A β-oxidation-resistant lipoxin A₄analog 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 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.

Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis

“…It is of interest to note that 15-epi-lipoxin A 4 , aspirin-triggered lipoxin A 4 (ATL), also is protective against colonic damage induced by dextran sodium sulfate (12). Along these lines, during the course of the present manuscript submission, the secondgeneration 3-oxa-lipoxin A 4 ͞ATL analogue was shown to be protective against TNBS colitis (20). RvE1 and ATL have different receptors, namely ChemR23 and ALX, which share structural similarity but different tissue distributions (8).…”

A pro-resolution mediator, prostaglandin D 2 , is specifically up-regulated in individuals in long-term remission from ulcerative colitis

“…Interference with the resolution process can result in a progression from acute to chronic inflammation and impaired healing of tissue injury. In the context of colitis, it is noteworthy that lipoxin analogs have been reported to accelerate resolution in rodent models (17,18), whereas expression of annexin A1 has been shown to be elevated in human UC (19) and contribute significantly to mucosal healing in rodent models of gastrointestinal injury (20).…”

Bacteria in the Intestine, Helpful Residents or Enemies from Within?

“…These lipid mediators are important in the control and resolution of low-grade inflammation throughout the body and contribute to the maintenance of immunologic homeostasis in the intestine. Indeed, it is possible that lipoxins downregulate bacterially induced inflammation in vivo, as exciting data from recent studies show that lipoxin A 4 analogues attenuate the induction of a range of proinflammatory genes by IEC in response to S. enterica serovar Typhimurium infection and also reduce inflammation in colitis models (34,43). In addition, we reported for the first time that the expression of the antibacterial endotoxin-neutralizing protein bactericidal/permeabilityincreasing protein (BPI) is upregulated by the stable lipoxin analogue ATLa in a range of epithelial cell lines (13).…”