Enhanced production of nitric oxide by bone marrow cells and increased
sensitivity to macrophage colony-stimulating factor (CSF) and
granulocyte-macrophage CSF after benzene treatment of mice
CJ Punjabi, JD Laskin, SM Hwang, L MacEachern and DL Laskin
Rutgers University, Piscataway, NJ 08855-0789.
Nitric oxide is a short-lived reactive mediator that inhibits bone marrow
(BM) cell proliferation induced by granulocyte-macrophage colony-
stimulating factor (GM-CSF). The present studies show that nitric oxide
also inhibits macrophage colony-stimulating factor (M-CSF)-induced growth
of mouse BM cells, an effect that was dependent on the presence of an
inflammatory mediator and blocked by the nitric oxide synthase inhibitor,
NG-monomethyl-L-arginine (L-NMA). Treatment of mice with the hematotoxicant
benzene (800 mg/kg, intraperitoneally, two times per day, for 2 days)
resulted in a significant increase in nitric oxide production by BM cells
stimulated with lipopolysaccharide (LPS) and interferon gamma alone or in
combination with M-CSF or GM-CSF. Cells from benzene-treated mice also
displayed increased sensitivity to the growth-promoting effects of M-CSF
and GM-CSF. These results suggest that benzene treatment of mice primes BM
cells to inducers of nitric oxide. Northern blot analysis showed that this
was, at least in part, caused by increased expression of mRNA for inducible
nitric oxide synthase (iNOS). Surprisingly, treatment of mice with L-NMA
was found to cause a depression in BM cell proliferation and to potentiate
benzene-induced decreases in BM cellularity and increases in nitric oxide
production. L-NMA administration also augmented nitric oxide production by
BM cells. These data indicate that L-NMA is hematotoxic and suggest that it
may have actions distinct from inhibition of nitric oxide synthase in the
BM.
Volume 83,
Issue 11,
pp. 3255-3263,
06/01/1994
Copyright © 1994 by The American Society of Hematology
