Balenga Nariman A, Klichinsky Michael, Xie Zhihui, Chan Eunice C, Zhao Ming, Jude Joseph, Laviolette Michel, Panettieri Reynold A, Druey Kirk M
Molecular Signal Transduction Section, Laboratory of Allergic Diseases, NIAID/NIH, 50 South Drive Room 4154, Bethesda, Maryland 20892-8305, USA.
Pulmonary, Allergy and Critical Care Division, Airways Biology Initiative, University of Pennsylvania, 125 South 31st Street, Philadelphia, Pennsylvania 19104-3413, USA.
Nat Commun. 2015 Apr 13;6:6763. doi: 10.1038/ncomms7763.
Asthma, a common disorder that affects >250 million people worldwide, is defined by exaggerated bronchoconstriction to inflammatory mediators including acetylcholine (ACh), bradykinin and histamine-also termed airway hyper-responsiveness. Nearly 10% of people with asthma have severe, treatment-resistant disease, which is frequently associated with immunoglobulin-E sensitization to ubiquitous fungi, typically Aspergillus fumigatus (Af). Here we show that a major Af allergen, Asp f13, which is a serine protease, alkaline protease 1 (Alp 1), promotes airway hyper-responsiveness by infiltrating the bronchial submucosa and disrupting airway smooth muscle (ASM) cell-extracellular matrix (ECM) interactions. Alp 1-mediated ECM degradation evokes pathophysiological RhoA-dependent Ca(2+) sensitivity and bronchoconstriction. These findings support a pathogenic mechanism in asthma and other lung diseases associated with epithelial barrier impairment, whereby ASM cells respond directly to inhaled environmental allergens to generate airway hyper-responsiveness.
哮喘是一种常见疾病，全球有超过2.5亿人受其影响，其定义为对包括乙酰胆碱（ACh）、缓激肽和组胺在内的炎症介质出现过度支气管收缩，也称为气道高反应性。近10%的哮喘患者患有严重的难治性疾病，这通常与对普遍存在的真菌（通常为烟曲霉（Af））的免疫球蛋白E致敏有关。我们在此表明，一种主要的Af变应原Asp f13，即丝氨酸蛋白酶碱性蛋白酶1（Alp 1），通过浸润支气管黏膜下层并破坏气道平滑肌（ASM）细胞与细胞外基质（ECM）的相互作用来促进气道高反应性。Alp 1介导的ECM降解引发病理生理的RhoA依赖性Ca（2+）敏感性和支气管收缩。这些发现支持了哮喘及其他与上皮屏障损伤相关的肺部疾病的致病机制，即ASM细胞直接对吸入的环境变应原作出反应以产生气道高反应性。
