Mechanisms of airway neurogenic inflammation by asthma-inducing allergens

描述（由申请人提供）：哮喘是最常见的气道慢性炎症性疾病。它影响了大约3410万美国人的一生，并且哮喘患者的数量持续增长。使用吸入短效β-2激动剂的标准治疗仅对急性症状有效。虽然避免过敏原和刺激物，同时使用吸入皮质类固醇可能会帮助一些患者，这些预防措施仍然是无效的，完全阻止哮喘。此外，哮喘病例对可用的标准治疗有不同的反应。因此，找到特定的哮喘亚组的具体机制，对各种类型的治疗反应良好，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发生和维持中起着关键作用。这是公认的 气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释放的神经肽诱导的，这些神经肽支配具有结状（ND）、颈静脉和背根（T1-T6）神经节（DRG）起源的感觉神经元的C纤维。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是未知的。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），触发神经源性炎症，可以释放从感觉神经末梢支配的气道时，刺激某些过敏原。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的关键问题，我们假设某些哮喘诱导性霉菌和屋尘螨过敏原-DerP 1，DerP3&9和PenC 13-属于蛋白酶家族，通过激活支配这些气道的感觉神经元并通过敏化丙烯醛和香芹酚的作用来引发气道炎症（强烈的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说提出了霉菌和屋尘螨过敏原引起气道炎症的不同机制，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.