Inhibition of antigen-induced arthritis in guinea pigs by a selective LTB4 receptor antagonist LY293111Na.
OBJECTIVE
To investigate the role of leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) in the development and progression of antigen-induced arthritis (AIA) in guinea pigs and rats.


METHODS
Arthritis was induced by injecting cationic amidated bovine serum albumin (aBSA) into the knee joint of immunized guinea pigs or rats. The effect of a potent and selective LTB4 receptor antagonist, LY29311INa (2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]-propoxy]-phenoxy]benzoic acid sodium salt) was compared with those of indomethacin and dexamethasone. The effect of LY293111Na on adjuvant arthritis in rats was also examined.


RESULTS
LY293 111Na (5 to 50 mg/kg b.i.d.) significantly inhibited knee joint swelling and histopathological changes of AIA in guinea pigs, but not in rats. Especially its protective effect against bone and cartilage destruction was substantial. In contrast, the cyclooxygenase inhibitor indomethacin significantly inhibited AIA in rats, but slightly inhibited in guinea pigs, while dexamethasone markedly inhibited AIA in both guinea pigs and rats. Increases of LTB4 and myeloperoxidase (MPO) activity were observed in the knee joint tissue of AIA guinea pigs, and LY293111Na dose-dependently inhibited the increase of MPO activity. Moreover, in adjuvant arthritic rats, LY293111Na showed slight inhibitory effect, while indomethacin showed marked inhibition.


CONCLUSIONS
LTB4 but not PGE2 appeared to play important roles as an effective mediator in joint, particularly in cartilage and bone destruction of AIA in guinea pigs probably by inducing polymorphonuclear leukocytes (PMNs) chemotaxis to the joint tissue. In contrast, PGE2 but not LTB4 is an important mediator of arthritis in rats.
Kuwabara
K
K
Discovery Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
Jyoyama
H
H
Fleisch
J H
JH
Hori
Y
Y
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001565:Benzoates / Q000627:therapeutic use*; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism / Q000502:physiology; D005260:Female; D006168:Guinea Pigs; D007213:Indomethacin / Q000494:pharmacology; D007596:Joints / Q000201:enzymology / Q000378:metabolism; D020024:Leukotriene Antagonists / Q000627:therapeutic use*; D007975:Leukotriene B4 / Q000378:metabolism / Q000502:physiology; D020556:Neutrophil Infiltration / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*; D012710:Serum Albumin, Bovine
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; C094099:LY 293111; D020024:Leukotriene Antagonists; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D012710:Serum Albumin, Bovine; D003907:Dexamethasone; D009195:Peroxidase; D015232:Dinoprostone; D007213:Indomethacin