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过敏原激发后的呼吸道感染（肺炎支原体）如何传播慢性支气管高反应性和气道重塑。此外，确定即使在持续的过敏原挑战下，急性消除或阻断感染过程是否也能防止慢性“哮喘样”状态的发展。从该小鼠模型中获得的知识将有助于了解过敏原和感染之间的相互作用，这些相互作用涉及导致气道重塑和持续支气管高反应性的慢性炎症变化。此外，该模型将加深我们对改变感染影响的急性干预措施如何改变慢性支气管高反应性和气道重塑的发展的理解。此外，还将确定参与这种慢性哮喘模型的 Th-1、Th-2 细胞因子反应以及神经源性炎症反应。 然后，该信息可用于设计人类哮喘受试者的研究，以确定肺炎支原体是否会导致不同的哮喘表型，从而需要新的治疗方法。因此，该项目的具体目标是： 具体目标 1. 确定单独重复过敏原激发和过敏原与感染之间相互作用之间慢性支气管高反应性严重程度的差异。 具体目标2.进一步评估慢性支气管高反应性和气道重塑的产生机制。这将通过急性阻断或消除肺炎支原体并长期描述其影响来实现。干预措施包括先天免疫、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到气道组织的能力；表面活性蛋白和皮质类固醇的组合；并通过抗生素迅速消除感染。 具体目标 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。 BALB/c 小鼠将用于该项目。我们已经证明，这些小鼠在肺炎支原体呼吸道感染后会增加支气管高反应性和气道炎症。这与 Th-1 细胞因子表达减少有关。此外，我们还发现，如果过敏原致敏和攻击后发生支原体感染，这些小鼠的支气管高反应性、炎症和气道阻塞会显着增加。因此，它是评估上述具体目标的一个经过验证的模型。