Mechanisms of airway neurogenic inflammation by asthma-inducing allergens

描述(申请人提供)：哮喘是最常见的慢性呼吸道炎症性疾病。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继续增长。使用吸入短效β-2激动剂的标准治疗只对急性症状有效。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会对一些患者有所帮助，但这些预防措施在完全阻止哮喘方面仍然无效。此外，哮喘病例对可用标准治疗的反应也各不相同。因此，找到对不同类型治疗反应良好的特定哮喘亚组的具体机制是目前哮喘研究的关键目标。过敏原和环境刺激物在儿童和成人哮喘的启动和维持中起着关键作用。它被广泛接受 认为呼吸道炎症在哮喘患者气道高反应性(AHR)的发生发展中起重要作用。最近的证据表明，动物和人类哮喘期间的呼吸道炎症可能至少部分是神经原性的。这种神经源性炎症是由呼吸道释放的神经肽支配结状(ND)、颈静脉和背根(T1-T6)神经节(DRG)的感觉神经元的C纤维引起的。然而，涉及过敏原以及过敏原和环境刺激物组合引起的神经源性呼吸道炎症的分子和生理机制在很大程度上还不清楚。其中一种可能性是，P物质(SP)和降钙素基因相关肽(CGRP)等神经肽可在某些过敏原的刺激下从支配呼吸道的感觉神经末梢释放出来，从而引发神经源性炎症。根据这一机制，某些过敏原将能够促进神经原性急性和/或慢性呼吸道炎症。为了解决这一关键问题，即暴露于某些过敏原如何导致神经性呼吸道炎症，我们假设属于蛋白酶家族的某些引起哮喘的霉菌和室内尘螨变应原--DerP1、DerP3&9和PenC13--通过激活支配这些呼吸道的感觉神经元，并通过敏化丙烯醛和香芹酚(有效的烟草烟雾和环境刺激物)对感觉神经元的影响而引发呼吸道炎症。这一概念创新的假说提出了霉菌和屋尘螨变应原引起的呼吸道炎症的不同机制，具有很强的科学和医学发展潜力。

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.