The effects of recombinant human granulocyte-colony stimulating factor on vascular dysfunction and splanchnic ischaemia-reperfusion injury.
1. 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.
Squadrito
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F
Institute of Pharmacology, School of Medicine, University of Messina, Italy.
Altavilla
D
D
Squadrito
G
G
Campo
G M
GM
Ioculano
M
M
Ammedolia
L
L
Arlotta
M
M
Saitta
A
A
Caputi
A P
AP
D000818:Animals; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D008297:Male; D008641:Mesenteric Vascular Occlusion / Q000503:physiopathology*; D009504:Neutrophils / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis; D009195:Peroxidase / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D015427:Reperfusion Injury / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014661:Vasoconstriction / Q000187:drug effects
D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D010656:Phenylephrine; D009569:Nitric Oxide; D009195:Peroxidase