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

• 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
• 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

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.

项目总结/摘要 继发性水肿是一种常见而可怕的疾病，发生在接受各种治疗的患者中。 实体肿瘤的据估计，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继续发展为水肿。一旦疾病发展，通常 进行性并导致显著的功能障碍、复发性感染和生活质量下降。 目前的治疗是姑息性的，旨在治疗症状和预防进展，而不是治愈疾病。 潜在的解剖异常因此，开发这种疾病的新疗法是一个重要的问题。 目标. 最近的研究表明，辅助性T细胞2（Th2）分化的CD4+细胞的浸润是一个重要的， 通过调节纤维脂肪组织沉积，防止 侧支扩张，减少淋巴泵，并导致淋巴渗漏/功能障碍。然而，在这方面， 激活这些Th2炎症反应的细胞机制仍然未知。初步 研究发现，表皮可能在调节Th2炎症反应中起重要作用， 对水肿的反应。例如，我们发现Th2诱导细胞因子的表达- 已知在其他慢性皮肤病中协调Th2炎症的细胞因子-通过 单侧上肢水肿患者水肿组织中的角质形成细胞。我们有 还发现丝氨酸蛋白酶的表达是调节Th2诱导细胞因子的重要机制， 在其他皮肤疾病中的表达也增加。使用小鼠模型，我们发现表皮 变化，包括皮肤屏障蛋白和Th2诱导细胞因子的表达减少， Th2分化的CD4+细胞浸润。基于这些初步研究，以及病理生理学 其他Th2介导的慢性皮肤病，我们将测试的假设，受损的皮肤屏障功能， 皮肤pH调节淋巴损伤后角质形成细胞Th2诱导细胞因子的表达。我们 这项研究是创新性的，因为表皮的作用尚未阐明。我们知识上的差距 与表皮变化一样重要的是水肿中的显著发现。我们将测试我们的假设， 分析单侧乳腺癌患者的皮肤屏障功能、pH和Th2诱导细胞因子表达 癌症相关性水肿在其他研究中，我们将使用动物模型来分析细胞机制 调节表皮Th2诱导细胞因子表达的细胞因子，以及这些变化如何调节 水肿的病理生理学