A β-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 β-oxidation-resistant 3-oxa-ATL analog, were examined in trinitrobenzenesulphonate (TNBS)-induced colitis. When dosed orall...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2004-11, Vol.101 (44), p.15736-15741
Main Authors: Fiorucci, Stefano, Wallace, John L., Mencarelli, Andrea, Distrutti, Eleonora, Rizzo, Giovanni, Farneti, Silvana, Morelli, Antonio, Tseng, Jih-Lie, Suramanyam, Babu, Guilford, William J., Parkinson, John F., Ignarro, Louis J.
Format: Article
Language:English
Subjects:
Analog
Animals
Anti-Inflammatory Agents, Non-Steroidal - chemistry
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Base Sequence
Biological Sciences
Bowel disease
Colitis
Colitis - drug therapy
Colitis - genetics
Colitis - immunology
Colitis - pathology
Crohn disease
Cytokines
Dosage
Female
Haptens - toxicity
Immune system
Inflammation
Lipoxins - chemistry
Lipoxins - pharmacology
Male
Medical treatment
Messenger RNA
Mice
Mice, Inbred BALB C
Mice, SCID
Mucosa
Neutrophil infiltration
Oxidation
Oxidation-Reduction
Rats
Rats, Wistar
RNA, Messenger - genetics
RNA, Messenger - metabolism
T lymphocytes
Trinitrobenzenesulfonic Acid - immunology
Trinitrobenzenesulfonic Acid - toxicity
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 β-oxidation-resistant 3-oxa-ATL analog, were examined in trinitrobenzenesulphonate (TNBS)-induced colitis. When dosed orally once daily, 300 and 1,000 μg/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 α, IL-2, and IFN-γ. 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 ≈75% inhibition of mucosal tumor necrosis factor α 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0404722101