MODULATION OF AIRWAY INFLAMMATION BY EPITHELIAL INTEGRINS

气道壁中炎性细胞的流入和活化是 在很大程度上依赖于炎性细胞因子的局部释放。 虽然许多注意力集中在来自白细胞的细胞因子上， 现在清楚的是，气道上皮细胞，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 几种细胞因子可以深刻地影响气道炎症。在 在非上皮细胞中，细胞因子基因表达的调节是至关重要的。 依赖于由细胞外基质通过 跨膜受体整合素家族。类似的存在 调节气道上皮细胞的细胞因子基因表达， 有助于解释气道重塑和持续气道共存 哮喘中的炎症我们最近培育了一系列小鼠 在β-6整联蛋白亚基中表达无效突变，该亚基 其表达局限于上皮细胞，特别是在肺中， 皮肤表达这种突变的小鼠正常发育和繁殖， 毛囊周围均有炎性细胞浸润， 在整个肺和呼吸道，与整合素的作用一致， 在调节炎性细胞募集中的衍生信号和/或 这些网站的激活。在拟议的研究中，我们将有系统地 检查正常细胞外的各种成分的影响， 基质和基质蛋白在受损和发炎的气道中富集， 已知细胞因子的组成性和刺激性合成和分泌 由气道上皮细胞合成。一旦我们确定了 各种基质蛋白的作用，我们将研究各种 这些反应中的整合素。对于这些实验，我们将使用阻塞 抗整联蛋白抗体、基质蛋白的重组片段 被设计成由特定的气道上皮细胞唯一识别 整联蛋白和来源于表达 整合素基因的突变。最后，为了确定 整合素和基质衍生的细胞因子调节在体内，我们将研究 炎症细胞的流入，选定细胞因子的产生， 以及小鼠在体内气道反应性的改变， 整合素或整合素配体缺陷的患者受到急性攻击，或 慢性地通过免疫或非免疫炎症刺激。 通过这些研究，我们希望确定气道的改变 上皮整合素和/或它们的配体可能有助于慢性炎症， 以持续性哮喘为特征的气道炎症。

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.