Mycoplasma-induced Airway Remodeling in Human Asthma

在20-30%的病例中，肺炎支原体是引起社区获得性肺炎的原因，它还会引起气管支气管炎、咽炎和细支气管炎。我们最近的研究表明，肺炎支原体存在于慢性、稳定哮喘患者的气道中，大环内酯类药物治疗可改善肺功能，但仅适用于聚合酶链反应（PCR）显示肺炎支原体阳性的哮喘患者。慢性肺支原体感染大鼠导致P物质配体神经激肽-1 （NK-1）受体表达增加，P物质敏感性增加和血管重构。此外，P物质增加成纤维细胞的增殖。我们实验室的初步数据

Mycoplasma pneumoniae is the cause of community acquired pneumonia in 20-30% of cases, and also causes tracheobronchitis, pharyngitis and bronchiolitis. We have recently shown that M. pneumoniae is present in the airways of patients with chronic, stable asthma, and that treatment with a macrolide improves lung function, but only in those asthmatics who demonstrate positivity for M. pneumoniae by polymerase chain reaction (PCR). Chronic M. pulmonis infection in the rat results in increased expression of the neurokinin-1 (NK-1) receptor, the ligand for substance P, increased substance P sensitivity and vascular remodeling. Additionally, substance P increases fibroblast proliferation. Preliminary data from our laboratory demonstrates that M. pneumoniae added to epithelial cell culture induces substance P production, a new observation. Therefore, we hypothesize that infection with M. pneumoniae modifies airway responses in asthmatics by increasing substance P sensitivity and airway fibroblast proliferation, resulting in altered airway structure (remodeling) and function. Therapy with a neurokinin receptor antagonist will reduce airway edema, airway inflammation and fibroblast proliferation, particularly in those patients where M. pneumoniae is present in the airway. To test this hypothesis, we will first determine expression of the tachykinins substance P and neurokinin A, their receptors, airway vascularity and collagen deposition in the airway mucosa of normal controls and asthmatic subjects who are PCR(+) and (-) for M. pneumoniae. Using an in vitro model of M. pneumoniae infection, we will determine the role of substance P on the bronchial epithelial cell inflammatory response and airway fibroblast proliferative response after exposure to M. pneumoniae in normal controls and PCR (+) and PCR (-) asthmatic subjects. We then will determine if substance P sensitivity is increased in PCR (+) asthmatics by performing substance P inhalational challenges, and assessing airway function and edema. Finally, we will determine changes in airway function, inflammation and edema after treatment with a neurokinin antagonist. Information learned from this proposal will allow us to determine whether the presence of M. pneumoniae in the airway alters airway function and contributes to remodeling by increasing airway vascularity and collagen deposition. The presence of M. pneumoniae in the lower airway may result in a unique asthma phenotype that may require treatment focusing upon neurogenic inflammation.