Efficacy of recombinant granulocyte colony-stimulating factor (rhG-CSF) in experimental colitis.
Inflammatory bowel disease is associated with mucosal neutrophil recruitment and activatation, mediated in part by arachidonic acid metabolites. G-CSF attenuates the immune response to sepsis and ameliorates glycogen storage disease Ib-related colitis. These actions may be effected through the shedding of neutrophil adhesion molecules, or inhibition of proinflammatory mediator synthesis. Immune complex colitis was used to evaluate the effect of rhG-CSF on colonic mucosal inflammation, neutrophil recruitment and the generation of eicosanoids. Immune complex colitis was induced in White New Zealand rabbits. Animals were pretreated with rhG-CSF either 24 h before induction, or at induction, with dosages of 50 and 200 micrograms/kg. rhG-CSF caused a time- and dose-dependent neutrophilia in all animals. Pretreatment with rhG-CSF resulted in increased tissue myeloperoxidase levels, despite a histologically similar mucosal polymorphonuclear cell infiltrate between treated and control colitis groups. Leukotriene B4 (LTB4) and thromboxane B2 (TXB2) dialysis fluid levels were lower in treated animals, in particular in the groups receiving two doses (LTB4: both P < 0.01; TXB2: both P < 0.01. Prostaglandin E2 (PGE2) levels in dialysis fluid of the rhG-CSF-treated animals showed no difference from controls. In this model of experimental colitis, high-dose therapy with G-CSF resulted in a marked decrease of proinflammatory mediators, but mucosal generation of the protective PGE2 was preserved. These results suggest that prolonged high-dose therapy with G-CSF may have anti-inflammatory effects in colitis.
Hommes
D W
DW
Department of Gastroenterology and Hepatology, University of Amsterdam, The Netherlands.
Meenan
J
J
Dijkhuizen
S
S
Ten Kate
F J
FJ
Tytgat
G N
GN
Van Deventer
S J
SJ
D000818:Animals; D000936:Antigen-Antibody Complex / Q000633:toxicity*; D003092:Colitis / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D015314:Dialysis Solutions / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology* / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D009928:Organ Specificity; D009195:Peroxidase / Q000378:metabolism; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology* / Q000627:therapeutic use*
D000936:Antigen-Antibody Complex; D015314:Dialysis Solutions; D015777:Eicosanoids; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D009195:Peroxidase