Modulating Nrf2-Reguated GSH Production to Prevent Hospital-Acquired Infections

调节 Nrf2 调节的 GSH 产生以预防医院获得性感染

• 批准号: 8777761
• 负责人: Yusen Liu
• 金额: $ 18.61万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8777761
• 关键词: Accounting; Animals; Anti-Bacterial Agents; Antioxidants; Bacteremia; Bacteria; Bacterial Infections; Blood; Blood Circulation; Bone Marrow; Catalytic Domain; Cessation of life; Critical Illness; Cytosol; Death Rate; Defect; Development; Embryo; Enzymes; Escherichia coli; Exhibits; Failure; Functional disorder; Genes; Glutamate-Cysteine Ligase; Glutathione; Glutathione Disulfide; Glutathione Reductase; Goals; Health system; Histology; Hospitals; Host Defense; Immune; Immunity; Immunosuppression; In Vitro; Infection; Inflammation; Inflammatory Response; Intensive Care Units; Investigation; Knock-out; Knockout Mice; Laboratories; Lead; Leukocytes; Ligase; LoxP-flanked allele; Mediating; Morbidity - disease rate; Multi-Drug Resistance; Mus; Mutant Strains Mice; Myelogenous; Natural regeneration; Nosocomial Infections; Organ; Organism; Outcome; Oxidative Stress; Pathway interactions; Patients; Phagocytosis; Pharmaceutical Preparations; Pneumonia; Pre-Clinical Model; Predisposition; Prevention; Process; Production; Prophylactic treatment; Reduced Glutathione; Regulation; Respiratory Burst; Role; Staphylococcus aureus; Streptococcus Group B; System; Testing; Therapeutic; Urinary tract infection; Ventilator; animal mortality; bactericide; cost; cytokine; efficacy testing; fighting; improved; in vivo; killings; mortality; neonatal sepsis; neutrophil; novel therapeutic intervention; novel therapeutics; oxidative damage; pathogen; prevent; public health relevance; recombinase; response; transcription factor

DESCRIPTION (provided by applicant): Hospital-acquired infections are a major cause of mortality and morbidity in intensive care units, and critically ill patients are particularly susceptible to bacterial infections due to immunosuppression. Since an increasingly greater portion of the hospital-acquired infections are caused by multidrug-resistant organisms, new therapeutic approaches are needed to prevent and treat bacterial infections in intensive care units. Our long- term goal is to develop an effective therapeutic strategy to overcome immunosuppression in critically ill patients through bolstering the bactericidal activity of neutrophils. Critically ill patients often display increased oxidative stress and have decreased levels of glutathione (GSH), a major intracellular antioxidant. GSH is generated through two pathways: de novo synthesis and regeneration from oxidized glutathione (GSSG). Recent studies in our laboratory demonstrated that mice lacking glutathione reductase (Gsr), which catalyzes GSH regeneration from GSSG, are highly vulnerable to infection by several bacterial species associated with hospital-acquired infections, as indicated by high rates of death, severe organ damage, and enhanced inflammation. The underlying cause of the increased vulnerability to bacterial infection is the failure to kill the infecting organism. In the absence of Gsr, neutrophils, the primary white blood cells responsible for bacterial eradication, cannot efficientl ingest and kill the infecting bacteria, likely due to excessive oxidative damage to the neutrophils themselves. Our studies indicate that GSH regeneration is pivotal for neutrophil-mediated host defense, raising the intriguing question of whether excessive oxidative stress is itself responsible for the immunosuppression seen in critically ill patients. Our findings strongly suggest that de novo GSH synthesis will be crucial for an effective immune defense against bacterial pathogens, since Gsr activity depends on de novo GSH synthesis, i.e. without GSH there can be no GSSG. The rate-limiting step in de novo GSH synthesis is glutamate-cysteine ligase, which consists of a catalytic subunit (Gclc) and a modulatory subunit (Gclm). The transcription factor Nrf2 regulates the expression of Gsr, Gclm, and Gclc, and thus Nrf2 modulates both de novo GSH synthesis and GSH regeneration from GSSG. The central hypothesis of our proposal is that the GSH antioxidant system modulated by Nrf2 facilitates host defense by maintaining bactericidal activity in neutrophils. The objectives of this proposal are to determine the role of GSH in neutrophil-mediated host defense and to assess the efficacy of Nrf2 activation as an approach to enhance host defense. The specific aims of this R21 proposal are to define the functions of the two GSH-generating pathways in anti-bacterial immune defense (Aim 1), and to evaluate the efficacy of Nrf2 activation as a therapeutic strategy to bolster neutrophil bactericidal activity (Aim 2). Our studies will elucidate a potential mechanism underlying immunosuppression in critically ill patients. Our studies will also facilitate the development of novel therapeutic drugs for the prevention and treatment of hospital-acquired infections in intensive care units.

描述（由申请人提供）：医院获得性感染是重症监护病房死亡和发病的主要原因，危重病人由于免疫抑制特别容易受到细菌感染。由于越来越多的医院获得性感染是由耐多药生物体引起的，因此需要新的治疗方法来预防和治疗重症监护病房中的细菌感染。我们的长期目标是开发一种有效的治疗策略，通过增强中性粒细胞的杀菌活性来克服危重病人的免疫抑制。危重病人经常表现出氧化应激增加，谷胱甘肽（GSH）水平下降，这是一种主要的细胞内抗氧化剂。谷胱甘肽通过两种途径产生：从头合成和氧化谷胱甘肽（GSSG）再生。我们实验室最近的研究表明，缺乏谷胱甘肽还原酶（Gsr）的小鼠极易受到与医院获得性感染相关的几种细菌的感染，这表明死亡率高，器官严重受损，炎症加剧。谷胱甘肽还原酶能催化GSH从GSSG再生。对细菌感染的脆弱性增加的根本原因是未能杀死感染的生物体。在缺乏Gsr的情况下，中性粒细胞，主要负责消灭细菌的白细胞，不能有效地摄取和杀死感染细菌，可能是由于中性粒细胞过度氧化损伤