DEVELOPMENT OF DIAGNOSIS AND TREATMENT BASED ON PATHOPHYSIOLOGY OF CHRONIC COUGH

一、基础研究1)建立了豚鼠特应性咳嗽和咳嗽变异性哮喘模型。1)利用特应性咳嗽模型，揭示了抗原诱导中性内肽酶失活导致的P物质水平升高在抗原诱导的咳嗽敏感性增加中起重要作用，组胺和P物质之间可能存在相互作用。2)利用咳嗽变异性哮喘模型，明确了咳嗽是通过抗原诱导的支气管膜引起的，而与速激肽无关。我们研制了一种对豚鼠呼吸道施加定量机械压力应力的装置。机械压力应激对气道诱发的咳嗽反射超敏反应与气道中性粒细胞炎症有关，提示咳嗽和咳嗽超敏反应之间存在自我延续的循环。除特应性咳嗽和咳嗽变异型哮喘的病理生理特点不同外，我们还阐明了这两种疾病的远期结局也不同：咳嗽变异型哮喘患者中有近30%的患者在几年内发展为典型的哮喘，而特应性咳嗽患者中无一例发生。支气管高反应性和不长期吸入糖皮质激素是典型咳嗽变异型哮喘发病的危险因素。我们的前瞻性研究证实，咳嗽变异型哮喘、特应性咳嗽和鼻气管综合征是日本慢性咳嗽的常见原因。

I. Basic research1. guinea pig models for atopic cough and cough variant asthma have been developed.1) Using the atopic cough model, it has been disclosure d that increased level of substance P resulted from antigen-induced inactivation of neutral endopeptidase is important in the antigen-induced increase in cough sensitivity, and that there may bean interaction between histamine and substance P.2) Using the cough variant asthma model, It is clarified that cough is elicited via antigen-induced bronchoconstridion, and that leukotrienes, but not tachykinins, are involved in the cough.2. We developed a apparatus to give quantitative mechanical pressure stress to guinea pig airway. The Mechanical pressure stress to airway induced cough reflex hypersensitivity associated with airway neutrophilic inflammation., suggesting self-perpetuating cycle between cough and cough hypersensitivity.II. Clinical research1. In addition to the difference of pathophysiologic feature between atopic cough and cough variant astluna, we elucidated the long-term outcome is also different between these two condition.: Nearly 30% patients with cough variant asthma develops typical asthma within several years but no patient with atopic cough does.2. Bronchial hyperresponsiveness and no use of long-tern inhaled corticosteroids were risk factors of typical asthma onset from cough variant asthma.3. Our prospective study confirmed that cough variant asthma, atopic cough and sinobronchial syndrome are common causes of chronic cough in Japan.