Influence Of Systemic Inflammation On The Effects Of Rec

临床前和临床研究表明，重组粒细胞集落刺激因子(G-CSF)治疗可以提高中性粒细胞减少患者的宿主防御能力，降低感染和脓毒症的风险。临床前研究表明，在免疫活性宿主的脓毒症期间，使用G-CSF治疗也可能是有益的。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。可能与这一临床经验一致，我们在一系列犬类研究中发现，G-CSF治疗在不同部位和不同剂量的大肠杆菌挑战中具有不同的效果。为了更好地确定这两个因素对G-CSF效果的影响，我们开发了一个包含多因素研究设计的脓毒症大鼠模型，允许同时评估多个变量。在这些研究中，在静脉注射大肠杆菌的情况下，G-CSF在所有细菌剂量下增加了致死率。然而，通过支气管内和腹膜腔内的攻击，G-CSF在低和高细菌剂量下提高了存活率，但在中等剂量下似乎是有害的。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的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、内毒素和肿瘤坏死因子与抑制这两种G-CSF作用有关。临床上，G-CSF对血管外感染和有限菌血症的患者可能有最大的益处。正在进行进一步的研究，以确定G-CSF对血管内挑战的有害影响是否与与全身炎症相关的介质(如肿瘤坏死因子)特别相关。

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.