Lipoxin biosynthesis in inflammatory bowel disease.
OBJECTIVE
Lipoxins are anti-inflammatory lipid mediators that are produced in gut mucosa, which serve to limit and resolve persistent inflammation. The purpose of this study was to evaluate colonic lipoxin biosynthesis in patients with ulcerative colitis (UC) to establish a possible biochemical basis for persistent inflammation in UC.


METHODS
Colonic mucosa from patients with UC or organ donors (controls) was placed into tissue culture for 90 min. The conditioned media was assayed (ELISA) for lipoxin A4 (LXA) and the biologically active isomer 15-epi-LXA4 (aspirin triggered lipoxin, ATL). Mucosal tissue 15-lipoxygenase protein was determined by Western blot.


RESULTS
Patient colonic mucosa produced significantly lower (12-fold) amounts of LXA, relative to organ donors. This occurred irregardless of patient steroid treatment. However, patient tissue responded to in vitro aspirin by synthesizing biologically active ATL. For the first time, human colonic mucosa was found to synthesize 15-lipoxygenase-2, an epithelial-derived isoenzyme used for lipoxin synthesis. These levels were significantly lower in UC patients compared to the control tissue. Finally, mice chronically treated with a putative selective 15-lipoxygenase inhibitor (PD 146176) experienced significantly worse intestinal function during experimental colitis, relative to untreated mice.


CONCLUSIONS
Colonic mucosa from UC patients demonstrated defective lipoxin biosynthesis, which may contribute to the inability of these patients to resolve persistent colonic inflammation.
Mangino
Martin J
MJ
Department of Surgery, University of Wisconsin Medical School, 600 Highland Avenue, Madison, WI 53792, USA. mjmangino@vcu.edu
Brounts
Lionel
L
Harms
Bruce
B
Heise
Charles
C
D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D003093:Colitis, Ulcerative / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005449:Fluorenes / Q000008:administration & dosage; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D044045:Lipoxins / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors; D051379:Mice
C106248:6,11-dihydro-5-thia-11-aza-benzo(a)-fluorene; D004791:Enzyme Inhibitors; D005449:Fluorenes; D044045:Lipoxins; D016859:Lipoxygenase Inhibitors; C040527:lipoxin A4; C458528:ALOX15B protein, human; D001093:Arachidonate 15-Lipoxygenase