Mycoplasma-induced Airway Remodeling in Human Asthma

肺炎支原体在20%-30%的病例中是社区获得性肺炎的原因，还可引起气管支气管炎、咽炎和毛细支气管炎。我们最近发现肺炎支原体存在于慢性稳定期哮喘患者的呼吸道中，使用大环内酯类药物治疗可以改善肺功能，但仅限于聚合酶链式反应(PCR)肺炎支原体阳性的哮喘患者。大鼠慢性肺支原体感染导致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，血管重塑。此外，P物质还能促进成纤维细胞的增殖。我们实验室的初步数据 证明了在上皮细胞培养中加入肺炎支原体可以诱导P物质的产生，这是一项新的观察。因此，我们假设肺炎支原体感染通过增加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。使用神经激肽受体拮抗剂治疗将减少呼吸道水肿、气道炎症和成纤维细胞增殖，特别是在那些呼吸道存在肺炎支原体的患者中。为了验证这一假设，我们将首先确定速激肽的表达。 肺炎支原体聚合酶链式反应阳性和阴性的正常对照组和哮喘患者的P物质和神经激肽A及其受体、气道血管和气道粘膜胶原沉积。利用肺炎支原体感染的体外模型，我们将确定P物质在正常对照组、聚合酶链式反应阳性和聚合酶链式反应阴性哮喘患者暴露于肺炎支原体后对支气管上皮细胞炎症反应和呼吸道成纤维细胞增殖反应的作用。然后，我们将通过实施P物质吸入激发，并评估呼吸道功能和水肿，来确定P物质敏感性是否在PCR(+)哮喘患者中增加。最后，我们将确定神经激动素拮抗剂治疗后的气道功能、炎症和水肿的变化。从这项提案中学到的信息将使我们 目的：确定肺炎支原体在呼吸道中的存在是否通过增加气道血管和胶原沉积来改变气道功能和促进重塑。下呼吸道肺炎支原体的存在可能导致一种独特的哮喘表型，可能需要重点治疗神经源性炎症。

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.