CHEMOKINES IN THE PATHOGENESIS OF ASTHMA

哮喘发病机制中的趋化因子

• 批准号: 6106522
• 负责人: Daniel G. Remick
• 金额: $ 13.05万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-11-01 至 1999-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6106522
• 关键词: asthma; chemokine; cockroach; disease /disorder model; dust; environmental toxicology; enzyme linked immunosorbent assay; histology; inflammation; laboratory mouse; neutralizing antibody; pathologic process; respiratory function; western blottings

Chemokines in the Pathogenesis of Asthma. Asthma represents a serious health problem particularly for inner city children. Recent studies have identified that many of the asthmatic attacks are triggered by exposure to cockroach allergens however, the mediators within the lung that dictate progression of disease have still not been fully defined. While many potential mediators have been examined previously, asthma still exacts a toll on the patients. More specific, targeted therapy has the potential to improve the treatment of asthma by identifying those mediators directly responsible for the pathogenesis of the disease. This project will test the hypothesis that asthma-like pulmonary injury is mediated by the local production of chemokines. Chemokines are small molecular weight peptides which induce the chemotaxis and recruitment of inflammatory cells. They are powerful mediators with long lasting and potent biological activities. Our first specific aim will determine the acute and chronic pulmonary inflammation that develops after direct injection of the chemokines into the lung. The assessment of the injury will include histologic and morphometric analysis as well as an assessment of the innervation of the airways. The second specific aim will develop a mouse model of asthma-like pulmonary inflammation in response to cockroach allergens. This model will be established by locating households with high levels of cockroach allergens (done in conjunction with the other two research projects) and using this material to immunize the mice. The mice will be challenged by exposure to aerosols containing the dust with the cockroach allergens and the pulmonary injury carefully quantitated including an analysis of innervation of the airways. Our third specific aim will investigate the biochemical pathways responsible for the upregulation of the chemokines in cells sensitized and then challenged with cockroach allergens. We will focus on reactive oxygen and reactive nitrogen intermediates since they have been demonstrated to increased the transcription of chemokines. Our last specific aim will rigorously test the central hypothesis that chemokines are important in the pathogenesis of asthma. This will be tested by blocking the biological activity of the chemokines with specific neutralizing antibodies and determining if there is a reduction in the pulmonary inflammation induced by repeated exposures to the cockroach allergens. Successful completion of our project will both delineate the underlying mechanisms of disease and identify potential novel targets for intervention.

趋化因子在哮喘发病机制中的作用哮喘是一种严重的 健康问题，特别是对市中心的儿童。最近的研究表明 发现许多哮喘发作是由暴露于 然而，蟑螂变应原是肺内决定 疾病的发展仍然没有得到充分的定义。虽然很多人 潜在的介质以前已经被检查过了，哮喘仍然需要 给病人造成的损失。更具体地说，靶向治疗有可能 通过直接识别这些介质来改进哮喘的治疗 对这种疾病的发病机制负有责任。该项目将测试 哮喘样肺损伤是由局部介导的假说 趋化因子的产生。趋化因子是一种小分子多肽 诱导炎性细胞的趋化和募集。他们 是具有持久和强大生物活性的强有力的介体。 我们的第一个具体目标是确定急性和慢性肺病 将趋化因子直接注入体内后发生的炎症 肺部。对损伤的评估将包括组织学和 形态计量学分析及神经支配的评价 航空公司。第二个具体目标是开发一种类似哮喘的小鼠模型 蟑螂变应原引起的肺部炎症。这款车型将 通过定位蟑螂水平较高的家庭来建立 过敏原(与其他两个研究项目一起完成)和 用这种材料给小鼠免疫。小鼠将受到挑战， 暴露于含有蟑螂变应原粉尘的气雾剂和 仔细量化的肺损伤包括分析 呼吸道的神经支配。我们的第三个具体目标是调查 趋化因子上调的生化途径 细胞致敏，然后用蟑螂过敏原攻击。我们会 关注活性氧和活性氮中间体，因为它们 已被证明能增加趋化因子的转录。我们的 最后一个具体目标将严格检验中心假设 趋化因子在哮喘的发病机制中起重要作用。这将是 通过特异性阻断趋化因子的生物活性进行测试 中和抗体并确定是否有减少的 蟑螂反复暴露引起的肺部炎症 过敏原。我们的项目的成功完成将既勾勒出 疾病的潜在机制，并确定潜在的新靶点 干预。