Mechanisms of Chlorine Hypersensitivity in Asthma

哮喘中氯过敏的机制

• 批准号: 7857981
• 负责人: SVEN-ERIC JORDT
• 金额: $ 27.88万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7857981
• 关键词: Acetylcysteine; Acrolein; Acute; Adrenergic Agonists; Aerosols; Affect; Afferent Neurons; Affinity; American; Animal Model; Ankyrins; Antioxidants; Asthma; Blood Vessels; Breathing; Bronchial Spasm; Bulla; C Fiber; Caring; Cells; Chemical Agents; Chemical Exposure; Chemical Injury; Chemical Warfare Agents; Chemicals; Child; Chlorine; Chronic Rhinitis; Collaborations; Cutaneous; Data; Denervation; Deposition; Development; Edema; Elderly; Electrophysiology (science); Exposure to; Extravasation; Eye; Family; Gases; Goals; Histamine Receptor; Hypersensitivity; Image; Imaging Techniques; In Vitro; Individual; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Intervention; Ion Channel; Irritants; Lead; Life; Lung; Lung diseases; Measures; Mediating; Modeling; Modification; Molecular; Molecular Target; Mucous Membrane; Mucous body substance; Mus; Mustard Gas; Nerve Block; Neurons; Neuropeptides; Nitrites; Obstruction; Ovalbumin; Pain; Panic; Pathway interactions; Patients; Phosgene; Plasma; Plethysmography; Poison; Population; Prevention therapy; Principal Investigator; Property; Protocols documentation; Reflex action; Regulation; Research; Respiratory System; Rhinitis; Role; Sensory; Sensory Nerve Endings; Sensory Receptors; Signal Pathway; Skin; Stimulus; Structure of trigeminal ganglion; TRP channel; Techniques; Thick; Tissues; Toxic Environmental Substances; Universities; Ventilatory Depression; Vesicants; allyl isothiocyanate; ascorbate; cellular imaging; channel blockers; constriction; desensitization; efficacy testing; high risk; in vivo; irritation; mustard oil; novel; omega-Chloroacetophenone; patient population; prevent; programs; pulmonary agents; receptor; relating to nervous system; research study; respiratory; response; sensor; spinal nerve posterior root

An estimated 13 million Americans are affected by asthma. This patient population is at high risk during exposures to pulmonary agents and irritant chemicals, including chlorine, tear gases and various industrial agents. Even at low chlorine exposure levels, asthma patients respond with rapid airway constriction and obstruction, bronchospasm, mucus secretion and pain, leading to panic and incapacitation. Thus, asthma patients require special and rapid care. The goal of our research is to develop pharmacological approaches for the treatment of asthma patients after exposure to chlorine and other pulmonary agents. The immediate airway responses to chlorine and other irritants are initiated by chemosensory neurons innervating the airways. In asthma patients these neurons are highly sensitized to chemical stimuli. In our CounterACT research in the last year we found convincing evidence for a pre-eminent role of the ion channel TRPA1 as the primary chlorine sensor in airway sensory neurons. We found TRPA1 to be strongly activated by chlorine in primary and heterologous cells. In addition, TRPA1-deficient mice displayed greatly reduced respiratory depression in response to chlorine, indicating that TRPA1 is the major neuronal chlorine sensor in vivo. TRPA1 and other TRP ion channels are known to be sensitized by inflammatory signaling pathways activated during asthma, thereby increasing the sensitivity of airway neurons to chlorine and other chemical threats. We hypothesize that post-exposure administration of TRP channel antagonists, in combination with adrenergic agonists and antioxidants, will counteract life-threatening hypersensitivity responses in asthma patients to chlorine and other pulmonary chemical threats. To examine this hypothesis we aim to (1) compare responses of wild-type and TRP-channel deficient mice to chlorine in the background of the ovalbumin asthma model, (2) Establish pharmacological measures to counteract chlorine hypersensitivity responses and chlorine-induced tissue damage in asthma and (3) Analyze the mechanism of TRPA1 activation and sensitization by chlorine, and its reversal.

据估计，有 1300 万美国人患有哮喘。该患者群体在此期间处于高风险状态 接触肺部制剂和刺激性化学物质，包括氯气、催泪瓦斯和各种工业物质 代理。即使氯暴露水平较低，哮喘患者也会出现快速气道收缩和 阻塞、支气管痉挛、粘液分泌和疼痛，导致恐慌和丧失能力。因此，哮喘 患者需要特殊和快速的护理。我们研究的目标是开发药理学方法 治疗接触氯和其他肺部制剂后的哮喘患者。 对氯和其他刺激物的立即气道反应是由化学感应神经元发起的 支配气道。在哮喘患者中，这些神经元对化学刺激高度敏感。在我们的 去年的 CounterACT 研究中，我们发现了令人信服的证据，证明离子通道的卓越作用 TRPA1 作为气道感觉神经元中的主要氯传感器。我们发现 TRPA1 被强烈激活 原代细胞和异源细胞中的氯。此外，TRPA1缺陷的小鼠表现出大大降低 对氯的反应抑制呼吸，表明TRPA1是主要的神经元氯传感器 体内。 TRPA1 和其他 TRP 离子通道已知可通过炎症信号通路致敏 在哮喘期间激活，从而增加气道神经元对氯和其他化学物质的敏感性 威胁。我们假设暴露后给予 TRP 通道拮抗剂，并结合 肾上腺素能激动剂和抗氧化剂，将抵消哮喘中危及生命的超敏反应 患者肺部受到氯和其他化学物质的威胁。 为了检验这一假设，我们的目标是 (1) 比较野生型和 TRP 通道缺陷小鼠的反应 卵清蛋白哮喘模型背景下的氯，（2）建立药理学措施 抵消哮喘中的氯过敏反应和氯引起的组织损伤；(3) 分析 TRPA1 被氯激活和敏化的机制及其逆转。