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Blood, Vol. 93 No. 4 (February 15), 1999:
pp. 1399-1405
Activation of Nitric Oxide Release and Oxidative Metabolism by
Leukotrienes B4, C4, and D4 in
Human Polymorphonuclear Leukocytes
Gerd Lärfars,
Frédérique Lantoine,
Marie-Aude Devynck,
Jan Palmblad, and
Hans Gyllenhammar
From the Department of Hematology and the Center for Inflammation and
Hematology Research, the Karolinska Institute at Huddinge
University Hospital, Huddinge, Sweden; and Pharmacology,
René Descartes University, Necker Medical School, CNRS URA 1482, Paris, France.
Because arachidonate metabolites are potent mediators of
inflammation, we have studied the effects of leukotriene B4
(LTB4) and the cysteinyl leukotrienes C4 and
D4 (LTC4 and LTD4) on the release
of nitric oxide (NO), in vitro, by human polymorphonuclear granulocytes
(PMN). Two independent and highly sensitive real-time methods were used
for these studies, ie, the NO-dependent oxidation of oxyhemoglobin
(HbO2) to methemoglobin and a NO-sensitive
microelectrode. When activated with LTB4, LTC4,
or LTD4, but not with other lipoxygenase products such as
5S-HETE, 5-oxo-ETE or 5S,12S-diHETE, PMN
produced NO in a stimulus- and concentration-dependent manner. The rank order of potency was LTB4 = LTC4 > LTD4, corresponding to 232 ± 50 pmol of
NO/106 PMN for 100 nmol/L LTB4 after 30 minutes. The kinetic properties of the responses were similar for all
three leukotrienes with a maximum response at 13 ± 3 minutes.
Cysteinyl leukotriene and LTB4 antagonists inhibited the
agonist-induced NO production by 70%, and treatment with Bordetella
pertussis toxin, or chelation of cytosolic Ca2+,
[Ca2+]i, also efficiently inhibited this
response. In contrast, treatment of PMN with cytochalasin B (5 µg/mL)
enhanced the LTB4-induced NO formation by 86%. Thus, this
is the first demonstration that the cysteinyl leukotrienes
LTC4 and LTD4, as well as LTB4,
activate NO release from human PMN by surface receptor, G-protein and
[Ca2+]i-dependent mechanisms. This effect
differs from activation of the nicotinamide adenine dinucleotide
phosphate (NADPH) oxidase, for which only LTB4
is an activator.
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