Lipoxin A₄stable analogs inhibit leukocyte rolling and adherence in the rat mesenteric microvasculature: Role of P-selectin

Abstract

Three different stable lipoxin A 4 (LXA 4 ) analogs (i.e., 16-phenoxy-LXA 4 -Me, 15-cyclohexyl-LXA 4 -Me, and 15-R/S-methyl-LXA 4 -Me) were studied for their ability to modulate leukocyte-endothelial cell interactions in the rat mesenteric microvasculature. Superfusion of the rat mesentery with 50 mol/liter N G-nitro-L-arginine methyl ester (L-NAME) caused a significant, time-dependent increase in leukocyte rolling (56 ؎ 8 cells/min; P < 0.01 vs. control) and leukocyte adherence (12.5 ؎ 1.2 cells/100 m length of venule; P < 0.01 vs. control) after 120 min of superfusion. Concomitant superfusion of the rat mesentery with 10 nmol/liter of each of three lipoxin analogs consistently and markedly attenuated L-NAME-induced leukocyte rolling to 10 ؎ 4 (P < 0.01), 4 ؎ 1 (P < 0.01), and 32 ؎ 7 (P < 0.05) cells/min, and adherence to 4 ؎ 0.8 (P < 0.01), 1.1 ؎ 0.4 (P < 0.01), and 7 ؎ 0.7 (P < 0.05) cells/100 m length of venule (16-phenoxy-LXA 4 -Me, 15-cyclohexyl-LXA 4 -Me, and 15-R/S-methyl-LXA 4 -Me, respectively). No alterations of systemic blood pressure or mesenteric venular shear rates were observed in any group. Immunohistochemical up-regulation of P-selectin expression on intestinal venular endothelium was significantly increased (P < 0.01) after exposure to L-NAME, and this was significantly attenuated by these lipoxin analogs (P < 0.01). Thus, in vivo superfusion of the rat mesentery with stable lipoxin analogs at 10 nmol/liter reduces L-NAME-induced leukocyte rolling and adherence in the mesenteric rat microvasculature by attenuating P-selectin expression. This anti-inf lammatory mechanism may represent a novel and potent regulatory action of lipoxins on the immune system.Lipoxins represent a relatively new class of arachidonic acid derivatives (i.e., trihydroxytetraene eicosanoids) that are produced by activated leukocytes, which, in turn, are able to modulate leukocyte functions (1). In vitro data indicate that one member of the naturally occurring lipoxins, (i.e., lipoxin A 4 , namely LXA 4 ), inhibits both neutrophil and eosinophil chemotaxis at nanomolar concentrations (2, 3) and blocks polymorphonuclear neutrophil (PMN) transmigration across epithelial cells (4) and endothelial monolayers (5). Similar actions also are demonstrable in vivo where LXA 4 exerts vasodilator properties (6-9), blocks both PMN diapedesis from postcapillary venules (10), and inhibits PMN entry in inflamed renal tissues in animal models of glomerulonephritis (11).Nevertheless, we know of no specific information elucidating detailed mechanisms by which naturally occurring lipoxins and their synthetic stable analogs can directly modulate the interaction of leukocytes with vascular endothelial cells. LXA 4 , as with other autacoids, is rapidly inactivated in the local extracellular milieu. Analogs of LXA 4 were designed and prepared by total organic synthesis so that they resist rapid inactivation and retain potent biological activities (12). A goal of this study was to use these metabolically stable analogs to investigate the i...

Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice

“…In particular, they block chemotaxis and adherence to microvasculature, inhibit nuclear factor-kB activation in leukocytes, and block the release of proinflammatory cytokines such as interleukin-6, interleukin-8, and tumor necrosis factor-a. 16,[35][36][37][38] A potential limitation of our study is that microgram quantities of ATL were required to limit lung injury in our experiments, whereas others have reported that nanogram amounts of proresolving lipid mediators For personal use only. on March 28, 2019.…”

Selectivity of Recombinant Human Leukotriene D4, Leukotriene B4, and Lipoxin A4 Receptors with Aspirin-Triggered 15-epi-LXA4 and Regulation of Vascular and Inflammatory Responses

“…11 However, the rank order of cysteinyl LTs in inducing surface expression of P-selectin, a well-characterized vascular action of cysteinyl-LT, and the inability of selective CysLT 1 receptor antagonists to inhibit this response suggest that these endothelial receptors are likely distinct from CysLT 1 . 16,24,25 Although the CysLT 1 receptor was identified and cloned by other investigators, 14,18 it was not formally cloned or identified from human vascular endothelial cells. The available evidence that this receptor was indeed a major endothelial receptor remained incomplete.…”

A vasculo-protective circuit centered on lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 operative in murine microcirculation

“…7,8 Although inflammation is a life-saving process and must be highly efficient against bacteria invasion, "inflammation from within"-that is, in the vasculature-must be tightly controlled to avoid widespread damage. Thus, low doses of LXA 4 inhibit polymorphonuclear cells (PMN) accumulation both in postischemic mesenteric tissues 9,10 and in distant organs such as the lung 11 ; similarly, AnxA1 and erythropoietin are potent inhibitors of myocardial infarct, stroke, and vascular reperfusion injury. [12][13][14] In situations where reperfusion occurs, such as renal transplantation, LXA 4 15 and resolvins 16 are highly protective, and the same has been reported recently for AnxA1 mimetics.…”