ALVEOLAR MACROPHAGE ACTIVATION BY INTEGRIN KNOCK-OUT

整合素敲除激活肺泡巨噬细胞

• 批准号: 6151286
• 负责人: David G Morris
• 金额: $ 4.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6151286
• 关键词: alveolar macrophages; animal genetic material tag; cell cell interaction; cell communication molecule; genetically modified animals; immunogenetics; inflammation; integrins; laboratory mouse; leukocyte activation /transformation; mixed tissue /cell culture; pulmonary fibrosis /granuloma; respiratory epithelium

Pulmonary inflammation is pivotal in many respiratory disorders including asthma, ARDS, and pulmonary fibrosis. Recent evidence suggests that the epithelial integrin alphavbeta6 may be important in pulmonary and dermal inflammation. In particular, inactivation of the beta6 subunit of the alphavbeta6 integrin in mice either by creation of a null mutant (beta6 minus/minus), or by treatment with inactivating antibody or peptide results in airway hyperresponsiveness, lymphocytic bronchiolitis, dermatitis and particularly, histological evidence of macrophage activation. Alphavbeta6 is expressed primarily on epithelial cells, unregulated in response to injury and is known to be a receptor for the extracellular matrix proteins fibronectin, tenascin, and vitronection. Macrophages secrete a wide array of cytokines which modulate the activation, recruitment and responses of other inflammatory cells, particularly lymphocytes. The observation that elimination of alphavbeta6 expression may result in alveolar macrophage activation suggests that changes in integrin expression on a surface of respiratory epithelia can result in macrophage activation either indirectly through secretion of inflammatory mediators, or through direct cell-cell interactions. These experiments will define the mechanisms of this inflammatory activation focusing on the role of alveolar macrophages and epithelial cell-macrophage interactions. Following full in vivo characterization of the activation profile of alveolar macrophages from null and wild type mice, an in vivo assay system will be developed to replicate epithelial-macrophage interactions. The in vivo and in vitro effects of inactivating antibodies and peptides, as well as the effect of the null mutation on the direct and indirect interactions between respiratory epithelia and alveolar macrophages will be examined. Ultimately these experiments will provide a better understanding of the role of integrins in pulmonary inflammation and may provide important insights into novel therapeutic strategies.

肺部炎症是许多呼吸系统疾病的关键，包括哮喘、ARDS和肺纤维化。 最近的证据表明，上皮整合素α v β 6可能是重要的肺部和皮肤炎症。 特别地，通过产生无效突变体（β 6负/负）或通过用灭活抗体或肽处理来灭活小鼠中α v β 6整联蛋白的β 6亚基，导致气道高反应性、淋巴细胞性细支气管炎、皮炎，特别是巨噬细胞活化的组织学证据。α v β 6主要在上皮细胞上表达，对损伤的反应不受调节，并且已知是细胞外基质蛋白纤连蛋白、生腱蛋白和玻连蛋白的受体。 巨噬细胞分泌多种细胞因子，其调节其它炎性细胞（特别是淋巴细胞）的活化、募集和反应。 α v β 6表达的消除可导致肺泡巨噬细胞活化的观察结果表明，呼吸道上皮细胞表面上整联蛋白表达的变化可通过炎症介质的分泌间接地或通过直接的细胞-细胞相互作用导致巨噬细胞活化。这些实验将确定这种炎症激活的机制，重点是肺泡巨噬细胞和上皮细胞-巨噬细胞相互作用的作用。 在对空小鼠和野生型小鼠肺泡巨噬细胞的活化特征进行全面体内表征后，将开发一种体内测定系统，以复制上皮-巨噬细胞相互作用。 将检查灭活抗体和肽的体内和体外作用，以及无效突变对呼吸道上皮细胞和肺泡巨噬细胞之间的直接和间接相互作用的作用。最终，这些实验将提供一个更好的理解整合素在肺部炎症的作用，并可能提供新的治疗策略的重要见解。