Complement C5 inhibition as sepsis therapy

补体 C5 抑制作为脓毒症治疗

• 批准号: 10569623
• 负责人: FLOREA LUPU
• 金额: $ 63.34万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-09 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569623
• 关键词: Affect; Amplifiers; Anaphylatoxins; Animal Model; Animals; Antibiotics; Anticoagulants; Anticoagulation; Antimicrobial Effect; Aspartate Transaminase; Attenuated; Bacillus; Bacillus anthracis; Bacteremia; Bacteria; Basic Science; Biological Markers; Blood Circulation; Blood Coagulation Disorders; Blood Urea Nitrogen; C5a anaphylatoxin receptor; Cause of Death; Cell Death; Cessation of life; Coagulation Process; Combined Modality Therapy; Complement; Complement 3 Convertase; Complement 3b; Complement 5a; Complement Activation; Complement Membrane Attack Complex; Complement component C5; Complex; Contact Inhibition; Creatinine; Data; Development; Disease; Disease Progression; Early treatment; Escherichia; Escherichia coli; Functional disorder; Genus staphylococcus; Goals; Gram-Negative Bacteria; Hemolysis; Host Defense; Hour; Immune Tolerance; Immune response; Impairment; Individual; Infection; Inflammation; Inflammatory Response; Intensive Care Units; Kidney Failure; Lead; Lethal Dose 50; Life; Lipopolysaccharides; Mediating; Mediator; Modeling; Multiple Organ Failure; Myocardial dysfunction; Organ; Organ failure; Papio; Pathogenesis; Pathway interactions; Patients; Peptidoglycan; Phagocytosis; Plasma; Play; Prothrombin time assay; Recovery; Reperfusion Injury; Role; Sepsis; Septicemia; Shock; Signal Transduction; Staphylococcus aureus; Syndrome; System; Testing; Therapeutic; Thrombosis; Time; Tissues; Vascular Diseases; activation product; antagonist; clinically relevant; complement pathway; effective therapy; hypoperfusion; improved; improved outcome; inhibiting antibody; inhibitor; innovation; microbial; nonhuman primate; novel; novel therapeutics; pathogen; pre-clinical research; preservation; prevent; receptor; response; septic; septic patients; systemic inflammatory response; targeted treatment

PROJECT SUMMARY Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. Sepsis is a leading cause of death in intensive care units. The contact of pathogens with the intravascular compartment of the host leads to systemic inflammation, wherein activation of the complement and coagulation systems plays critical roles. The objectives of this proposal are to investigate the role of complement activation and its crosstalk with inflammation and coagulation to sepsis progression and multiple organ failure (MOF) and, whether blocking complement activation at the C5 level could prevent MOF and improve the outcome of sepsis. We will use clinically relevant models of sepsis caused by two of the most common pathogens, Escherichia coli and Staphylococcus aureus to: (i) determine the contribution of complement and coagulation to pathogenesis of microthrombosis, vascular dysfunction, organ failure and death; (ii) test stage-specific therapies targeting the complement and coagulation cascades to provide organ protection and survival benefit in sepsis-induced progressive MOF. Successful completion of these aims will determine: (i) whether timed complement inhibition at the C5 level could be used as an effective therapy for sepsis-induced MOF; (ii) if inhibition of C5a receptor-1 signaling could attenuate disease progression and provide organ protection; (iii) if combination therapies employing early treatment with an anticoagulant and a delayed treatment with a C5 inhibitor will provide synergistic protection in cases of high septic bacteremia/shock. Altogether, our project will combine basic and preclinical research to verify novel hypotheses on the pathophysiology of both Gram-negative and Gram-positive sepsis, and test innovative approaches, which in the long-term may save lives from this deadly disease with no specific cure.

项目概要 脓毒症是一种由宿主对感染反应失调引起的危及生命的器官功能障碍。败血症是一种 重症监护病房死亡的主要原因。病原体与血管内室的接触 宿主导致全身炎症，其中补体和凝血系统的激活发挥作用 关键角色。 该提案的目的是研究补体激活的作用及其与补体激活的串扰 炎症和凝血对脓毒症进展和多器官衰竭 (MOF) 的影响，以及是否阻断 C5 水平的补体激活可以预防 MOF 并改善脓毒症的结果。 我们将使用由两种最常见病原体大肠杆菌引起的脓毒症的临床相关模型 和金黄色葡萄球菌：(i) 确定补体和凝血对发病机制的贡献 微血栓形成、血管功能障碍、器官衰竭和死亡； (ii) 测试针对特定阶段的疗法 补体和凝血级联在脓毒症引起的情况下提供器官保护和生存益处 渐进式 MOF。 这些目标的成功完成将决定：(i) 是否在 C5 水平进行定时补体抑制 可作为脓毒症引起的 MOF 的有效治疗方法； (ii) 抑制 C5a 受体 1 信号传导是否可以 减缓疾病进展并提供器官保护； (iii) 如果早期采用联合疗法 抗凝剂治疗和 C5 抑制剂延迟治疗将提供协同保护 在严重败血症菌血症/休克的情况下。 总而言之，我们的项目将结合基础研究和临床前研究来验证关于 革兰氏阴性和革兰氏阳性脓毒症的病理生理学，并测试创新方法，其中 从长远来看，这种致命疾病可能会挽救生命，而没有具体的治疗方法。