Effect of beta-glucan on sepsis

β-葡聚糖对脓毒症的作用

• 批准号: 7796750
• 负责人: Courtni Takiyah Newsome
• 金额: $ 2.14万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796750
• 关键词: Adverse effects; Agaricales; Algae; Animals; Attenuated; Bacteria; Cell Wall; Cell physiology; Cells; Cessation of life; Characteristics; Clinical; Clinical Research; Clinical Trials; Colorectal; Development; Disease; Generations; Genetic Transcription; Glucans; Host Defense; Immune; Immune response; Immune system; Immunocompromised Host; In Vitro; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Injury; Intensive Care Units; Interleukin-1 beta; Laboratories; Leukocyte Chemotaxis; Leukocytes; Ligation; Literature; Mammalian Cell; Mediating; Mediator of activation protein; Molecular; Morbidity - disease rate; Mus; NF-kappa B; Operative Surgical Procedures; Organ failure; Patients; Pattern; Pharmaceutical Preparations; Phase III Clinical Trials; Postoperative Period; Preparation; Production; Property; Proteins; Puncture procedure; Radiation therapy; Randomized; Reactive Oxygen Species; Reporting; Respiratory Burst; Saccharomyces cerevisiae; Sepsis; Serum; TNF gene; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Treatment Protocols; Tumor Necrosis Factor-alpha; Vascular Plant; antimicrobial; apoptosis in lymphocytes; attenuation; beta-Glucans; chemotherapy; clinically relevant; cytokine; design; fungus; human TNF protein; improved; in vivo; macrophage; microbicide; mortality; neutrophil; overexpression; pathogen; poly-1-6-glucopyranosyl-1-3-glucopyranose glucan; pre-clinical; prophylactic; research study; response; septic; theories; tumor

DESCRIPTION (provided by applicant): Beta-glucan is a class of long-chain glucose polymers in beta-(1,3)(1,6) linkage. Beta-glucans are found in the cell wall of fungi, as well as in mushrooms, algae, higher plants, and some bacteria but are not found in mammalian cells and are considered a pathogen-associated molecular pattern (PAMP). Beta-glucans have been shown to have several immunological effects and can stimulate cells of the innate immune system. Priming immune cell function can be of clinical benefit in theory, however, it often results in the overproduction of pro-inflammatory cytokines that may have detrimental consequences to the patient. The soluble, highly purified beta-glucan PGG glucan, which was prepared from Saccharomyces cerevisiae, has been shown to prime antimicrobial functions, including increasing the oxidative burst response, microbicidal activity, and the chemotaxis of leukocytes, without stimulating the production of pro-inflammatory cytokines. Previous in vitro studies were conducted to determine whether this absence of cytokine production is due to a suppressor mechanism. These studies have shown that beta-glucan pretreatment results in attenuation of LPS-induced TNF message, diminishment of LPS-induced TNF protein production, and attenuation of LPS- induced NF- kappa B mediated transcription. Beta-glucan pretreatment was also shown to attenuate LPS- induced serum TNF production in vivo . The prophylactic effects of beta-glucan have been evaluated in preclinical and clinical trials, however, it is unknown if PGG-beta-glucan can be beneficial when given to a patient or an experimental animal that is already infected. Studies described in this proposal are designed to investigate the effects of beta-glucan in septic mice. The specific aims are:1)To determine the effects of PGG-beta-glucan on the host response of mice to polymicrobial sepsis using treatment protocols that includes prophylactic administration, 2) To determine the effects of PGG-beta-glucan on the mortality of mice to polymicrobial sepsis using treatment protocols that administers PGG-beta-glucan to mice only after the onset of infection. The potential development of beta-glucan as a therapeutic agent with negligible side effects could aid immunocompromised patients, including those undergoing chemotherapy and those with uncontrolled inflammation.

描述（由申请人提供）：β-葡聚糖是一类以β-(1,3)(1,6)键连接的长链葡萄糖聚合物。 β-葡聚糖存在于真菌、蘑菇、藻类、高等植物和一些细菌的细胞壁中，但在哺乳动物细胞中未发现，被认为是病原体相关分子模式 (PAMP)。 β-葡聚糖已被证明具有多种免疫作用，可以刺激先天免疫系统的细胞。理论上，启动免疫细胞功能可能具有临床益处，然而，它通常会导致促炎细胞因子的过量产生，从而可能对患者产生不利后果。可溶性、高度纯化的 β-葡聚糖 PGG 葡聚糖是从酿酒酵母中制备的，已被证明具有启动抗菌功能，包括增加氧化爆发反应、杀菌活性和白细胞的趋化性，而不刺激促炎物质的产生。细胞因子。之前进行的体外研究是为了确定细胞因子产生的缺失是否是由于抑制机制所致。这些研究表明，β-葡聚糖预处理导致 LPS 诱导的 TNF 信息减弱、LPS 诱导的 TNF 蛋白产生减少以及 LPS 诱导的 NF-κ B 介导的转录减弱。 β-葡聚糖预处理也被证明可以减弱 LPS 诱导的体内血清 TNF 的产生。 β-葡聚糖的预防作用已在临床前和临床试验中得到评估，然而，尚不清楚将 PGG-β-葡聚糖给予已感染的患者或实验动物是否有益。该提案中描述的研究旨在研究 β-葡聚糖对脓毒症小鼠的影响。具体目标是：1) 确定 PGG-β-葡聚糖对使用包括预防性给药在内的治疗方案的小鼠对多种微生物败血症的宿主反应的影响，2) 确定 PGG-β-葡聚糖对小鼠死亡率的影响使用仅在感染发作后才向小鼠施用 PGG-β-葡聚糖的治疗方案，对小鼠进行多种微生物败血症的治疗。 β-葡聚糖作为副作用可忽略不计的治疗剂的潜在发展可以帮助免疫功能低下的患者，包括正在接受化疗的患者和炎症不受控制的患者。