Lipoxins: pro-resolution lipid mediators in intestinal inflammation

Abstract

Many inflammatory processes are self-limiting, suggesting the existence of endogenous anti-inflammatory mechanisms. Among the lipid mediators generated during cell-cell interactions are the lipoxins (LX, including LXA(4) and B(4)), a distinct class of lipoxygenase-derived eicosanoids. Aspirin acetylation of cyclooxygenase 2 also promotes the generation of a series of 15-epimers of LXA(4), known as aspirin-triggered lipoxins (ATL), that may account for some of the bioactivity profile of aspirin and possibly of nonsteroidal anti-inflammatory drugs. Native LX are rapidly inactivated in vivo, and stable analogs of LXA(4), LXB(4), and ATL have been synthesized that possess enhanced bioavailability and potency as anti-inflammatory eicosanoids. Here, we review current in vitro, ex vivo, and in vivo evidence supporting cytoprotective and proresolution roles for LX in intestinal inflammation. LXA(4), LXA(4) analogs, and ATL analogs inhibit neutrophil chemotaxis, adhesion to epithelium, and epithelial cell chemokine release. In addition, LX blunt TNF-alpha-stimulated inflammatory responses, cyclooxygenase product generation, and epithelial cell apoptosis and are cytoprotective for cytokine-activated colonic mucosa ex vivo. LX, ATL, and synthetic LX analogs have already been demonstrated to possess impressive antiinflammatory and proresolution efficacy in a range of experimental models of inflammation in vivo. Further elucidation of the role of LX in intestinal epithelial cell biology and immune function may yield novel therapeutic approaches in inflammatory bowel disease and possibly gastrointestinal cancer.