A beta-oxidation-resistant lipoxin A4 analog treats hapten-induced colitis by attenuating inflammation and immune dysfunction.
Lipoxins and aspirin-triggered 15-epi-lipoxins (ATL) are counter-regulatory eicosanoids with potent antiinflammatory actions. Oral efficacy and mechanism of action of ZK-192, a beta-oxidation-resistant 3-oxa-ATL analog, were examined in trinitrobenzenesulphonate (TNBS)-induced colitis. When dosed orally once daily, 300 and 1,000 mug/kg ZK-192 markedly attenuated TNBS colitis in rodents both in preventive and therapeutic regimens. ZK-192 attenuated weight loss, macroscopic and histologic colon injury, mucosal neutrophil infiltration, and colon wall thickening. ZK-192 was as effective as 3-10 mg/kg oral prednisolone. ZK-192 decreased mucosal mRNA levels for several inflammatory mediators: inducible nitric oxide synthase, cyclooxygenase 2, and macrophage inflammatory protein 2. ZK-192 also decreased mucosal mRNA and protein levels of T helper 1 effector cytokines: tumor necrosis factor alpha, IL-2, and IFN-gamma. Systemic levels of these cytokines were also dramatically attenuated. CD3/CD28-mediated costimulation of T helper 1 effector cytokine release in lamina propria mononuclear cells was markedly inhibited by ZK-192 ex vivo and in vitro. ZK-192 also prevented colitis in lymphocyte-deficient severe combined immunodeficient mice, with approximately 75% inhibition of mucosal tumor necrosis factor alpha and IL-2 levels. The results are further evidence that innate immune cells function as triggers for hapten-induced colitis. The combined antiinflammatory and immunomodulatory effects of ZK-192 in TNBS colitis suggest that ATL analogs may be an attractive oral treatment approach for inflammatory bowel diseases.
Fiorucci
Stefano
S
Clinica di Gastroenterologia ed Endoscopia Digestiva, Dipartimento di Medicina Clinica e Patologia, Universita di Perugia, 06122 Perugia, Italy.
Wallace
John L
JL
Mencarelli
Andrea
A
Distrutti
Eleonora
E
Rizzo
Giovanni
G
Farneti
Silvana
S
Morelli
Antonio
A
Tseng
Jih-Lie
JL
Suramanyam
Babu
B
Guilford
William J
WJ
Parkinson
John F
JF
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D003092:Colitis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D006241:Haptens / Q000633:toxicity; D044045:Lipoxins / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014302:Trinitrobenzenesulfonic Acid / Q000276:immunology / Q000633:toxicity
C485115:16-(4-fluorophenoxy)-3-oxa-5,6,15-trihydroxy-7,9,13-hexadecatrien-11-ynoic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D006241:Haptens; D044045:Lipoxins; D012333:RNA, Messenger; D014302:Trinitrobenzenesulfonic Acid