Phosphodiesterases as Therapeutic Targets: Translational

磷酸二酯酶作为治疗靶点：转化

• 批准号: 7158516
• 负责人: VINCENT MANGANIELLO
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7158516
• 关键词: MHC class II antigen; alveolar macrophages; atorvastatin; chemokine; clinical research; cytokine; cytotoxic T lymphocyte; dendritic cells; drug screening /evaluation; flow cytometry; gene expression; helper T lymphocyte; human subject; immunomodulators; inflammation; interstitial lung diseases; lipopolysaccharides; lovastatin; phosphodiesterase inhibitors; phosphodiesterases; sarcoidosis; tissue /cell culture

Basic science studies: Statins act as pleiotropic immune modulators and have been reported to improve clinical outcomes in murine models of multiple sclerosis. Since the pathological formation of sarcoid granulomas is driven in part by highly polarized T helper (Th)-1 immune responses to unidentified infectious or environmental antigens, we evaluated effects of atorvastatin and mevastatin on (1) the expression of co-stimulatory and activation molecules on blood monocyte-derived human dendritic cells (DC) obtained from normal volunteers (NV); (2) differentiation of human naive Th1 lymphocytes; and, (3) production of Th1 cytokines and chemokines in alveolar macrophages from patients with pulmonary sarcoidosis. Effects of statins on the expression, by immature DC, of co-stimulatory and activation molecules in response to E.coli LPS 0128:B12 were assessed by flow cytometry. Incubation of DC with 50 micro M atorvastatin or mevastatin, between days 4 and 6 of culture, reduced the LPS(1 micro g/mL)-induced expression of CD86, CD83, CD80, and HLA-DR. In naive T-lymphocytes, purified from human umbilical cord blood and cultured under Th1 conditions, 1 micro M atorvastatin reduced the expression of CXCR3+ CD4+ T-lymphocytes. In alveolar macrophages from sarcoid patients (not on immunosuppressive medications), 30 micro M atorvastatin significantly inhibited the production of IP-10, Mig, MCP-1, MIP-1alpha;, and MIP-1Beta. At 10 micro M, atorvastatin also inhibited the production of IP-10 and MCP-1. Thus, statins, by decreasing the expression of co-stimulatory and activation molecules on dendritic cells, and by suppressing T-cell differentiation and chemokine production in alveolar macrophages, might have beneficial effects in patients with sarcoidosis.

基础科学研究：他汀类药物充当多效免疫调节剂，据报道可以改善多发性硬化症的鼠模型中的临床结果。由于结节性肉芽肿的病理形成部分是由高度极化的T助手（Th）-1对未识别的感染性或环境抗原的免疫反应驱动的，因此我们评估了阿托伐他汀和甲氟烷对（1）共刺激和激活分子表达的影响（1）从正常志愿者（NV）获得的血液单核细胞衍生的人树突状细胞（DC）上； （2）人类幼稚Th1淋巴细胞的分化； （3）肺结节病患者肺泡巨噬细胞中Th1细胞因子和趋化因子的产生。他汀类药物对响应E.Coli LPS 0128：B12的共刺激和激活分子对表达的影响，通过流式细胞仪评估。在培养的第4至6天之间，与50个微甲伐他汀或甲状腺素的50个微伴原蛋白或Mevastatin一起孵育，降低了LPS（1 micro G/ml）诱导的CD86，CD83，CD80和HLA-DR的表达。在天真的T淋巴细胞中，从人的脐带血纯化并在TH1条件下培养，1微米曲伐他汀降低了CXCR3+ CD4+ T淋巴细胞的表达。在结节患者的肺泡巨噬细胞中（不接受免疫抑制药物），30个微瘤蛋白显着抑制IP-10，MIG，MCP-1，MIP-1Alpha； MIP-1Beta的产生。在10微米时，阿托伐他汀也抑制了IP-10和MCP-1的产生。因此，他汀类药物通过降低树突状细胞上的共刺激性和激活分子的表达，并抑制肺泡巨噬细胞中T细胞分化和趋化因子的产生，可能对结节病患者产生有益的作用。