ALVEOLAR MACROPHAGE ACTIVATION BY INTEGRIN KNOCK-OUT

肺部炎症在许多呼吸系统疾病中起关键作用，包括哮喘、ARDS和肺纤维化。最近的证据表明，上皮整合素αvbeta6可能在肺部和真皮炎症中起重要作用。特别是，通过创建零突变(β6负/负)或通过灭活抗体或肽治疗使小鼠整合素αvbeta6的β6亚单位失活，会导致呼吸道高反应性、淋巴细胞性毛细支气管炎、皮炎，特别是巨噬细胞激活的组织学证据。Alphavbeta6主要在上皮细胞上表达，在损伤反应中不受调控，已知是细胞外基质蛋白纤维连接蛋白、腱连接蛋白和玻璃体连接蛋白的受体。巨噬细胞分泌广泛的细胞因子，调节其他炎症细胞的激活、募集和反应，特别是淋巴细胞。消除αvbeta6表达可能导致肺泡巨噬细胞活化的观察表明，呼吸道上皮细胞表面整合素表达的变化可以通过分泌炎症介质间接导致巨噬细胞激活，也可以通过细胞-细胞直接相互作用导致巨噬细胞激活。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的作用和上皮细胞-巨噬细胞的相互作用。在对空白型和野生型小鼠肺泡巨噬细胞的激活情况进行了全面的体内表征后，将开发一种体内检测系统来复制上皮-巨噬细胞的相互作用。将检测灭活抗体和多肽在体内和体外的作用，以及零突变对呼吸道上皮细胞和肺泡巨噬细胞之间直接和间接相互作用的影响。最终，这些实验将更好地了解整合素在肺部炎症中的作用，并可能为新的治疗策略提供重要的见解。

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.