Effects of Therapeutic Recombinant Granulocyte Colony Stimulating Factor

治疗性重组粒细胞集落刺激因子的作用

• 批准号: 6227873
• 负责人: Peter Q Eichacker
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6227873
• 关键词: bacterial disease; colony stimulating factor; dogs; granulocyte; immunosuppression; leukocyte activation /transformation; leukocyte count; microorganism disease chemotherapy; nonhuman therapy evaluation; peritonitis; recombinant proteins

The Effects of Therapeutic Recombinant Granulocyte Colony Stimulating Factor with Intraperitoneal E. Recombinant granulocyte colony stimulating factor (G-CSF) increases circulating neutrophil number and function. Administration of G-CSF improves host defense and decreases morbidity associated with infection in immunocompromised patients and animal models. It is unclear whether therapeutic administration of G- CSF will have benefi-cial or harmful effects in immunocompetent patients at risk of or developing infection. We have shown that G-CSF pretreatment in a canine model of lethal bacterial peritonitis increases circulating neutrophil numbers, accelerates bacteria and endotoxin clearance and improves cardiovascular function and survival. In a subsequent set of studies, we evaluated the effects of G-CSF administered therapeutically at the onset of bacterial sepsis rather than prophylactically. In these studies we found that therapeutic G-CSF even if given at very high dosages did not result in increased circulating neutrophil numbers during the septic period and did not offer a protective advantage. These findings suggest that sepsis associated events may either directly inhibit the stimulatory effects of exogenous G-CSF, or alternatively result in a maximal inflammatory response by the host which is insensitive to the effects of exogenous G-CSF. These studies suggest that therapeutic administration of G-CSF in patients presenting with lethal bacterial sepsis may have little benefit.

腹腔注射重组粒细胞集落刺激因子e治疗性重组粒细胞集落刺激因子（G-CSF）可增加循环中性粒细胞数量和功能。在免疫功能低下患者和动物模型中，给予G-CSF可改善宿主防御并降低与感染相关的发病率。目前尚不清楚G- CSF的治疗性给药对有感染或发展感染风险的免疫功能正常的患者是否有益或有害。我们已经证明，在致死性细菌性腹膜炎犬模型中，G-CSF预处理可以增加循环中性粒细胞数量，加速细菌和内毒素的清除，改善心血管功能和生存率。在随后的一组研究中，我们评估了在细菌性脓毒症发病时给予G-CSF治疗而不是预防的效果。在这些研究中，我们发现，即使给予非常高剂量的治疗性G-CSF，也不会导致脓毒症期间循环中性粒细胞数量的增加，也不会提供保护优势。这些发现表明，脓毒症相关事件可能直接抑制外源性G-CSF的刺激作用，或者导致宿主对外源性G-CSF的影响不敏感的最大炎症反应。这些研究表明，对致死性细菌性败血症患者给予G-CSF治疗可能没有什么益处。