Effect of ischemia on intestinal CYP-derived eicosanoids production.

<p>Synthesis of eicosanoids from arachidonic acid (AA) was measured by liquid chromatography-tandem mass spectrometry in control mice (naïve and sham operated mice) and following 50 minutes of ischemia. Data represent means ± SEM of 6 to 8 mice per group. *p<0.05, and ***p<0.001 <i>versus</i> the corresponding sham operated group.</p

Effect of ischemia on intestinal docosanoid metabolites production.

<p>Synthesis of docosanoids from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) was measured by liquid chromatography-tandem mass spectrometry in control mice (naïve and sham operated mice) and following 50 minutes of ischemia. Data represent means ± SEM of 6 to 8 mice per group. *p<0.05, and **p<0.01 <i>versus</i> the corresponding sham operated group.</p

<i>In vivo</i> effects of systemic treatment with the transient receptor potential vanilloid-4 antagonist HC-067047 (50 mg/kg i.p.) or its vehicle.

<p>A, histological damage; B, microscopic damage (white) and MPO activity (grey); C–E chemokine (KC, MCP-1 and IL-6) tissue protein expression. Data in B, C, D and E represent means ± SEM of 6 to 8 mice per group. *p<0.05, **p<0.01, ***p<0.001 <i>versus</i> the corresponding sham operated group +p<0.05 <i>versus</i> the indicated I–R group.</p

Effect of ischemia followed by reperfusion from 2 to 48 hours on intestinal eicosanoids/docosanoid production.

<p><b>A</b>–<b>D</b> Synthesis of eicosanoids derived from COX-(<b>A</b>) LOX-(<b>B</b>) CYP-(<b>C</b>) arachidonic acid (AA) or its precursor the dihomo-γ-linolenic acid (DGLA) metabolism. <b>D,</b> Synthesis of docosanoid derived from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) metabolism. Data are expressed as fold increase <i>versus</i> corresponding sham operated group and represent means ± SEM of 6 to 8 mice per group.</p

Temporal schemes of PUFA-producing enzymes and metabolites upon ischemia-reperfusion.

<p><b>A</b>, Kinetic scheme of COX, LOX and CYP activation based on PUFA metabolites enzymatic biosynthesis. Early ischemia induces LOX metabolite biosynthesis, while COX activation seems to play a major role during the first hours after reperfusion (2 and 5 hours). CYP-derived metabolite synthesis starts immediately during ischemia and up to 5 hours reperfusion. <b>B,</b> Scheme of temporal PUFA metabolites production during intestinal ischemia reperfusion injury. Ischemic episodes (induction of the inflammatory response) lead to a concomitant early production of both the neutrophil chemo-attractant LTB₄ and the vascular-protective LxA₄. Immediate biosynthesis of LxA₄ could assure an appropriate counterbalance role against ischemic damage. From 2 hours and up to 5-h reperfusion, PGE₂ (such as other COX-derived metabolites) production was strongly increased fitting with the concomitant peaks of mucosal damage (2 hours) and granulocyte recruitment (5 hours). LTB₄ (such as other LOX-derived metabolites) again significantly increased after 5 h of reperfusion, suggesting that at this time-point, additional cell source (potentially granulocytes) is responsible for the biosynthesis of LOX metabolites. At 24-h after reperfusion, all PUFA metabolites were decreased, to reach basal levels after 48 h of reperfusion, except for mediators known to take part into the resolution of inflammation: the RvE precursor 18-HEPE and the PPARγ agonist, 15d-PGJ₂.</p