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β-（1,3）（1,6）链接中的一类长链葡萄糖聚合物。在真菌的细胞壁以及蘑菇，藻类，较高植物和某些细菌中发现了β-葡聚糖，但在哺乳动物细胞中未发现，被认为是病原体相关的分子模式（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。但是，从理论上讲，启动免疫细胞功能可能具有临床益处，但是，它通常导致促炎性细胞因子的过量生产可能对患者产生有害后果。由酿酒酵母制备的可溶性，高度纯化的β-葡聚糖PGG葡聚糖已被证明是促抗菌功能的主要抗菌功能，包括增加氧化爆发反应，微生物活性和白细胞的趋化性，而无需刺激促炎性疾病的产生。进行了先前的体外研究，以确定缺乏细胞因子的产生是由于抑制机制引起的。这些研究表明，β-葡聚糖预处理导致LPS诱导的TNF消息的衰减，LPS诱导的TNF蛋白产生的减少以及LPS诱导的NF-KAPPA B介导的转录的衰减。 β-葡聚糖预处理还显示可减轻LPS诱导的体内血清TNF产生。在临床前和临床试验中已经评估了β-葡聚糖的预防作用，但是，尚不清楚PGG-beta-glucan在给予患者或已经感染的患者时是否有益。该提案中描述的研究旨在研究β-葡聚糖对化粪池小鼠的影响。具体目的是：1）确定PGG-beta-glucan对小鼠对多因素性脓毒症的宿主反应的影响，使用包括预防性给药的治疗方案，2）2）确定PGG-β-葡聚糖对使用治疗方案的PGG-BETASERSERSTERS PGGE-BETA-BETA-BETA-GLUCANE的影响PGG-BETA-GLUCAN对小鼠对小鼠对pgemicial sepsis的死亡的影响。 β-葡聚糖作为具有可忽略的副作用的治疗剂的潜在发展可以帮助免疫功能低下的患者，包括接受化学疗法的患者以及患有不受控制的炎症患者。