J. Nath et A. Powledge, MODULATION OF HUMAN NEUTROPHIL INFLAMMATORY RESPONSES BY NITRIC-OXIDE- STUDIES IN UNPRIMED AND LPS-PRIMED CELLS, Journal of leukocyte biology, 62(6), 1997, pp. 805-816
Because nitric oxide (NO) can act both as a regulatory and as a toxic
molecule, we have studied N-formyl-methionyl-leucyl-phenylalanine (fML
F) -stimulated responses of human neutrophils (PMNs) during various co
nditions of NO modulation in unprimed and bacterial lipopolysaccharide
(LPS) -primed cells, Effects of various NO modulators were assessed o
n stimulated superoxide (O-2(-)) generation, granule exocytosis, homot
ypic aggregation, and rises in intracellular free Ca2+ ([Ca2+](i)), Si
gnificant differences in the effects of various NO modulators on infla
mmatory responses of PMNs kept in stirred suspension versus those kept
under static and/or adherent conditions, were observed, L-arginine, t
he physiological substrate for NO synthase (NOS), and N-G-nitro-L-argi
nine methyl ester, an inhibitor of NOS, both caused a 40-50% inhibitio
n of LPS-induced priming of O-2(-) generation in PMNs in stirred suspe
nsion, but not in LPS-primed PMNs under static or adherent conditions,
The NO donors, sodium nitroprusside and S-nitroso-N-acetylpenicillami
ne, completely abrogated the LPS-induced priming of O-2(-) generation
in PMNs in suspension, while causing only a 40-50% inhibition in PMNs
under static or adherent conditions, The Ca2+ ionophore, A23187, preve
nted the LPS-induced priming of O-2(-) generation without affecting O-
2(-) generation in unprimed PMNs. LPS priming of PMNs induced about a
twofold increase in fMLF-stimulated homotypic aggregation, exocytosis
of secondary granules, and rises in [Ca2+](i). In related studies, we
also provide definitive evidence for enzymatic formation of NO in huma
n PMNs and demonstrate a significant decrease in NO levels in LPS-prim
ed PMNs. Taken together, these findings indicate that NO modulates PMN
inflammatory responses and plays a protective role in printing and ac
tivation processes of inflammatory PMNs.