Role of epidermis in regulating inflammatory skin manifestations of post-surgical lymphedema

表皮在调节术后淋巴水肿炎症性皮肤表现中的作用

基本信息

批准号：
10606927
负责人：
Babak J Mehrara
金额：
$ 23.36万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-21 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10606927
关键词：
Acidity Alkalinization American Animal Model Antibiotics Atopic Dermatitis Biopsy CD4 Positive T Lymphocytes Cells Chronic Clinical Deformity Deposition Dermis Developed Countries Development Disease Disease Progression Epidermis Functional disorder Goals Gynecologic High Prevalence Histologic Hospitalization Immune response Impairment Infectious Skin Diseases Infiltration Inflammation Inflammatory Inflammatory Response Injury Intravenous Kininogenase Knowledge Lymphatic Lymphedema Mediating Mediator Methods Mus Outcome PAR-2 Receptor Pain Palliative Care Pathologic Pathology Pathway interactions Patients Peptide Hydrolases Pharmaceutical Preparations Phase I Clinical Trials Physical therapy Play Positioning Attribute Pre-Clinical Model Prevention Proteins Quality of life Reaction Recurrence Risk Role Serine Protease Serine Proteinase Inhibitors Severity of illness Signal Pathway Skin Skin Abnormalities Skin Manifestations Solid Neoplasm Stains Stratum corneum Surgical complication Swelling T-Lymphocyte TSLP gene Testing Tissues Upper Extremity Urologic Cancer breast surgery cancer complication cancer therapy chronic inflammatory skin cytokine effective therapy functional disability iatrogenic injury improved inhibiting antibody innovation keratinocyte laboratory experience loss of function lymphatic pump lymphatic vessel malignant breast neoplasm melanoma mouse model novel palliative prevent recurrent infection reduce symptoms response sarcoma secondary lymphedema skin barrier skin disorder symptom treatment tumor urologic

项目摘要

PROJECT SUMMARY/ABSTRACT Secondary lymphedema is a common and dreaded disease that occurs in patients treated for a variety of solid tumors. An estimated 20–40% of Americans treated surgically for breast cancer, melanoma, gynecological or urologic tumors go on to develop lymphedema. Once the disease develops, it is usually progressive and causes significant functional impairment, recurrent infections, and decreased quality of life. Current treatments are palliative, aiming to treat symptoms and prevent progression rather than cure the underlying anatomic abnormalities. Thus, development of novel treatments for this disease is an important goal. Recent studies have shown that infiltration of T helper 2 (Th2)-differentiated CD4+ cells is an important mediator of lymphedema development by regulating fibroadipose tissue deposition, preventing formation of collateral lymphatics, decreasing lymphatic pumping, and causing lymphatic leakiness/dysfunction. However, the cellular mechanisms that activate these Th2 inflammatory responses remain unknown. In preliminary studies, we have found that the epidermis may play an important role in regulating Th2 inflammatory responses in lymphedema. For example, we have found that the expression of Th2-inducing cytokines— cytokines known to coordinate Th2 inflammation in other chronic skin disorders—is significantly increased by keratinocytes in lymphedematous tissues of patients with unilateral upper extremity lymphedema. We have also found that the expression of serine proteases, an important mechanism regulating Th2-inducing cytokine expression in other skin disorders, is also increased. Using mouse models, we have found that epidermal changes, including decreased expression of skin barrier proteins and of Th2-inducing cytokines, precedes infiltration of Th2 differentiated CD4+ cells. Based on these preliminary studies, as well as the pathophysiology of other Th2-mediated chronic skin disorders, we will test the hypothesis that impaired skin barrier function and skin pH regulate the expression of Th2-inducing cytokines by keratinocytes following lymphatic injury. Our study is innovative because the role of the epidermis has not been elucidated. This gap in our knowledge is important as epidermal changes are a prominent finding in lymphedema. We will test our hypothesis by analyzing skin barrier function, pH, and Th2-inducing cytokine expression in patients with unilateral breast cancer-related lymphedema. In other studies, we will use animal models to analyze the cellular mechanisms that regulate epidermal Th2-inducing cytokine expression and how these changes regulate the pathophysiology of lymphedema.

项目概要/摘要继发性淋巴水肿是一种常见且可怕的疾病，发生在接受各种治疗的患者中据估计，有 20-40% 的美国人接受了乳腺癌、黑色素瘤、妇科或泌尿系统肿瘤一旦发展，通常会出现淋巴水肿。进行性并导致严重的功能障碍、反复感染和生活质量下降。目前的治疗是姑息性的，旨在治疗症状并预防进展，而不是治愈疾病因此，开发针对这种疾病的新疗法非常重要。目标。最近的研究表明，辅助 T 2 (Th2) 分化的 CD4+ 细胞的浸润是一个重要的因素。通过调节纤维脂肪组织沉积，防止形成淋巴水肿发展的介质侧支淋巴管，减少淋巴泵，并导致淋巴漏/功能障碍。激活这些 Th2 炎症反应的细胞机制目前仍不清楚。研究发现，表皮可能在调节Th2炎症中发挥重要作用例如，我们发现 Th2 诱导细胞因子的表达—— 已知可协调其他慢性皮肤病中 Th2 炎症的细胞因子——显着增加单侧上肢淋巴水肿患者淋巴水肿组织中的角质形成细胞。还发现丝氨酸蛋白酶的表达，这是调节 Th2 诱导细胞因子的重要机制使用小鼠模型，我们发现表皮中的表达也增加。变化，包括皮肤屏障蛋白和 Th2 诱导细胞因子表达减少，先于基于这些初步研究以及病理生理学，Th2 分化的 CD4+ 细胞的浸润。对于其他 Th2 介导的慢性皮肤病，我们将检验皮肤屏障功能受损和皮肤 pH 值可调节淋巴损伤后角质形成细胞的 Th2 诱导细胞因子的表达。这项研究具有创新性，因为我们的知识空白尚未阐明。重要的是，表皮变化是淋巴水肿的一个突出发现，我们将通过以下方式检验我们的假设。分析单侧乳房患者的皮肤屏障功能、pH 值和 Th2 诱导细胞因子表达在其他研究中，我们将使用动物模型来分析细胞机制。调节表皮 Th2 诱导细胞因子的表达以及这些变化如何调节淋巴水肿的病理生理学。