Mycoplasma-induced Airway Remodeling in Human Asthma

肺炎支原体是20-30%的社区获得性肺炎的病因，也可引起气管支气管炎、咽炎和细支气管炎。我们最近证明了M.肺炎支原体存在于慢性、稳定型哮喘患者的气道中，大环内酯类药物治疗可改善肺功能，但仅适用于肺炎支原体阳性的哮喘患者。pneumoniae的PCR产物。慢性M.大鼠中的肺炎链球菌感染导致神经激肽-1（NK-1）受体（P物质的配体）的表达增加，P物质敏感性增加和血管重塑。此外，P物质增加成纤维细胞增殖。我们实验室的初步数据 证明了M.一项新的观察发现，将肺炎链球菌添加到上皮细胞培养物中可诱导P物质的产生。因此，我们推测M.肺炎通过增加P物质敏感性和气道成纤维细胞增殖来改变哮喘患者的气道反应，导致气道结构（重塑）和功能改变。用神经激肽受体拮抗剂治疗将减少气道水肿，气道炎症和成纤维细胞增殖，特别是在那些M。肺炎存在于气道中。为了验证这一假设，我们将首先确定速激肽的表达， P物质和神经激肽A及其受体、气道血管和胶原沉积。肺炎。利用M.肺炎支原体感染后，我们将确定P物质在支气管上皮细胞炎症反应和气道成纤维细胞增殖反应中的作用。正常对照以及PCR（+）和PCR（-）哮喘受试者中的肺炎。然后，我们将通过进行P物质吸入激发试验和评估气道功能和水肿来确定PCR（+）哮喘患者的P物质敏感性是否增加。最后，我们将确定用神经激肽拮抗剂治疗后气道功能、炎症和水肿的变化。从这份提案中获得的信息将使我们能够 以确定M.气道中的肺炎改变气道功能，并通过增加气道血管分布和胶原沉积而促进重塑。M的存在。下气道中的肺炎可能导致独特的哮喘表型，其可能需要集中于神经源性炎症的治疗。

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.