CD44 mediated airway hyperresponsiveness and inflammation induced by allergen

CD44 介导的气道高反应性和过敏原诱导的炎症

• 批准号: 6663418
• 负责人: Ellen Pure'
• 金额: $ 32.1万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6663418
• 关键词: CD44 molecule; allergens; asthma; bone marrow; bronchomotion; diagnostic respiratory lavage; human subject; inflammation; laboratory mouse; nuclear factor kappa beta; patient oriented research; receptor binding; receptor expression; respiratory epithelium; respiratory hypersensitivity; smooth muscle; tissue /cell culture

(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.

（申请人的摘要）CD 44是广泛表达的细胞粘附分子 (CAM)作为透明质酸（HA）的主要受体， 细胞外基质糖胺聚糖CD 44表达上调， 上皮细胞、嗜酸性粒细胞和T淋巴细胞上发现， 哮喘在支气管肺泡灌洗（BAL）中恢复的HA水平 哮喘患者的发病率也会增加，并且与疾病的严重程度相关。在 初步研究我们调查了CD 44在发展中的作用， 气道炎症和气道高反应性（AHR）在抗原致敏 小鼠CD 44缺乏对白细胞的募集没有影响， 产生抗原特异性IgE，但气道高反应性显著 与野生型同窝对照相比降低。此外，行政 野生型小鼠抗CD 44抗体抑制抗原诱导的气道 与正常大鼠IG处理的小鼠相比，的目标 拟议的研究是通过以下方式确定分子和细胞机制： 其中CD 44促进抗原诱导的AHR。我们提出以下具体建议： 目标：1.检验CD 44促进小鼠中抗原诱导的AHR的假设。 我们还将检验AHR和气道的发展 炎症与CD 44的功能性活化有关， 透明质酸的低分子量促炎片段的积聚 在老鼠和人类身上。2.确定CD 44表达的相对贡献 骨髓造血细胞与非造血细胞 实质细胞对AHR的影响，并确定可溶性CD 44在气道中的作用 炎症和AHR。我们将确定造血细胞上的CD 44 或在骨髓嵌合体中单独对非造血细胞的作用促进气道 炎症和AHR。可溶性CD 44对抗原诱导的细胞凋亡的贡献 还将测定气道炎症和AHR。为了确定 以及CD 44促进AHR和气道重塑的分子机制， 将：3）确定CD 44在矩阵组织中的作用; 4）测试 假设配体与CD 44的结合会影响 气道平滑肌细胞和上皮细胞通过激活NF-kB， Ras依赖性信号通路。由于CD 44在细胞凋亡中起着重要作用， 炎症和似乎促进AHR，但不需要正常的 白细胞循环，它是特别有吸引力的潜在目标， 哮喘的新型治疗干预。对细胞的理解 因此，CD 44促进AHR的分子机制可能提供 确定治疗干预的目标。