Special Reports and ReviewsLipoxins: Pro-resolution lipid mediators in intestinal inflammation☆,☆☆
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).
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.
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Resolution of inflammation in inflammatory bowel disease
2017, The Lancet Gastroenterology and HepatologyCitation Excerpt :In addition, the treatment reduced the expression of pro-inflammatory cytokines.54 Further studies showed that lipoxins derived from n-6 polyunsaturated fatty acids have anti-inflammatory effects in mouse models of colitis.55,56 However, no clinical trials with these mediators have been initiated so far in patients with inflammatory bowel disease.
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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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