Effect of recombinant human granulocyte colony-stimulating factor administration in normal and experimentally infected newborn rats.
We investigated the effects of repetitive recombinant human granulocyte colony-stimulating factor (rhG-CSF) administration at three different doses (every 12 h times six doses, starting at 12-24 h of age) on the kinetics of neutrophil production in Sprague-Dawley rats. We determined WBC counts, differentials, the number of total nucleated cells, the myeloid mitotic pool cells (promyelocytes and myelocytes), the storage pool cells (metamyelocytes, bands, and polymorphonuclear cells [PMNs]) and the granulocyte-macrophage (granulocyte-macrophage colony-forming units, CFU-GM) and macrophage (macrophage colony-forming units, CFU-M) progenitor cells of the bone marrow, spleen, and the liver before the first dose of rhG-CSF administration and 12 h after the second, fourth, and sixth dose. Control animals were given the diluent by the same schedule. Recombinant human G-CSF-treated rats showed a significant dose-dependent increase in the number of total WBC and neutrophil counts at all time points compared to control rats. The total number of CFU-GM and myeloid mitotic pool cells (marrow plus spleen plus liver) progressively increased with age in both control and G-CSF groups, but the G-CSF treated groups showed a significantly larger number of mitotic pool cells at hour 24, continuing up to hour 72, compared to the control group. However, there was no significant difference at any time point in the number of CFU-G/GM as detected by the granulocyte-macrophage colony-stimulating factor (GM-CSF)-supported culture system. Priming of newborn rats with injections every 12 h of rhG-CSF times two doses, or six doses followed by inoculation of group B streptococci (GBS) did not significantly change the sepsis death rate of animals, although the neutrophil counts in infected rhG-CSF-primed animals were significantly larger than the infected control animals. Injection of human i.v. gammaglobulin 3 h following inoculation with GBS significantly improved the survival of animals compared to G-CSF administration or administration of the diluent alone (control). Thus G-CSF alone may not be beneficial for the treatment of neonates with sepsis. Additional work is needed to determine whether combination of G-CSF with antibiotics or other cytokines, such as GM-CSF or interleukin 6 (IL-6) may be of benefit.
Iguchi
K
K
Department of Pediatrics, Hurley Medical Center, Flint, Michigan 48502.
Inoue
S
S
Kumar
A
A
D000818:Animals; D000831:Animals, Newborn / Q000097:blood*; D001772:Blood Cell Count; D001853:Bone Marrow / Q000382:microbiology / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000382:microbiology / Q000473:pathology; D007962:Leukocytes / Q000166:cytology / Q000473:pathology; D008264:Macrophages / Q000382:microbiology / Q000473:pathology; D009504:Neutrophils / Q000166:cytology / Q000473:pathology*; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013154:Spleen / Q000166:cytology / Q000382:microbiology; D013290:Streptococcal Infections / Q000097:blood* / Q000628:therapy; D013292:Streptococcus agalactiae / Q000302:isolation & purification; D013997:Time Factors; D005719:gamma-Globulins / Q000627:therapeutic use
D011994:Recombinant Proteins; D005719:gamma-Globulins; D016179:Granulocyte Colony-Stimulating Factor