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，因为 未能充分消除空隙纤维性组织或由于 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，旨在促进回归或 消除腔隙纤维组织作为一种新的治疗方法 ARDS患者的治疗可能有效。初步研究表明 在修复阶段及时使用皮质类固醇进行干预 急性呼吸窘迫综合征可能加速空域纤维化的消退并改善患者 生死存亡。不幸的是，皮质类固醇在这一患者群体中的使用是 潜在危险，因为危及生命的风险增加 感染。然而，这些研究为战略提供了可信度。 旨在促进空隙纤维化的消退作为一种新的治疗方法 晚期ARDS患者的治疗途径。我们发现 细胞表面基质受体CD44介导肺成纤维细胞 侵入纤维蛋白层。肺组织的免疫组织化学研究 从死于肺泡纤维化的患者身上显示CD44表达 新形成的纤维组织中的间充质细胞连接CD44和 肝纤维化反应与CD44与抗CD44抗体的关系 肺肌成纤维细胞凋亡。这表明，肌动蛋白的连接状态 CD44可能在成纤维细胞活性调节中发挥作用。我们有 显示成纤维细胞的凋亡在一定程度上导致了，但不仅仅是 脱离表明抗CD44抗体触发了另一种亲和力 细胞凋亡信号。研究已将细胞凋亡与细胞周期中断联系起来 黏附与细胞周期蛋白A升高和细胞周期蛋白活化的关系 细胞周期蛋白A依赖的激酶。我们实验室的工作表明 CD44与抗体的结合与两种周期蛋白的增加相关 A和p21。初步研究表明，实验性的下调 细胞周期蛋白A和p21的表达显著减弱抗CD44抗体诱导的 细胞凋亡识别了这些蛋白的重要功能。在……里面 我们的竞争更新，我们计划检查分子基础， 抗CD44抗体诱导成纤维细胞凋亡。如何结扎的发现 CD44参与成纤维细胞的凋亡途径可能为深入了解 促进空隙退缩的治疗剂的研究进展 未能从ARDS中恢复的患者的纤维化。

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.