CD44 mediated airway hyperresponsiveness and inflammation induced by allergen

CD44是一种广泛表达的细胞黏附分子 (CaM)作为透明质酸(HA)的主要受体， 细胞外基质糖胺聚糖。CD44的表达上调有 在慢性支气管炎患者的上皮细胞、嗜酸性粒细胞和T淋巴细胞上已被发现 哮喘。支气管肺泡灌洗液(BAL)中恢复的HA水平 哮喘患者也会增加，并与疾病的严重程度相关。在……里面 初步研究我们探讨了CD44在骨肉瘤发生发展中的作用 抗原致敏大鼠的气道炎症和高反应性 老鼠。CD44缺乏对白细胞的募集或 产生抗原特异性IgE，但呼吸道高反应性明显 与野生型窝产仔对照相比有所减少。此外，行政管理 针对野生型小鼠的抗CD44抗体可抑制抗原诱导的呼吸道 高反应性与正常大鼠免疫球蛋白处理的小鼠比较。的目标是 建议的研究是通过以下方式确定分子和细胞机制 CD44促进抗原诱导的AHR。我们提出了以下具体建议 目的：1.验证CD44促进抗原诱导的小鼠AHR的假设。 我们还将检验AHR和呼吸道发育的假设 炎症与CD44和CD44的功能激活有关 低相对分子质量透明质酸致炎片段的蓄积 在老鼠和人类身上。2.确定CD44表达的相对贡献率 关于骨髓源性造血细胞与非造血细胞的比较 实质细胞在AHR上的表达及可溶性CD44在呼吸道中的作用 炎症和AHR。我们将确定CD44在任何一种造血细胞上 或在骨髓嵌合体中单独作用于非造血细胞促进呼吸道 炎症和AHR。可溶性CD44在抗原诱导中的作用 还将测定呼吸道炎症和AHR。以确定细胞 CD44促进AHR和气道重塑的分子机制 将：3)确定CD44在矩阵组织中的角色；以及4)测试 CD44配体结合影响CD44合成功能的假说 激活核转录因子-kB和血管内皮细胞的作用 RAS依赖的信号通路。由于CD44在疾病中扮演着重要的角色 炎症似乎促进了AHR，但正常情况下并不是必需的 白细胞循环，它特别吸引人作为潜在的靶点 哮喘的新治疗干预措施。对细胞的理解 CD44促进AHR的分子机制因此可能提供 明确了治疗干预的目标。

(Applicant's Abstract) CD44 is a widely expressed cell adhesion molecule (CAM) that serves as a principal receptor for hyaluronan (HA), an extracellular matrix glycosaminoglycan. Up regulated expression of CD44 has been noted on epithelial cells, eosinophils and T lymphocytes in patients with asthma. Levels of HA recovered in the bronchoalveolar lavage (BAL) of asthmatics are also increased and correlate with severity of disease. In preliminary studies we investigated the role of CD44 in the development of airway inflammation and airway hyperreactivity (AHR) in antigen-sensitized mice. CD44- deficiency had no effect on the recruitment of leukocytes or production of antigen specific IgE but airway hyperreactivity was markedly reduced compared to wild-type littermate controls. Furthermore, administration of anti-CD44 antibodies to wild-type mice inhibited antigen-induced airway hyperreactivity compared to normal rat Ig treated mice. The goal of the proposed studies is to determine the molecular and cellular mechanisms by which CD44 promotes antigen-induced AHR. We propose the following specific aims: 1. Test the hypothesis that CD44 promotes antigen-induced AHR in mice. We will also test the hypothesis that development of AHR and airway inflammation is associated with functional activation of CD44 and the accumulation of low molecular weight pro-inflammatory fragments of hyaluronan in mice and humans. 2. Determine the relative contributions of CD44 expression on bone marrow-derived hematopoietic cells versus non-hematopoietic parenchymal cells on AHR and define the role of soluble CD44 in airway inflammation and AHR. We will determine if CD44 on either hematopoietic cells or on non-hematopoietic cells alone in bone marrow chimeras promotes airway inflammation and AHR. The contribution of soluble CD44 to antigen-induced airway inflammation and AHR will also be determined. To ascertain the cellular and molecular mechanisms by which CD44 promotes AHR and airway remodeling we will: 3) Determine the role of CD44 in matrix organization; and 4) Test the hypothesis that ligand binding to CD44 affects the synthetic function of airway smooth muscle cells and epithlelial cells by activating NF-kB and Ras-dependent signaling pathways. Since CD44 plays an important role in inflammation and appears to promote AHR but is not required for normal leukocyte circulation, it is particularly attractive as a potential target for novel therapeutic interventions in asthma. An understanding of the cellular and molecular mechanism by which CD44 promotes AHR may therefore provide defined targets for therapeutic interventions.