LYMPHOCYTE/EPITHELIAL INTERACTIONS IN MUCOSAL REMODELING

粘膜重塑中的淋巴细胞/上皮相互作用

• 批准号: 6109555
• 负责人: CAROL B BASBAUM
• 金额: $ 32.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6109555
• 关键词: JAK kinase; Mycoplasma; asthma; biomarker; bronchial mucus; cell cell interaction; cell differentiation; cell population study; cellular pathology; collagenase; flow cytometry; gel mobility shift assay; immunocytochemistry; immunofluorescence technique; inflammation; interleukin 9; laboratory mouse; lymphocyte; metalloendopeptidases; mucins; mycoplasmal pneumonia; polymerase chain reaction; respiratory epithelium; respiratory infections; transcription factor

The epithelium of chronically inflamed airways is characterized by mucus hypersecretion and shows 2 relevant adaptations: (a) mucous cell metaplasia, whereby individual epithelial cells differentiate to express mucin and (b) epithelial remodeling whereby the entire epithelial tissue layer becomes convoluted, invading connective tissue to form mucous crypts and glands. To identify molecular mechanisms underlying these changes requires the use of biochemical markers. Mucin can be considered a marker for mucous metaplasia as mucous differentiation is dependent on mucin gene expression. Metalloproteinases can be considered markers for epithelial remodeling as morphogenetic processes requiring connective tissue degradation are dependent on these enzymes. Seeking stimuli potentially controlling mucin and metalloproteinase expression in the inflamed airway we tested the effect of lymphocyte-derived cytokines. Product of both mixed lymphocyte reactions and fluid from asthmatic airways stimulated expression of the two markers at the RNA level. Experiments described below indicate that the Th2 cell mediator IL-9 is a major mucin stimulus in asthmatic airway fluid and that the T cell surface marker OX-47 (EMMPRIN) strongly stimulates metalloproteinases 1 and 9. Based on these relationships, we hypothesize that activated T cells in inflamed airways control mucous metaplasia and epithelial remodeling via IL-9 and EMMPRIN. Specific aim 1 will use mutant mice to determine which lymphocyte populations are required for M. pulmonis-induced mucin (Muc 5ac) and metalloproteinase (MMP-9) gene activation. Specific aim 2, using chemical inhibitors, dominant negative mutants and chimeric IL-9 receptor constructs, will test the hypothesis that IL-9 stimulates MUC5 AC in human bronchial epithelial cells via intersecting JAK-STAT and MAPK signaling pathways. Specific aim 3, using biochemical inhibitors, dominant negative mutants and a novel mutagenesis approach, will test the hypothesis that EMMPRIN stimulates MMP-1 in human fibroblasts via a p38-dependent mechanisms and will identify key elements of EMMPRIN-MMP signaling.

The epithelium of chronically inflamed airways is characterized by mucus hypersecretion and shows 2 relevant adaptations: (a) mucous cell metaplasia, whereby individual epithelial cells differentiate to express mucin and (b) epithelial remodeling whereby the entire epithelial tissue layer becomes convoluted, invading connective tissue to form mucous crypts and glands. 为了确定这些变化的分子机制，需要使用生化标记。 由于粘液分化取决于粘蛋白基因的表达，因此粘蛋白可以被认为是粘液化生的标志物。金属蛋白酶可以被认为是上皮重塑的标志物，因为需要结缔组织降解的形态发生过程取决于这些酶。在发炎的气道中寻求潜在控制粘蛋白和金属蛋白酶表达的刺激，我们测试了淋巴细胞衍生的细胞因子的作用。哮喘气道的混合淋巴细胞反应和流体的乘积刺激了RNA水平的两个标记。 Experiments described below indicate that the Th2 cell mediator IL-9 is a major mucin stimulus in asthmatic airway fluid and that the T cell surface marker OX-47 (EMMPRIN) strongly stimulates metalloproteinases 1 and 9. Based on these relationships, we hypothesize that activated T cells in inflamed airways control mucous metaplasia and epithelial remodeling via IL-9 and EMMPRIN.具体的目标1将使用突变小鼠来确定肺部肺炎支原体诱导的粘蛋白（MUC 5AC）和金属蛋白酶（MMP-9）基因激活所需的淋巴细胞群。 使用化学抑制剂，显性阴性突变体和嵌合IL-9受体构建体的特定目标2将测试以下假设：IL-9通过与JAK-STAT和MAPK信号通路相交的人支气管上皮细胞中刺激MUC5 AC。 具体目标3，使用生化抑制剂，显性阴性突变体和一种新型的诱变方法，将检验以下假设：Emmprin通过p38依赖性机制刺激人成纤维细胞中的MMP-1，并将识别EMMPRIN-MMP信号的关键元素。