Pulmonary Epithelial TRPV3 and Wood Smoke Injury

项目摘要/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，并 与多种人类疾病有关，每年估计有300-400万人额外死亡。像许多形式的颗粒物一样 材料(PM)、木材/生物质烟雾PM(WBSPM)具有气体毒性。接触WBSPM会增加人们的 易受呼吸道感染，加重哮喘，并导致肺气肿和慢性阻塞性肺病。暴露于 即使在现代社会，WBSPM往往也不可避免地与特定的分子和化学相互作用联系在一起 暴露于WBSPM已确定的急性和长期影响还没有完全了解。因此， 治疗因接触WBSPM而引起的呼吸道和其他疾病的能力，以及有效减少 对人类的风险是极其有限的。 我们提出了一种新的机制范式，说明WBSPM如何通过以下途径在肺部造成有害影响 激活钙离子通道瞬时受体电位香草酸-3(TRPV3)。我们的数据显示，WBSPM 激活TRPV3。对拟议的依赖于TRPV3的机械论范式的评估将提供 潜在地预测与WBSPM暴露相关的人类呼吸道疾病风险的基础数据 通过建立新的毒性机制。通过这样做，这项研究有可能揭示创新 发现预防和治疗这类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TRPV3似乎发挥作用的迹象 在应激/损伤后维持肺细胞/组织动态平衡的基础作用。 这项研究的动机是研究结果表明，TRPV3在人肺上皮细胞中表达，TRPV3是 由燃烧多种木材类型获得的PM中的特定化学物质选择性地激活，这种激活 与急性促炎和促凋亡信号相结合。此外，TRPV3是动态调节的 并参与肺细胞的适应性重新编程，亚急性呼吸道的形态变化 老鼠，以及肺功能受损。我们的假设是，TRPV3在调节急性和非典型肺炎中起双重作用。 WBSPM的促炎/细胞毒作用以及肺细胞对毒素进一步损伤的适应 和呼吸道重塑。具体目的是：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TRPV3、ER应激、COX2/Ptgs2和EGFR整合在肺损伤和 3)评价TRPV3作为WBSPM毒性的通用介体。

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.