Infection and Allergic Asthma: A Murine Model

感染和过敏性哮喘：小鼠模型

• 批准号: 7063424
• 负责人: RICHARD J MARTIN
• 金额: $ 21.01万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7063424
• 关键词: Mycoplasma pneumoniae; T lymphocyte; allergens; asthma; bacteria infection mechanism; cellular immunity; corticosteroids; disease /disorder model; enzyme linked immunosorbent assay; flow cytometry; histology; hypersensitivity; immunoglobulin E; immunoglobulin G; laboratory mouse; mycoplasmal pneumonia; polymerase chain reaction

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.

该项目拟议研究的总体目标是确定呼吸道感染（M。肺炎）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，即使持续过敏原攻击。从这种小鼠模型获得的知识将有助于了解过敏原和感染之间的相互作用，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如何改变感染的影响可以改变慢性支气管高反应性和气道重塑的发展的理解。此外，Th-1，Th-2细胞因子反应以及参与哮喘慢性模型的神经源性炎症反应将被确定。 这些信息可用于设计人类哮喘受试者的研究，以确定M。肺炎导致不同的哮喘表型，这保证了新的治疗方法。因此，该项目的具体目标是： 具体目标1。确定单独反复过敏原激发与过敏原和感染之间相互作用在慢性支气管高反应性严重程度上的差异。 具体目标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。这将通过封锁或消灭M来实现。肺炎急性和划定的影响慢性。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阻断支原体粘附气道组织的能力;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。 具体目标3。为了确定急性改变神经源性炎症反应如何改变慢性方面，即，支气管高反应性和气道重塑。 本项目将使用BALB/c小鼠。我们已经证明，这些小鼠在M.肺炎呼吸道感染。这与Th-1细胞因子表达减少有关。此外，我们已经表明，这些小鼠有一个显着增加支气管高反应性，炎症和气道阻塞，如果支原体感染过敏原致敏和挑战。因此，这是一个经过验证的模式，可以评估上述具体目标。