MECHANISMS OF CHEMOKINE EXPRESSION IN ASTHMA

哮喘中趋化因子表达的机制

• 批准号: 6039140
• 负责人: CRAIG M LILLY
• 金额: $ 23.48万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-15 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6039140
• 关键词: asthma; cell migration; chemoattractants; chemokine; clinical research; eosinophil; gene expression; genetic polymorphism; genetic susceptibility; genotype; human subject

Asthma associated morbidity, disability effects 54 out of every 1000 Americans. This chronic recurrent disease is known to be directly associated with inflammation of the airways. Asthmatic airways are infiltrated with inflammatory cells including eosinophils which are present even in asymptomatic asthmatics with normal lung function. Eosinophils in asthmatic airways are activated and release preformed toxic granular proteins; they contain peroxidases which generate toxic oxygen metabolites, they generate lipid mediators and proinflammatory cytokines which can produce airway hyperresponsiveness-the cardinal physiological feature of asthma. The importance of eosinophils to asthma is suggested by studies that correlate the resolution of asthma symptoms with the resolution of airway eosinophilia. Defining the mechanisms that selectively recruit eosinophils to the airways has the potential to identify novel therapeutic targets relevant to eosinophil mediated diseases including asthma. While many substances are chemotactic for eosinophils far fewer have chemotactic effects that are selective for cell types assoicated with asthma. Eotaxin is one substance that selectively activates these cell types. The discovery of eotaxin in an animal model of asthma has led to investigations of its associations with human disease. Indeed we have recently found that eotaxin is mobilized in asthmatic lungs after segmental allergen challenge and airway levels correlate with the numbers of eosinophils recruited into the lungs. Eotaxin is detectable in human plasma and is directly and independently associated with asthma diagnosis, and inversely related to baseline lung function. Eotaxin levels are increased in asthma exacerbations and elevated levels are associated with worse outcomes from acute asthma care. Our long term goal is to understand the mechanisms that mobilize eotaxin and related chemokines that recruit eosinophils to the airways. We propose to study the mechanisms that are responsible for eotaxin mobilization by studying its mobilization in in vitro systems, and in cells from subjects with common eotaxin polymorphisms that impair eotaxin expression. Specifically we propose: (1) To determine the mechanism(s) by which a coding region polymorphism of the eotaxin gene reduces eotaxin expression. (2) To define the mechanisms that alter eotaxin mRNA expression. (3) To explore mechanisms common to eotaxin and MCP-4 mobilization and define regulatory elements critical for the coordinated expression of these chemokines. This work will lead to a better understanding of the mechanisms by which eotaxin and the CCR3 receptor contribute to the asthamtic diathesis.

每 1000 名美国人中就有 54 人因哮喘相关发病和残疾。 已知这种慢性复发性疾病与气道炎症直接相关。 哮喘气道被包括嗜酸性粒细胞在内的炎症细胞浸润，即使在肺功能正常的无症状哮喘患者中也存在这种细胞。 哮喘气道中的嗜酸性粒细胞被激活并释放预先形成的有毒颗粒蛋白；它们含有产生有毒氧代谢物的过氧化物酶，它们产生脂质介质和促炎细胞因子，这些细胞因子可以产生气道高反应性——哮喘的主要生理特征。 将哮喘症状的缓解与气道嗜酸粒细胞增多的缓解相关联的研究表明了嗜酸性粒细胞对哮喘的重要性。 定义选择性地将嗜酸性粒细胞招募到气道的机制有可能确定与嗜酸性粒细胞介导的疾病（包括哮喘）相关的新治疗靶点。 虽然许多物质对嗜酸性粒细胞具有趋化作用，但对与哮喘相关的细胞类型具有选择性趋化作用的物质却少得多。 嗜酸细胞活化趋化因子是一种选择性激活这些细胞类型的物质。 在哮喘动物模型中发现嗜酸细胞趋化因子，引发了对其与人类疾病关联的研究。 事实上，我们最近发现，在节段性过敏原激发后，嗜酸性粒细胞活化趋化因子在哮喘肺部被动员，并且气道水平与招募到肺部的嗜酸性粒细胞数量相关。 嗜酸细胞活化趋化因子可在人血浆中检测到，与哮喘诊断直接且独立相关，与基线肺功能呈负相关。 哮喘急性发作时嗜酸细胞趋化因子水平升高，且升高的水平与急性哮喘治疗的较差结果相关。 我们的长期目标是了解动员嗜酸性粒细胞趋化因子和相关趋化因子将嗜酸性粒细胞招募到气道的机制。 我们建议通过研究嗜酸细胞趋化因子在体外系统中的动员以及在具有损害嗜酸细胞趋化因子表达的常见嗜酸细胞趋化因子多态性的受试者的细胞中的动员来研究负责嗜酸细胞趋化因子动员的机制。 具体来说，我们建议：（1）确定嗜酸细胞趋化因子基因的编码区多态性降低嗜酸细胞趋化因子表达的机制。 (2) 明确改变eotaxin mRNA表达的机制。 (3) 探索eotaxin和MCP-4动员的共同机制，并定义对这些趋化因子协调表达至关重要的调控元件。 这项工作将有助于更好地理解嗜酸细胞活化趋化因子和 CCR3 受体导致哮喘素质的机制。