Infection and Allergic Asthma: A Murine Model

该项目拟议研究的总体目标是确定过敏原挑战后的呼吸道感染(肺炎支原体)如何传播慢性支气管高反应性和呼吸道重塑。此外，为了确定急性消除或阻断感染过程是否能防止慢性“哮喘样”状态的发展，即使在持续的过敏原挑战下。从这个小鼠模型中获得的知识将有助于理解过敏原和感染之间的相互作用，这些相互作用涉及慢性炎症变化，产生气道重塑和持续的支气管高反应性。此外，该模型将增加我们对急性干预改变感染效果如何改变慢性支气管高反应性和呼吸道重塑的理解。此外，还将确定参与这一慢性哮喘模型的Th-1、Th-2细胞因子反应以及神经源性炎症反应。 然后，这些信息可以用于在人类哮喘受试者中设计研究，以确定肺炎支原体是否会导致一种不同的哮喘表型，从而需要新的治疗方法。因此，该项目的具体目标是： 具体目的1.确定反复过敏原激发和过敏原与感染之间的相互作用在慢性支气管高反应性严重程度上的差异。 具体目的2.进一步探讨慢性支气管高反应性和气道重塑的发生机制。这将通过尖锐地封锁或消除肺炎支原体并长期描述其影响来实现。干预措施将包括先天免疫、表面活性蛋白A和D；通过吸入皮质类固醇来阻断支原体附着在呼吸道组织上的能力；表面活性蛋白和皮质类固醇的组合；以及通过抗生素急性消除感染。 具体目的3.确定神经源性炎症反应的剧烈改变如何改变慢性方面，即支气管高反应性和气道重塑。 该项目将使用BALB/C小鼠。我们已经证明，这些小鼠增加了肺炎支原体呼吸道感染后的支气管高反应性和呼吸道炎症。这与Th-1细胞因子表达减少有关。此外，我们已经证明，如果支原体感染伴随着过敏原致敏和挑战，这些小鼠的支气管高反应性、炎症和呼吸道阻塞显著增加。因此，评估上述具体目标是一种行之有效的模型。

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.