++ ion channel transient receptor potential vanilloid-3 (TRPV3). Our data show that WBSPM activates TRPV3. Assessment of the proposed TRPV3-dependent mechanistic paradigm will provide fundamental data to potentially predict human risks for respiratory conditions associated with WBSPM exposure by establishing new mechanisms for toxicity. In doing so, this study has the potential to reveal innovative approaches to discover interventions for the prevention and treatment of such diseases, and perhaps more broadly, adverse effects caused by other pneumotoxins - based on indications that TRPV3 appears to play fundamental roles in maintaining lung cell/tissue homeostasis during stress/after injury. This study is motivated by results showing that TRPV3 is expressed by human lung epithelial cells, TRPV3 is selectively activated by specific chemicals in PM obtained from burning multiple wood types, and this activation is coupled to acute pro-inflammatory and pro-apoptotic signaling. Additionally, TRPV3 is dynamically regulated and is involved in adaptive reprogramming of lung cells, sub-acute morphological changes in the airways of mice, and compromised lung function. Our hypothesis is that TRPV3 plays dual roles in mediating both the acute pro-inflammatory/cytotoxic effects of WBSPM as well as adaptation of lung cells to resist further damage to toxins and airway remodeling. The specific aims are to: 1) further delineate the role of TRPV3 in acute and chronic WBSPM pneumotoxicity; 2) decipher TRPV3, ER stress, COX2/PTGS2, and EGFR integration in lung injury and repair; and 3) evaluate TRPV3 as a universal mediator of WBSPM toxicity.

项目摘要/摘要：木材和其他形式的生物质的燃烧会向空气中释放大量有毒物质，与多种人类疾病有关，估计每年有 3-400 万人死亡。像许多形式的颗粒物一样材料 (PM)、木材/生物质烟雾 PM (WBSPM) 具有肺毒性。 WBSPM 暴露增加了人们的易受呼吸道感染，加剧哮喘，并导致肺气肿和慢性阻塞性肺病。接触即使在现代社会，WBSPM 通常也是不可避免的，并且特定的分子和化学相互作用将暴露于 WBSPM 已确定的急性和长期影响尚未完全了解。据此，治疗因接触 WBSPM 导致的呼吸系统和其他疾病的能力，以及有效减少的方法对人类的风险极其有限。我们提出了一种新的机制范式来解释 WBSPM 如何对肺部造成有害影响，通过 Ca++ 离子通道瞬时受体电位 vanilloid-3 (TRPV3) 的激活。我们的数据显示，WBSPM 激活 TRPV3。对所提出的 TRPV3 依赖机制范式的评估将提供潜在预测与 WBSPM 暴露相关的人类呼吸系统疾病风险的基本数据通过建立新的毒性机制。这样做，这项研究有可能揭示创新发现预防和治疗此类疾病的干预措施的方法，也许还有更多广泛地说，其他肺炎毒素引起的不利影响 - 基于 TRPV3 似乎发挥作用的迹象在应激期间/受伤后维持肺细胞/组织稳态的基本作用。这项研究的动机是结果显示 TRPV3 由人肺上皮细胞表达，TRPV3 是通过燃烧多种木材获得的 PM 中的特定化学物质选择性激活，并且这种激活与急性促炎症和促凋亡信号传导相结合。此外，TRPV3 是动态调节的并参与肺细胞的适应性重编程、气道的亚急性形态变化小鼠，并损害肺功能。我们的假设是 TRPV3 在介导急性炎症反应中发挥双重作用。 WBSPM 的促炎/细胞毒性作用以及肺细胞抵抗毒素进一步损伤的适应和气道重塑。具体目标是：1）进一步阐明TRPV3在急性和慢性疾病中的作用。 WBSPM 肺毒性； 2) 破译肺损伤中的 TRPV3、ER 应激、COX2/PTGS2 和 EGFR 整合维修; 3) 评估 TRPV3 作为 WBSPM 毒性的通用介质。