Hyperbaric oxygen mechanisms of protection in sepsis

高压氧对脓毒症的保护机制

• 批准号: 6769746
• 负责人: JON A BURAS
• 金额: $ 20.41万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6769746
• 关键词: antibiotics; bacteria infection mechanism; bactericidal immunity; cellular immunity; chemotaxis; combination therapy; cytoprotection; enzyme linked immunosorbent assay; flow cytometry; hyperbaric oxygen therapy; immunomodulators; inflammation; intubation; laboratory rat; leukocyte activation /transformation; lung injury; lymphocyte proliferation; microorganism disease chemotherapy; nonhuman therapy evaluation; peritoneum; phagocytosis; receptor expression; septicemia; therapy adverse effect; western blottings

DESCRIPTION (provided by applicant): Sepsis is a significant cause of morbidity and mortality due to limited therapeutic interventions currently available. Hyperbaric oxygen (HBO) is a possible adjunctive therapy for treatment of sepsis. However, due to limited pre-clinical and clinical research data available, there is significant resistance to using this therapy by many physicians. Rigorous pre-clinical study is required to overcome the existing medical bias towards HBO as an adjunctive disease therapy. Current research in sepis suggests that improvement in disease outcome may be mediated through limiting early apoptosis of lymphocytes, creating a cytokine environment stimulating an active vs anergic adaptive immune response, and limiting lung inflammation that may lead to lung organ failure. There are no pre-clinical studies addressing the effect of HBO on these currently described pathophysiologic processes important to the development of sepsis. Prior pre-clinical studies have suggested that HBO may be effective in treating sepsis, however, most studies employed disease models and HBO treatments that were not clinically relevant. Our overall hypothesis is that HBO therapy may induce favorable changes in host defenses during the development of sepsis via novel oxidant-dependent signaling mechanisms. Our specific aims are as follows: AIM I: To define the mechanisms by which HBO treatment improves outcome during the early phase of sepsis development. A. What is the mechanism of HBO action in promoting enhanced innate immune cell function during early sepsis? B. What is the mechanism of HBO in prevention of lymphocyte apoptosis during sepsis? C. What is the mechanism of HBO action in reducing lung inflammation development during sepsis? Results of such studies will provide background support for clinical studies of HBO and may change practitioner bias against this therapy. Results from these studies may also have implications for general cell biology by elucidating novel pathways of oxidant signaling at both the intracellular and intercellular level.

描述（由申请人提供）：由于当前可用的治疗干预措施有限，败血症是发病率和死亡率的重要原因。高压氧（HBO）是一种治疗败血症的辅助治疗。但是，由于可用的临床前和临床研究数据有限，因此许多医生使用这种疗法具有显着的抵抗力。需要严格的临床前研究来克服现有的对HBO的医学偏见作为辅助疾病疗法。当前在SEPIS中的研究表明，疾病结局的改善可以通过限制淋巴细胞的早期凋亡来介导，从而创建一个刺激活性V和抗厌取性适应性免疫反应的细胞因子环境，并限制肺部炎症，从而导致肺部器官衰竭。尚无临床前研究解决HBO对当前描述的对败血症发展重要的病理生理过程的影响。先前的临床前研究表明，HBO可能有效地治疗败血症，但是，大多数研究采用了与临床无关的疾病模型和HBO治疗。我们的总体假设是HBO治疗可能诱导 通过新颖的氧化剂依赖性信号传导机制在败血症发展过程中宿主防御的有利变化。我们的具体目的如下： 目的I：定义HBO治疗在早期阶段提高结果的机制 败血症的发展。 答：HBO作用在败血症早期促进先天免疫细胞功能方面的机制是什么？ B. HBO在败血症过程中预防淋巴细胞凋亡的机制是什么？ C. HBO作用在减少败血症过程中肺部炎症发育的机制是什么？ 此类研究的结果将为HBO的临床研究提供背景支持，并可能改变从业者对这种疗法的偏见。这些研究的结果也可能通过阐明细胞内和细胞间水平的氧化剂信号传导的新途径来对通用细胞生物学产生影响。