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

Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15736-41. doi: 10.1073/pnas.0404722101. Epub 2004 Oct 25.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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