MODULATION OF AIRWAY INFLAMMATION BY EPITHELIAL INTEGRINS

炎症细胞在气道壁的流入和激活是 在很大程度上，依赖于局部炎性细胞因子的释放。 尽管很多注意力都集中在来自白细胞的细胞因子上， 现在清楚的是，呼吸道上皮细胞是数量最多的细胞类型 在气道壁中，它们自身能够合成和分泌 几种可以深刻影响呼吸道炎症的细胞因子。在……里面 非上皮细胞，细胞因子基因表达的调节至关重要 依赖于通过细胞外基质提供的信号 整合素家族的跨膜受体。相似基因的存在 调节呼吸道上皮细胞细胞因子基因表达可能 有助于解释气道重塑和持续性气道重塑共存的原因 哮喘中的炎症。我们最近培育了一系列小白鼠 表达β-6整合素亚单位的零突变，该亚单位 仅限于在上皮细胞中表达，特别是在肺和 皮肤。表达这种突变的小鼠发育和繁殖正常，但 均有炎性细胞在毛囊周围渗入并散在分布。 整个肺部和呼吸道，与整合素的作用一致- 炎性细胞募集和/或调控中的衍生信号 在这些站点中的激活。在建议的研究中，我们会有系统地 检查正常细胞外的不同成分的影响 基质和基质蛋白在损伤和炎症的呼吸道中丰富，on 已知的细胞因子的结构性和刺激性合成和分泌 由呼吸道上皮细胞合成。一旦我们确定了 各种基质蛋白的作用，我们将考察各种作用 这些反应中的整合素。对于这些实验，我们将使用阻塞 抗整合素抗体，基质蛋白的重组片段 设计成由特定的呼吸道上皮细胞唯一识别 整合素和小鼠呼吸道上皮细胞表达 整合素基因突变。最后，要确定 整合素和基质衍生的细胞因子在体内的调节，我们将检查 炎症细胞的涌入，选定的细胞因子的产生， 以及小鼠体内呼吸道反应性的变化 缺乏整合素或整合素配体的人受到尖锐的挑战 慢性由免疫性或非免疫性炎症刺激引起。 通过这些研究，我们希望确定呼吸道的改变是如何 上皮整合素和/或其配体可能导致慢性 以持续性哮喘为特征的呼吸道炎症。

The influx and activation of inflammatory cells in the airway wall is dependent, in large part, on the local release of inflammatory cytokines. Although much attention has focused on cytokines derived from leukocytes, it is now clear that airway epithelial cells, the most numerous Cell type in the airway wall, are themselves capable of synthesizing and secreting several cytokines that could profoundly influence airway inflammation. In non-epithelial cells, regulation of cytokine gene expression is critically dependent on signals provided from the extracellular matrix via the integrin family of transmembrane receptors. The existence of similar regulation of cytokine gene expression in airway epithelial cells could help to explain the coexistence of airway remodeling and persistent airway inflammation in asthma. We have recently generated lines of mice expressing a null mutation in the beta-6 integrin subunit, a subunit that is restricted in its expression to epithelia, especially in the lung and skin. Mice expressing this mutation develop and reproduce normally, but all have inflammatory cell infiltrates around hair follicles and scattered throughout the lungs and airways, consistent with a role for integrin- derived signals in regulation of inflammatory cell recruitment and/or activation in these sites. In the proposed studies, we will systematically examine the effects of various components of the normal extracellular matrix and of matrix proteins enriched in injured and inflamed airways, on the constitutive and stimulated synthesis and secretion of cytokines known to be synthesized by airway epithelial cells. Once we have determined the effects of various matrix proteins, we will examine the role of various integrins in these responses. For these experiments, we will use blocking anti-integrin antibodies, recombinant fragments of matrix proteins designed to be uniquely recognized by specific airway epithelial integrins, and murine airway epithelial cells derived from mice expressing mutations in integrin genes. Finally, to determine the significance of integrin and matrix-derived cytokine regulation in vivo, we will examine the influx of inflammatory cells, the production of selected cytokines, and the alterations in in vivo airway responsiveness produced when mice deficient in integrins or integrin ligands are challenged acutely or chronically by either immunologic or non-immunologic inflammatory stimuli. Through these studies, we hope to determine how alterations in airway epithelial integrins and/or their ligands could contribute to the chronic airway inflammation that characterizes persistent asthma.