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挑战后的呼吸道感染（M.肺炎）如何传播慢性支气管高反应性和气道重塑。此外，为了确定急性消除或封锁感染过程是否会阻止慢性“哮喘状”状态即使在持续的过敏原挑战中发展。从这种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，从而导致慢性炎症变化产生气道重塑和持续的支气管性过度反应性。此外，该模型将提高我们对急性干预如何改变感染作用的理解，可以改变慢性支气管高反应性和气道重塑的发展。此外，将确定这种慢性哮喘模型中涉及的TH-1，TH-2细胞因子反应以及神经源性炎症反应。 然后，这些信息可用于设计人类哮喘患者的研究，以确定肺炎支原体是否会导致不同的哮喘表型，以保证新的治疗方法。因此，该项目的具体目的是： 具体目的1。确定仅重复过敏原挑战与过敏原与感染之间的相互作用之间慢性支气管高反应的严重程度的差异。 具体目的2。进一步评估慢性支气管高应答和气道重塑的产生的机制。这将通过阻塞或消除肺炎支原体急性并长期描绘出效果来完成。干预措施将包括先天免疫，表面活性剂蛋白A和D；阻断了支原体通过吸入的皮质类固醇粘附在气道组织上的能力；表面活性剂蛋白和皮质类固醇的组合；和抗生素急性消除感染。 具体目标3。确定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。 BALB/C小鼠将在此项目中使用。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细胞因子表达降低有关。此外，我们已经表明，如果支原体感染遵循过敏原敏感和挑战，这些小鼠的支气管过度反应，炎症和气道阻塞的增加显着增加。因此，评估上述特定目的是一个经过验证的模型。