Infection and Allergic Asthma: A Murine Model

本项目研究的总体目标是确定呼吸道感染（肺炎支原体）如何在过敏原攻击后传播慢性支气管高反应性和气道重塑。此外，确定急性消除或阻断感染过程是否可以防止慢性“哮喘样”状态的发展，即使持续的过敏原挑战。从该小鼠模型中获得的知识将有助于理解过敏原与感染之间的相互作用，这些相互作用涉及产生气道重塑和持续支气管高反应性的慢性炎症变化。此外，该模型将增加我们对急性干预如何改变感染效果的理解，从而改变慢性支气管高反应性和气道重塑的发展。此外，Th-1、Th-2细胞因子反应以及神经源性炎症反应在慢性哮喘模型中的作用将被确定。

The overall objective of the proposed research for this project is to determine how a respiratory infection (M. pneumoniae) following an allergen challenge propagates chronic bronchial hyper-responsiveness and airway remodeling. Additionally, to determine if acute elimination or blockade of the infective process prevents a chronic "asthma-like" state from developing even with continued allergen challenge. The knowledge gained from this murine model will help in the understanding of the interaction between allergen and infection in regard to chronic inflammatory changes producing airway remodeling and sustained bronchial hyperresponsiveness. Additionally, the model will increase our understanding of how acute interventions altering the effect of an infection can alter the development of chronic bronchial hyperresponsiveness and airway remodeling. Furthermore the Th-1, Th-2 cytokine responses as well as neurogenic inflammatory responses that are involved in this chronic model of asthma will be determined. This information can then be used to design studies in human asthmatic subjects to determine if M. pneumoniae results in a different asthma phenotype that warrants new therapeutic approaches. Thus, the specific aims of this project are: Specific Aim 1. To determine the difference in the severity of chronic bronchial hyperresponsiveness between repeated allergen challenges alone and the interaction between allergen and infection. Specific Aim 2. To further evaluate the mechanisms involved in the production of chronic bronchial hyperresponsiveness and airway remodeling. This will be done by blockade or elimination of M. pneumoniae acutely and delineating the effects chronically. Interventions will include innate immunity, surfactant proteins A and D; blocking the ability of mycoplasma to adhere to airway tissue by inhaled corticosteroids; the combination of surfactant proteins and corticosteroids; and acute elimination of the infection by an antibiotic. Specific Aim 3. To determine how acutely altering neurogenic inflammatory responses may change the chronic aspect, i.e., bronchial hyperresponsiveness and airway remodeling. BALB/c mice will be used in this project. We have demonstrated that these mice increase bronchial hyperresponsiveness and airway inflammation following an M. pneumoniae respiratory infection. This is associated with decreased Th-1 cytokine expression. Additionally, we have shown that these mice have a marked increase in bronchial hyperresponsiveness, inflammation, and airway obstruction if the mycoplasma infection follows allergen sensitization and challenge. Therefore it is a proven model to evaluate the specific aims stated above.