Differential Effects of Arachidonic and Eicosapentaenoic Acid-Derived Eicosanoids on Polymorphonuclear Transmigration Across Endothelial Cell Cultures

Abstract

The beneficial effects of fish oil on inflammation have been attributed to the content of eicosapentaenoic (EPA)/docosahexaenoic acid. EPA is also a substrate for arachidonic acid (AA) cascade enzymes, but it induces the production of alternative eicosanoids such as 3-series prostanoids and 5-series leukotrienes, which are considered to be less proinflammatory than AA metabolites. However, the molecular basis of this action is poorly understood. In this study, we compared the effects of prostaglandin (PG) E 2 and PGE 3 on endothelium permeability, and the effects of leukotriene (LT) B 4 and LTB 5 on endothelium permeability and mononuclear adhesion and migration. In our study, both prostaglandins increased trans-endothelial Evans blue-albumin (EBA) permeability in a concentration-dependent manner. It is interesting that the effect of PGE 3 was significantly more pronounced than the effect of PGE 2 , and both were antagonized by EP 1 and EP 2 antagonists. LTB 4 and LTB 5 had a slight effect on EBA extravasation. However, we observed the enhancement of endothelial permeability in the presence of polymorphonuclear (PMN) cells, probably a consequence of an interplay between leukotriene and prostanoid effects. LTB 4 caused significant increases in the number of PMN cells adhering to endothelial cells, whereas LTB 5 did not induce a significant effect. This effect of LTB 4 appears BLT1 receptor-dependent and was mediated through the enhancement of lymphocyte function-associated antigen-1, membrane attack complex-1, E-selectin, and intercellular adhesion molecule-1 expression. Finally, we observed that, unlike LTB 5 , which had a weak effect, LTB 4 was a highly potent chemoattractant. An understanding of the differences in the effects of LTB 4 /LTB 5 on PMN cell adhesion and migration may help to explain the beneficial impact of -3 fatty acids in inflammatory processes.

Long-chain acyl-CoA synthetase 4 modulates prostaglandin E2 release from human arterial smooth muscle cells

“…It is possible, therefore, that ACSL4 in SMCs directly contributes to regulation of eicosanoid release from SMCs and their downstream effects in cell types within the vascular wall or lesions of atherosclerosis. For example, PGE 2 increases permeability of endothelial cell cultures ( 46 ), and longterm exposure of human monocytes/macrophages to PGE 2 enhances chemokine expression in these cells (47 ). Mouse models with smooth muscle-targeted ACSL4 deficiency would shed light onto the probable role of SMC ACSL4 in vascular injury or atherosclerosis.…”

Docosahexaenoic acid: one molecule diverse functions

“…Eicosanoids such as prostaglandins, thromboxanes and leukotrienes, are signaling molecules synthesized from the essential fatty acid arachidonic acid (AA), regulate blood clotting and important immune functions [131]. EPA, the precursor of DHA, can also act as a substrate for AA-cascade enzymes, but it induces the production of alternative eicosanoids such as 3-series prostanoids and 5-series leukotrienes, which are considered to be anti-inflammatory and/or less proinflammatory than AA-derived metabolites [132]. However, endogenous signaling by DHA-derived mediators (docosanoids) and their roles in brain circuitry have recently being reported, following the surprising discovery that a rapid increase in free DHA pool size occurs at the onset of seizures or brain injury.…”

The effects of dietary fish oil on inflammation, fibrosis and oxidative stress associated with obstructive renal injury in rats

“…We did not measure LTB 5 , but the fish oil diet in our study may have increased LTB 5 content in kidney tissue. Compared with LTB 4 , however, LTB 5 is a weaker chemoattractant, and it does not actually reduce leukocyte chemotaxis [31]. We therefore suggest that the lower number of macrophages in the kidney tissue of rats that were fed fish oil resulted mainly from reduced synthesis of LTB 4 , rather than increased formation of LTB 5 .…”