重组人粒细胞集落刺激因子对血管功能障碍和内脏缺血-再灌注损伤的影响。

The effects of recombinant human granulocyte-colony stimulating factor on vascular dysfunction and splanchnic ischaemia-reperfusion injury.

作者信息

Squadrito F, Altavilla D, Squadrito G, Campo G M, Ioculano M, Ammedolia L, Arlotta M, Saitta A, Caputi A P

机构信息

Institute of Pharmacology, School of Medicine, University of Messina, Italy.

出版信息

Br J Pharmacol. 1997 Jan;120(2):333-9. doi: 10.1038/sj.bjp.0700904.

DOI:10.1038/sj.bjp.0700904

PMID:9117128

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1564376/

Abstract

The aim of our study was to investigate the effects of recombinant human granulocyte-colony stimulating factor in a rat model of splanchnic ischaemia-reperfusion injury. 2. Male anaesthetized rats were subjected to clamping of the splanchnic arteries for 45 min. This surgical procedure resulted in an irreversible state of shock (splanchnic artery occlusion shock. SAO shock). Sham operated animals were used as controls. Survival rate, serum tumour necrosis factor-alpha (TNF-alpha), neutrophil count, bone marrow myeloid precursor cells, myeloperoxidase activity (MPO; studied as a quantitative means to assess leukocyte accumulation), mean arterial blood pressure and the responsiveness of aortic rings to phenylephrine (PE, 1 nM-10 microM) were studied. 3. SAO shocked rats had a decreased survival rate (0% at 4 h of reperfusion, while sham shocked rats survived more than 4 h), increased serum levels of TNF-alpha (201 +/- 10 u ml-1; sham shocked rats = undetectable), neutropenia, enhanced MPO activity in the ileum (0.11 +/- 0.06 u x 10(-3) g-1 tissue; sham shocked rats = 0.02 +/- 0.001 u x 10(-3) g-1 tissue) and in the lung (1.5 +/- 0.2 u x 10(-3) g-1 tissue; sham shocked rats = 0.19 +/- 0.05 u x 10(-3) g-1 tissue) and unchanged bone marrow myeloid precursor cells. Furthermore aortic rings from shocked rats showed a marked hyporeactivity to PE. 4. Administration of recombinant human granulocyte colony stimulating factor (rh G-CSF; 5, 10 and 20 micrograms kg-1 5 min following the release of occlusion) increased in a dose-dependent manner survival rate (90% at 4 h of reperfusion with the dose of 20 u x 10(-3) g kg-1), reduced serum TNF-alpha (13 +/- 5 u ml-1) and MPO activity in the ileum (0.065 +/- 0.002 u x 10(-3) g-1 tissue) and in the lung (0.7 +/- 0.03 microgram kg-1 tissue), improved neutropenia and mean arterial blood pressure but did not modify bone marrow myeloid progenitor cells. Furthermore rh G-CSF, either in vivo or in vitro (200 nM for 1 h in the organ bath), restored to control values the hyporeactivity to PE. Finally rh G-CSF potently inhibited the activity of inducible nitric oxide synthase in peritoneal macrophages activated with endotoxin. 5. Our results suggest that rh G-CSF protects against splanchnic ischaemia reperfusion injury by a mechanism(s) that does not depend upon its haematopoietic effects.

摘要

我们研究的目的是在大鼠内脏缺血-再灌注损伤模型中研究重组人粒细胞集落刺激因子的作用。2. 将雄性麻醉大鼠的内脏动脉夹闭45分钟。该手术操作导致不可逆的休克状态（内脏动脉闭塞性休克，SAO休克）。假手术动物用作对照。研究了存活率、血清肿瘤坏死因子-α（TNF-α）、中性粒细胞计数、骨髓髓系前体细胞、髓过氧化物酶活性（MPO；作为评估白细胞积聚的定量手段进行研究）、平均动脉血压以及主动脉环对去氧肾上腺素（PE，1 nM - 10 μM）的反应性。3. SAO休克大鼠的存活率降低（再灌注4小时时为0%，而假休克大鼠存活超过4小时），血清TNF-α水平升高（201 ± 10 u/ml；假休克大鼠未检测到），出现中性粒细胞减少，回肠（0.11 ± 0.06 u x 10⁻³ g⁻¹组织；假休克大鼠 = 0.02 ± 0.001 u x 10⁻³ g⁻¹组织）和肺（1.5 ± 0.2 u x 10⁻³ g⁻¹组织；假休克大鼠 = 0.19 ± 0.05 u x 10⁻³ g⁻¹组织）中的MPO活性增强，骨髓髓系前体细胞未改变。此外，休克大鼠的主动脉环对PE表现出明显的反应性降低。4. 在内脏动脉夹闭解除后5分钟给予重组人粒细胞集落刺激因子（rh G-CSF；5、10和20 μg/kg），可使存活率呈剂量依赖性增加（再灌注4小时时，20 u x 10⁻³ g/kg剂量组存活率为90%），降低血清TNF-α（13 ± 5 u/ml）以及回肠（0.065 ± 0.002 u x 10⁻³ g⁻¹组织）和肺（0.7 ± 0.03 μg/kg组织）中的MPO活性，改善中性粒细胞减少和平均动脉血压，但不改变骨髓髓系祖细胞。此外，rh G-CSF无论是在体内还是体外（在器官浴中200 nM作用1小时），均可使对PE的反应性降低恢复至对照值。最后，rh G-CSF可有效抑制内毒素激活的腹腔巨噬细胞中诱导型一氧化氮合酶的活性。5. 我们的结果表明，rh G-CSF通过不依赖其造血作用的机制来保护免受内脏缺血再灌注损伤。