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累，在美国，最常作为癌症治疗的手术并发症发生。尽管有3-5百万美国人患有淋巴水肿，但其病因尚不清楚，治疗方法也只能姑息治疗。根据我们的实验室数据以及淋巴水肿的临床表现，我们假设淋巴水肿的病理是继发于进行性纤维化，并由慢性t辅助（CD4+）细胞炎症介导。本建议的目的是确定淋巴液淤积如何引起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淋巴水肿的疗法。这种方法是创新的，因为以前的努力试图通过使用细胞因子增加淋巴修复和再生来治疗淋巴水肿。然而，这些细胞因子也可能导致肿瘤转移或复发，从而限制了这种方法在癌症患者中的适用性。这个建议是

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.