Role of inflammatory responses in initiation of atherosclerosis: effects of anti-inflammatory drugs on cuff-induced leukocyte accumulation and intimal thickening of rabbit carotid artery.
Immediately after a cuff-sheathing of rabbit carotid artery, a large number of leukocytes adhered to injured endothelium then infiltrated into the media. These inflammatory responses were followed by an atherosclerotic change, intimal thickening, of the artery. A simultaneous injection of dexamethasone (10 mg/kg i.m.) inhibited the leukocyte accumulation by 74% when evaluated 18 h thereafter. Similarly, 39% inhibition was obtained with the same dose of FR110302, a potent 5-lipoxygenase inhibitor. On the other hand, the same dose of indomethacin, a cyclooxygenase inhibitor, had little effect on the leukocyte accumulation. The intimal thickening which was evaluated 3 weeks after the cuff-treatment was attenuated by a daily dose (10 mg/kg i.m.) of dexamethasone or FR110302 but not by one of indomethacin. The inhibition by the two former drugs were 91 and 58%, respectively. In vitro, the three drugs in concentrations up to 10 microM hardly affected endothelial adhesion of PMN which was induced by LPS or IL-1. Though 10 microM of FR110302 and indomethacin significantly decreased PMN chemotaxis induced by LTB4, the decreases were less than that at 10 microM dexamethasone. These results confirm a possible linkage between inflammation and atherosclerosis, and suggest that 5-lipoxygenase products contribute to the initiation and development of atherosclerosis.
Hagihara
H
H
Tsukuba Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan.
Nomoto
A
A
Mutoh
S
S
Yamaguchi
I
I
Ono
T
T
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000473:pathology* / Q000503:physiopathology; D002339:Carotid Arteries / Q000473:pathology* / Q000648:ultrastructure; D002448:Cell Adhesion; D002465:Cell Movement; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000473:pathology / Q000648:ultrastructure; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000473:pathology; D008297:Male; D008855:Microscopy, Electron, Scanning; D009284:Naphthols / Q000494:pharmacology; D009504:Neutrophils / Q000473:pathology* / Q000502:physiology / Q000648:ultrastructure; D011804:Quinolines / Q000494:pharmacology; D011817:Rabbits
D000893:Anti-Inflammatory Agents; D009284:Naphthols; D011804:Quinolines; C074243:FR 110302; D003907:Dexamethasone; D007213:Indomethacin