Gastroenterology

Gastroenterology

Volume 124, Issue 4, April 2003, Pages 1043-1054
Gastroenterology

Special Reports and Reviews
Lipoxins: Pro-resolution lipid mediators in intestinal inflammation,☆☆

https://doi.org/10.1053/gast.2003.50154Get rights and content

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 LXA4 and B4), a distinct class of lipoxygenase-derived eicosanoids. Aspirin acetylation of cyclooxygenase 2 also promotes the generation of a series of 15-epimers of LXA4, 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 LXA4, LXB4, 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. LXA4, LXA4 analogs, and ATL analogs inhibit neutrophil chemotaxis, adhesion to epithelium, and epithelial cell chemokine release. In addition, LX blunt TNF-α-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.

Section snippets

Overview of LX biosynthesis

Eicosanoids are lipid mediators derived from arachidonic acid (AA), a 20-carbon unsaturated fatty acid. In mammalian tissues, metabolism of AA is catalyzed by 3 major enzymatic pathways: the cyclooxygenase (COX), lipoxygenase (LO), and epoxygenase pathways (Figure 1).

. Arachidonic acid metabolism and generation of lipoxins. The major biosynthetic pathways of lipoxins are catalyzed by the lipoxygenase (LO) enzyme system. LT, leukotriene; LO, lipoxygenase; 15(S)-HETE, 15(S)-hydroxyeicosatetraenoic

Metabolism of LX

Like most eicosanoids, LX are rapidly generated and metabolized in their local milieu. The major route leading to inactivation of LX in humans involves dehydrogenation at C-15 to oxo and dihydro products.34, 35, 36 LX may also be subject to ω-oxidation at C-20.36, 37 Stable analogs have been synthesized by modification at the C15, C16, and/or C20 position of LXA4.28 These stable analogs have been extensively studied and retain the bioactivity of native LX and ATL. Another important advance in

Influence of lipoxins on leukocyte trafficking in nonintestinal systems

Neutrophils are the principal effectors of acute inflammation. Recruitment of circulating neutrophils to the site of inflammation is a complex process orchestrated by chemotactic cytokines (chemokines) and adhesion molecules. In acute and chronic inflammatory disorders, these neutrophils are responsible for much of the tissue damage seen in the target organ. This process is mediated, in part, by reactive oxygen species and proteases.41

Clearance of neutrophils from an inflammatory focus is an

Temporal events in LX biosynthesis in action

Levy et al.29 recently demonstrated a “class switch” from pro- to anti-inflammatory eicosanoids that culminate in the resolution of inflammation. Temporal analysis of clinical and experimental inflammatory exudates showed early coordinated generation of leukotrienes and prostaglandins with neutrophil recruitment, followed by LX biosynthesis, which was concurrent with spontaneous resolution. This significant finding supports a dynamic endogenous mechanism early in host response to inflammation

Neutrophil-enterocyte interaction

The hallmark of active episodes of IBD is infiltration of the mucosa, lamina propria, and the crypts by a large number of neutrophils. Transmigration of neutrophils across the human intestinal epithelial cells leads to structural and functional compromise in epithelial integrity, alteration in mucosal electrolyte transport, and barrier function and free radical production, all of which contribute to the clinical syndrome of diarrhea and malabsorption in IBD.8, 56, 57 The inflammatory infiltrate

New therapeutic opportunity?

Current evidence implicate LX as key anti-inflammatory, cytoprotective, and proresolution eicosanoids that play an active part in the immune function of enterocytes that may lead to the resolution of intestinal inflammation. A hypothetical paradigm of how locally generated LX may promote the resolution of inflammation in the human intestinal mucosa is shown in Figure 4.

. Schematic representation of a crypt abscess at the center of intestinal inflammation and hypothetical targets for the induction

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    Address requests for reprints to: Jason Goh, M.D., B.A., M.R.C.P., Gastro-Intestinal Unit, University Hospital Birmingham NHS Trust, Queen Elizabeth and Selly Oak Hospitals, Radderbarn Road, Selly Oak, Birmingham, B29 6JD United Kingdom. e-mail: [email protected]; fax: (44) 121-627-8439.

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