MECHANISM OF INDUCTION OF FIBROBLAST APOPTOSIS BY ANTICD44 ANTIBODY

肺泡内纤维化是肺损伤的典型反应。 然而，在许多患者中，这种修复过程是无效的， 未能充分消除气腔纤维化组织或由于 进行性纤维化进行性肺泡纤维化是直接和 间接导致ARDS患者死亡的主要原因之一。 因此，旨在促进退化或 消除空气空间纤维化组织作为一种新的方法， 治疗ARDS患者可能有效。试点研究表明， 在修复阶段及时使用皮质类固醇， ARDS可加速气道纤维化的消退， 生存不幸的是，皮质类固醇在这一患者群体中的使用 由于危及生命的风险增加， 感染尽管如此，这些研究还是让人相信 作为一种新的治疗方法， 晚期ARDS患者的治疗方法。我们已经发现 细胞表面基质受体CD 44介导肺肌成纤维细胞 侵入纤维蛋白基质。肺组织的免疫组织化学研究 死于肺泡纤维化的患者显示CD 44表达 新形成的纤维化组织中的间充质细胞将CD 44与 纤维化反应和涉及CD 44与抗CD 44抗体触发 肺肌成纤维细胞凋亡这表明， CD 44可能在成纤维细胞活力的调节中起作用。我们有 显示成纤维细胞凋亡部分但不完全由 分离，表明抗CD 44抗体触发了额外的亲- 凋亡信号研究表明，细胞凋亡是由于 粘附与细胞周期蛋白A的升高和细胞周期蛋白A的激活有关。 细胞周期蛋白A依赖性激酶。我们实验室的工作表明， CD 44与抗体的连接与两种细胞周期蛋白的增加有关。 A和P21。初步研究表明，实验性下调 细胞周期蛋白A和p21显著减弱抗CD 44抗体诱导的 细胞凋亡鉴定这些蛋白质的重要功能作用。在 我们的竞争更新，我们计划检查的分子基础， 抗CD 44抗体诱导成纤维细胞凋亡。发现如何结扎 CD 44参与成纤维细胞凋亡途径可能提供洞察力， 促进空域回归的治疗剂的开发 纤维化患者无法从ARDS中恢复。

Intraalveolar fibrosis is a stereotypical reaction to lung injury. However, in many patients this reparative process is ineffective due to failure to adequately eliminate airspace fibrotic tissue or due to progressive fibrosis. Progressive alveolar fibrosis is directly and indirectly one of the leading causes of death in patients with ARDS. Therefore, therapeutic strategies designed to promote regression or elimination of airspace fibrotic tissue as a novel approach for the treatment of patients with ARDS may be effective. Pilot studies suggest that timely intervention with corticosteroids during the repair phase of ARDS may hasten resolution of airspace fibrosis and improve patient survival. Unfortunately, corticosteroid use in this patient population is potentially hazardous due to the increased risk of life-threatening infection. Nevertheless, these studies lend credence to strategies designed to promote regression of airspace fibrosis as a novel therapeutic approach for the treatment of patients with late ARDS. We have discovered that the cell surface matrix receptor, CD44, mediates lung myofibroblast invasion into fibrin matices. Immunohistochemical studies of lung tissue from patients who died with alveolar fibrosis show CD44 expressing mesenchymal cells in newly formed fibrotic tissue linking CD44 with the fibrotic response and implicating CD44 with anti-CD44 antibody triggers lung myofibroblast apoptosis. This suggests that the ligation state of CD44 may play a role in the regulation of fibroblast viability. We have shown that fibroblast apoptosis results in part, but not solely from detachment indicating that anti-CD44 antibody triggers an additional pro- apoptotic signal. Studies have linked apoptosis due to disruption of adhesion with increases in the elevation of cyclin A and activation of cyclin A dependent kinases. Work within our laboratory indicates that ligation of CD44 with antibody is associated with increases in both cyclin A and p21. Preliminary studies indicate that experimental down-regulation of cyclin A and p21 markedly attenuates anti-CD44 antibody induced apoptosis identifying an important functional role for these proteins. In our competing renewal, we plan to examine the molecular basis by which anti-CD44 antibody induces fibroblast apoptosis. Discovery of how ligation of CD44 engages the fibroblast apoptotic pathway may provide insight into the development of therapeutic agents which promote regression of airspace fibrosis in patients failing to recover from ARDS.