Pulmonary Epithelial TRPV3 and Wood Smoke Injury

肺上皮 TRPV3 和木材烟雾损伤

• 批准号: 9309534
• 负责人: Christopher A Reilly
• 金额: $ 34.05万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9309534
• 关键词: Acute; Adverse effects; Affect; Agonist; Air; Air Pollutants; Apoptotic; Asthma; Biological Assay; Biological Markers; Biomass; Breathing; 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; Injury; 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; Preventive Intervention; Process; Prosopis juliflora; Pulmonary Emphysema; Pulmonary Pathology; Reporting; Research; Respiration Disorders; Respiratory Tract Infections; Respiratory physiology; Risk; Role; Scheme; Seminal; Signal Transduction; Societies; Stress; Structure; Testing; Therapeutic Intervention; Tissues; Toxic effect; Toxicology; Toxin; Vanilloid; Wood material; airway remodeling; base; biomass fuel; biomass smoke; bronchial epithelium; celecoxib; chemical property; cigarette smoking; cytotoxic; cytotoxicity; experimental study; gene induction; human morbidity; improved; inhibitor/antagonist; injury and repair; innovation; lung injury; lung repair; metabolomics; novel; particle; prevent; receptor; repaired; respiratory; response; restoration; screening; wood smoke

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.

项目概要/摘要： 燃烧木材和其他形式的生物质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- 4百万人死亡。就像许多形式的微粒一样 木材/生物质烟雾PM（WBSPM）具有肺毒性。WBSPM暴露会增加人们的 易患呼吸道感染，加重哮喘，并导致肺气肿和COPD。暴露于 即使在现代社会中，WBSPM也往往是不可避免的，并且特定的分子和化学相互作用将 暴露于WBSPM的既定急性和长期影响尚未完全了解。因此 治疗暴露于WBSPM导致的呼吸道和其他疾病的能力，以及有效减少 对人类的危害非常有限。 我们提出了一种新的机制范式WBSPM如何在肺部造成有害影响，通过 激活Ca++离子通道瞬时受体电位香草素-3（TRPV 3）。我们的数据显示，WBSPM 激活TRPV 3。对所提出的TRPV 3依赖机制范式的评估将提供 潜在预测与WBSPM暴露相关的呼吸系统疾病的人类风险的基本数据 通过建立新的毒性机制。在这样做的过程中，这项研究有可能揭示创新的 发现预防和治疗这些疾病的干预措施的方法，也许还有更多 广泛地说，其他肺毒素引起的不良反应-基于TRPV 3似乎起作用的迹象， 在应激期间/损伤后维持肺细胞/组织稳态中的基本作用。 这项研究的动机是，结果表明TRPV 3是由人肺上皮细胞表达的，TRPV 3是 通过燃烧多种木材类型获得的PM中的特定化学物质选择性活化，并且这种活化 与急性促炎和促凋亡信号传导相关。此外，TRPV 3是动态调节的， 并参与肺细胞的适应性重编程，呼吸道的亚急性形态学变化， 以及肺功能受损我们的假设是TRPV 3在介导急性炎症和慢性炎症中起双重作用。 WBSPM的促炎/细胞毒性作用以及肺细胞的适应性以抵抗毒素的进一步损伤 和气道重塑具体目的是：1）进一步阐明TRPV 3在急性和慢性炎症中的作用。 WBSPM肺毒性; 2）解读肺损伤中的TRPV 3、ER应激、COX 2/PTGS 2和EGFR整合， 修复;和3）评估TRPV 3作为WBSPM毒性的通用介质。