Mechanisms of airway neurogenic inflammation by asthma-inducing allergens

哮喘诱发过敏原引起气道神经源性炎症的机制

• 批准号: 8356178
• 负责人: ARMEN N AKOPIAN
• 金额: $ 18.68万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-03 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356178
• 关键词: Acrolein; Acute; Address; Adrenal Cortex Hormones; Adult; Adverse effects; Affect; Afferent Neurons; Agonist; Allergens; American; Animals; Asthma; Breathing; Bronchi; C Fiber; Calcitonin Gene-Related Peptide; Childhood Asthma; Chronic; Country; Cysteine Protease; Development; Disease; Environmental Irritants; Environmental Pollution; Etiology; Exposure to; Family; Foundations; Future; Ganglia; Goals; Healthcare; House Dust Mite Allergens; Human; Individual; Inflammation; Inflammatory; Irritants; Link; Maintenance; Medical; Molds; Molecular; Muscle Contraction; Nature; Neurogenic Inflammation; Neurons; Neuropeptides; Outcome; Patients; Peptide Hydrolases; Peptides; Peripheral Nervous System; Pharmaceutical Preparations; Physiological; Play; Pollution; Population; Pyroglyphidae; Research; Role; Serine Protease; Smog; Smooth Muscle; Specificity; Subgroup; Substance P; Symptoms; Tobacco smoke; afferent nerve; airway hyperresponsiveness; airway inflammation; asthmatic patient; cigarette smoking; design; flexibility; innovation; novel; novel strategies; novel therapeutics; receptor; research study; respiratory; response; spinal nerve posterior root; standard care

DESCRIPTION (provided by applicant): Asthma is the most common chronic inflammatory disease of the airways. It affects approximately 34.1 million Americans throughout their lifetime, and the number of people with asthma continues to grow. Standard treatment using an inhaled short-acting beta-2 agonist is only effective against acute symptoms. Though avoiding allergens and irritants while utilizing inhaled corticosteroids may help some patients, these preventatives are still ineffective in completely deterring asthma. Furthermore, cases of asthma will have varying responses to the standard treatments available. Accordingly, finding the specific mechanisms for the defined subgroups of asthma that respond well to various types of treatments is a current critical goal of asthma research. Allergens and environmental irritants play a key role in initiation and maintenance of asthma in children and adults. It is well accepted that airway inflammation plays an important role in the development of airway hyperresponsiveness (AHR) in asthmatic patients. Recent evidence demonstrates airway inflammation during asthma in animals and humans may be at least partially neurogenic in nature. This neurogenic inflammation is induced by neuropeptides released from airway innervating C-fibers of sensory neurons with nodose (ND), jugular, and dorsal root (T1-T6) ganglia (DRG) origin. However, the molecular and physiological mechanisms involving allergens and a combination of allergens and environmental irritants inducing neurogenic inflammation of airways are largely unknown. One of the possibilities is that neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP), which trigger neurogenic inflammation, could be released from sensory nerve terminals innervating airways upon stimulation by certain allergens. According to this mechanism, certain allergens would be able to promote neurogenic acute and/or chronic inflammation of the airways. To address this critical question of how exposure to certain allergens results in initiation of neurogenic inflammation of the airways, we hypothesize that certain asthma-inducing mold and house dust mite allergens - DerP1, DerP3&9 and PenC13 - belonging to the protease family initiate inflammation of the airways by activating the sensory neurons innervating these airways and by sensitizing the effects of acrolein and carvacrol (potent tobacco smoke and environmental irritants) on sensory neurons. This conceptually innovative hypothesis which proposes distinct mechanisms of airway inflammation by mold and house dust mite allergens has a strong potential for scientific and medical developments. PUBLIC HEALTH RELEVANCE: The management of asthma represents a major scientific and health care challenge as many of the currently used medications are ineffective in completely deterring asthma or may produce debilitating side effects. Here we propose a novel hypothesis for the initiation of neurogenic inflammation of airways by certain house dust mite and mold asthma-inducing allergens, and by a combination of these allergens and environmental irritants from cigarette smoke, smog and pollution. This conceptually innovative hypothesis has implications for both the scientific and medical fields by expanding our understanding of the role of the peripheral nervous system in initiation of airway inflammation by certain allergens, and by creating a foundation for novel therapeutic strategies aiming to correct the underlying causes of the initiation of asthma by allergens and environmental irritants.

描述（由申请人提供）：哮喘是最常见的慢性气道炎症性疾病。它影响着大约 3410 万美国人的一生，而且哮喘患者的数量还在持续增长。使用吸入短效 β2 激动剂的标准治疗仅对急性症状有效。尽管在使用吸入皮质类固醇的同时避免过敏原和刺激物可能对某些患者有帮助，但这些预防措施仍然无法有效完全阻止哮喘。此外，哮喘病例对可用的标准治疗会有不同的反应。因此，寻找对各种类型的治疗反应良好的特定哮喘亚组的具体机制是哮喘研究当前的关键目标。 过敏原和环境刺激物在儿童和成人哮喘的发生和维持中起着关键作用。它被广泛接受 气道炎症在哮喘患者气道高反应性（AHR）的发展中起着重要作用。最近的证据表明，动物和人类哮喘期间的气道炎症可能至少部分是神经源性的。这种神经源性炎症是由气道神经支配感觉神经元 C 纤维释放的神经肽诱导的，这些感觉神经元具有结状 (ND)、颈静脉和背根 (T1-T6) 神经节 (DRG) 起源。然而，涉及过敏原以及过敏原和环境刺激物的组合诱导气道神经源性炎症的分子和生理机制在很大程度上尚不清楚。其中一种可能性是，神经肽，如 P 物质 (SP) 和降钙素基因相关肽 (CGRP)，会在某些过敏原刺激下从支配气道的感觉神经末梢释放，从而引发神经源性炎症。根据这种机制，某些过敏原将能够促进气道的神经源性急性和/或慢性炎症。为了解决暴露于某些过敏原如何导致气道神经源性炎症这一关键问题，我们假设某些诱发哮喘的霉菌和屋尘螨过敏原（DerP1、DerP3&9 和 PenC13）属于蛋白酶家族，会引发气道炎症。通过激活支配这些气道的感觉神经元以及使丙烯醛和香芹酚（强效烟草烟雾和环境刺激物）对感觉神经元的影响。这一概念上的创新假设提出了霉菌和屋尘螨过敏原引起气道炎症的独特机制，具有巨大的科学和医学发展潜力。 公众健康相关性：哮喘的治疗是一项重大的科学和卫生保健挑战，因为目前使用的许多药物不能完全有效地阻止哮喘，或者可能产生使人衰弱的副作用。在这里，我们提出了一种新的假设，即某些屋尘螨和霉菌诱发哮喘的过敏原，以及这些过敏原与香烟烟雾、烟雾和污染等环境刺激物的组合，会引发气道神经源性炎症。这一概念上的创新假说对科学和医学领域都有影响，它扩大了我们对周围神经系统在某些过敏原引发气道炎症中的作用的理解，并为旨在纠正过敏原根本原因的新治疗策略奠定了基础。过敏原和环境刺激物引发哮喘。