A beta-oxidation-resistant lipoxin A4 analog treats hapten-induced colitis by attenuating inflammation and immune dysfunction.

Abstract

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.

• Authors: Stefano Fiorucci, John L Wallace, Andrea Mencarelli, Eleonora Distrutti, Giovanni Rizzo, Silvana Farneti, Antonio Morelli, Jih-Lie Tseng, Babu Suramanyam, William J Guilford, John F Parkinson
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 101 Issue 44 Pg. 15736-41 (11 02 2004) ISSN: 0027-8424 [Print] United States
• PMID: 15505205 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 16-(4-fluorophenoxy)-3-oxa-5,6,15-trihydroxy-7,9,13-hexadecatrien-11-ynoic acid
• Anti-Inflammatory Agents, Non-Steroidal
• Haptens
• Lipoxins
• RNA, Messenger
• Trinitrobenzenesulfonic Acid

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemistry, pharmacology)
• Base Sequence
• Colitis (drug therapy, genetics, immunology, pathology)
• Female
• Haptens (toxicity)
• Lipoxins (chemistry, pharmacology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Oxidation-Reduction
• RNA, Messenger (genetics, metabolism)
• Rats
• Rats, Wistar
• Trinitrobenzenesulfonic Acid (immunology, toxicity)