Modulation of macrophage procoagulant activity by arachidonic acid metabolites.
Macrophage (M phi)-mediated fibrin deposition via induction of procoagulant activity (PCA) is an important component of the host response during various infections. While endotoxin (LPS) is a well-known stimulus of PCA, the factors modulating its activity within the inflammatory microenvironment are unknown. The purpose of these studies was to determine the relative roles of two pathways of arachidonic acid metabolism, i.e., the cyclooxygenase (CO) and 5-lipoxygenase (5-LO) pathways, in modulating M phi PCA induction by LPS. Thioglycolate-elicited murine peritoneal M phi were treated with the CO inhibitor indomethacin (INDO), the 5-LO inhibitor nordihydroguaiaretic acid (NDGA), or control vehicle for 15 min prior to a 4-hr exposure to LPS (10 micrograms/ml). The ability of M phi to shorten the clotting time of plasma (i.e., PCA) was measured and clotting times were converted to PCA units via a thromboplastin standard. While CO blockade had no effect on PCA induction by LPS (without INDO 30 microM 446 +/- 131, with INDO 30 microM 546 +/- 193, mU/2 x 10(6) cells, n = 4), NDGA caused a dose-dependent inhibition (IC50 = 3 microM) without affecting cell viability (without NDGA 3 microM 446 +/- 131, with NDGA 3 microM 191 +/- 67, mU/2 x 10(6) cells, n = 6, P less than 0.05). Induction of PCA by Escherichia coli was similarly inhibited (E. coli 10(6) alone = 518 +/- 130; with NDGA 3 microM = 234 +/- 100, n = 2). Combined NDGA/INDO reduced PCA comparable to NDGA alone, ruling out the possibility that NDGA acted through generation of inhibitory prostanoids like PGE2.(ABSTRACT TRUNCATED AT 250 WORDS)
Kucey
D S
DS
Department of Surgery, University of Toronto, Ontario, Canada.
Cheung
P Y
PY
Marshall
J C
JC
Rotstein
O D
OD
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001779:Blood Coagulation Factors / Q000096:biosynthesis*; D015232:Dinoprostone / Q000502:physiology; D004926:Escherichia coli / Q000472:pathogenicity; D005260:Female; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology; D009637:Masoprocol / Q000494:pharmacology; D051379:Mice
D001779:Blood Coagulation Factors; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; C045072:macrophage procoagulant activity; D016718:Arachidonic Acid; D009637:Masoprocol; D015232:Dinoprostone