Mechanisms of fibrosis and lymphatic dysfunction in post-surgical lymphedema

描述（由申请人提供）：淋巴水肿是组织中富含蛋白质的液体的积聚，在美国，最常见的是癌症治疗的手术并发症。尽管有3-5百万美国人患有水肿，但其病因尚不清楚，治疗仍然是姑息性的。根据我们的实验室数据以及水肿的临床表现，我们假设水肿的病理学继发于进行性纤维化，并由慢性T辅助细胞（CD 4+）炎症介导。本提案的目的是确定淋巴液淤滞如何导致组织纤维化和淋巴功能障碍。我们的长期目标是通过破坏停滞、纤维化和淋巴功能障碍的循环来开发治疗或预防水肿的疗法。这种方法是创新的，因为先前的努力试图通过使用细胞因子增强淋巴修复和再生来治疗水肿。然而，这些细胞因子也可引起肿瘤转移或复发，从而限制了该方法在癌症患者中的适用性。这项建议是 相关，因为水肿是癌症治疗的常见和病态并发症，对于其没有经证实的预防方法，并且治疗是姑息性的。我们计划通过三个具体目标来实现我们的目标。目的1：确定促纤维化细胞因子的细胞来源。这一目的将使用转基因小鼠、抗体耗竭和小鼠尾和腋窝解剖模型中的过继转移实验来检验工作假设，即CD 4 + T细胞是促纤维化细胞因子的主要来源。目的2：确定促纤维化细胞因子的表达是如何调节的。这一目的将测试工作假设，即淋巴停滞导致Th 2细胞炎症和IL 4和IL 13表达，并且这些细胞因子相互作用导致纤维化和淋巴功能障碍。我们将使用来自内科或外科治疗前后的水肿患者的临床标本以及我们的小鼠尾模型。目的3：确定促纤维化细胞因子如何调节淋巴功能和纤维化。这一目的将测试工作假设，即继发于纤维化的淋巴功能受损是T细胞和Th 2细胞因子对淋巴系统的间接作用的结果，而不是淋巴管生成细胞因子表达的下调。

DESCRIPTION (provided by applicant): Lymphedema is the accumulation of protein rich fluid in tissues, and in the US, occurs most commonly as a surgical complication of cancer treatment. Despite the fact that 3-5 million Americans suffer from lymphedema, its etiology is unknown and treatment remains palliative. Based on our laboratory data as well as the clinical presentation of lymphedema we hypothesize that the pathology of lymphedema is secondary to progressive fibrosis and is mediated by chronic T-helper (CD4+) cell inflammation. The objective of this proposal is to determine how lymphatic fluid stasis causes tissue fibrosis and lymphatic dysfunction. Our long-term objective is to develop therapies to treat or prevent lymphedema by disrupting the cycle of stasis, fibrosis, and lymphatic dysfunction. This approach is innovative since previous efforts have attempted to treat lymphedema by augmenting lymphatic repair and regeneration using cytokines. These cytokines, however, can also cause tumor metastasis or recurrence thereby limiting the applicability of this approach in cancer patients. This proposal is relevant since lymphedema is a common and morbid complication of cancer treatment for which there is no proven preventative methods and treatment is palliative. We plan to achieve our objectives using 3 specific aims. Aim 1: Determine the cellular sources of profibrotic cytokines. This aim will test the working hypothesis that CD4+ T-cells are the primary source of profibrotic cytokines using transgenic mice, antibody depletion, and adoptive transfer experiments in a mouse-tail and axillary dissection model. Aim 2: Determine how the expression of profibrotic cytokines is regulated. This aim will test the working hypothesis is that lymphatic stasis causes Th2 cell inflammation and IL4 and IL13 expression and that these cytokines interact to cause fibrosis and lymphatic dysfunction. We will use clinical specimens from patients with lymphedema before and after medical or surgical treatment as well as our mouse tail model. Aim 3: Determine how profibrotic cytokines regulate lymphatic function and fibrosis. This aim will test the working hypothesis that impaired lymphatic function secondary to fibrosis is a consequence of indirect effects of T-cells and Th2 cytokines on the lymphatic system rather than down-regulation of lymphangiogenic cytokine expression.