Influence Of Systemic Inflammation On The Effects Of Rec

全身炎症对 Rec 效果的影响

• 批准号: 6546515
• 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/6546515
• 关键词: Escherichia coli infections; bacteria infection mechanism; bacterial disease; blood toxicology; colony stimulating factor; endotoxins; immunohematology; inflammation; injury /disease stressor; laboratory rat; neutrophil; phagocytosis; tumor necrosis factor alpha

Preclinical and clinical studies showed that treatment with recombinant granulocyte colony stimulating factor (G-CSF) could improve host defense and reduce the risk of infection and sepsis in neutropenic patients. Preclinical studies suggested that treatment with G-CSF might also be beneficial during sepsis in the immunocompetent host. Despite these findings, G-CSF in early studies has not been beneficial in nonneutropenic patients with sepsis. Possibly consistent with this clinical experience, we found in a series of canine studies, that G-CSF treatment had variable effects with E. coli bacteria challenges at differing sites and in differing dosages. To better determine the influence of these two factors on the effects of G-CSF we developed a rat model of sepsis incorporating a multifactorial study design which permits simultaneous assessment of multiple variables. In these studies, with intravenous E. coli challenge, G-CSF increased lethality at all bacterial dosages. However, with intrabronchial and intraperitoneal challenge, G-CSF improved survival with low and high bacterial dosages, but appeared harmful with an intermediate dose. Laboratory investigations suggest that the variable effects of G-CSF on outcome in this study are related in part to its ability to increase circulating neutrophil numbers and the clearance of microbial and host inflammatory mediators. High levels of circulating bacteria, endotoxin and TNF were associated with inhibition of both of these G-CSF effects. Clinically, this study suggests that G-CSF may have its greatest beneficial effect in patients with extravascular infection and limited bacteremia. Further studies are being designed to determine whether the harmful effects of G-CSF with intravascular challenge are related specifically to mediators associated with systemic inflammation such as TNF.

临床前和临床研究表明，重组粒细胞集落刺激因子（G-CSF）治疗可以提高宿主防御能力，降低中性粒细胞减少患者感染和败血症的风险。临床前研究表明，G-CSF 治疗在免疫功能正常的宿主败血症期间也可能有益。尽管有这些发现，早期研究中的 G-CSF 对非中性粒细胞减少的脓毒症患者并无益处。我们在一系列犬类研究中发现，G-CSF 治疗对不同部位和不同剂量的大肠杆菌攻击具有不同的效果，这可能与这一临床经验一致。为了更好地确定这两个因素对 G-CSF 效果的影响，我们开发了脓毒症大鼠模型，该模型结合了多因素研究设计，允许同时评估多个变量。在这些研究中，通过静脉注射大肠杆菌攻击，G-CSF 增加了所有细菌剂量的致死率。然而，对于支气管内和腹膜内攻击，G-CSF 在低和高细菌剂量下均可提高存活率，但在中等剂量下则显得有害。实验室研究表明，G-CSF 对本研究结果的不同影响部分与其增加循环中性粒细胞数量以及清除微生物和宿主炎症介质的能力有关。高水平的循环细菌、内毒素和 TNF 与这两种 G-CSF 作用的抑制有关。临床上，这项研究表明，G-CSF可能对血管外感染和有限菌血症患者发挥最大的有益作用。进一步的研究正在设计中，以确定 G-CSF 血管内激发的有害影响是否与与全身炎症相关的介质（如 TNF）专门相关。