15-hydroxy-5-8-11-13-eicosatetraenoic-acid and Glomerulonephritis

Topics: Animals; Glomerulonephritis; Humans; Hydroxyeicosatetraenoic Acids; Kidney Glomerulus; Leukotrienes; Lipoxins; Lipoxygenase; Macrophages; Neutrophils

The 5-lipoxygenated metabolites of arachidonic acid, the leukotrienes, are increasingly recognized as major mediators of early glomerular hemodynamic and structural deterioration during experimental glomerulonephritis. Generation of these metabolites is largely by infiltrating leukocytes, but can also occur by intrinsic glomerular cells via transcellular metabolism of intermediates. In several animal models of glomerulonephritis and other renal pathologic states, leukotrienes have been shown to exert adverse effects in the glomerulus. Leukotriene B4 augments neutrophil infiltration, and leukotrienes C4 and D4 mediate potent vasoconstrictor effects on the glomerular microcirculation. Selective blockade of the 5-lipoxygenase pathway in the course of glomerular injury is associated with a significant amelioration of the deterioration of renal hemodynamic and structural parameters. 15-S-hydroxyeicosatetraenoic acid (15-S-HETE), the immediate product of arachidonate 15-lipoxygenase, and the lipoxins, which are produced by sequential 15- and 5- or 5- and 12-lipoxygenation of arachidonic acid are also generated in the course of glomerular injury. These eicosanoids have actions that contrast with those of leukotrienes. 15-S-HETE antagonizes leukotriene-induced neutrophil chemotaxis and lipoxin A4 antagonizes the effects of leukotrienes C4 and D4 on the glomerular microcirculation. The contrasting effects of 5- and 15-lipoxygenase products may represent endogenous pro- and anti-inflammatory influences that could ultimately regulate the extent and severity of glomerular inflammation. The recent availability of safe and effective 5-lipoxygenase inhibitors will be helpful to test the effect of blocking leukotriene production on the course of human glomerulonephritis and other disease states.

Topics: Animals; Glomerulonephritis; Graft Rejection; Humans; Hydroxyeicosatetraenoic Acids; Kidney Transplantation; Leukotrienes; Lipoxygenase; Lipoxygenase Inhibitors

In Figure 2, a schematic summary of current evidence implicates products of the 15-lipoxygenase pathway of arachidonic acid metabolism, principally 15-(S)-HETE and LXA4, as endogenous antagonists for the proinflammatory actions of leukotrienes. In this review, we have presented evidence for the pathophysiologic relevance of leukotrienes in glomerular immune injury and the emerging data on the multifaceted, counter-inflammatory actions of 15-lipoxygenase products as they relate specifically to the renal glomerulus. Clearly, these concepts are of a broader nature and would be expected to pertain to inflammatory reactions in general, whether they be in the glomerulus, the renal interstitium, or in extrarenal sites. The extent to which these early observations can be exploited to design strategies for the control of self-destructive inflammatory reactions in the kidney and elsewhere will be determined by future studies. Imaginative design of molecular tools for the manipulation of these enzyme systems in vivo, however, represents a potentially fruitful area of research toward the attainment of a highly worthwhile goal--the cure of glomerulonephritis.

Topics: Animals; Arachidonate 15-Lipoxygenase; Arachidonic Acid; Glomerulonephritis; Humans; Hydroxyeicosatetraenoic Acids; Leukotrienes

In the first few hours following immune complex deposition and complement-mediated neutrophil (PMN) infiltration, glomerular generation rates of the arachidonate 5-lipoxygenase (5-LO) derivatives leukotrienes (LT) C4, D4, and B4 are stimulated markedly. These LTs exert effects on glomerular functions which include reduction in the glomerular ultrafiltration coefficient and glomerular filtration rates, exacerbation of proteinuria, and amplification of PMN-provoked glomerular damage through LTB4-induced PMN chemotaxis, adhesion, and activation. Following this early burst, glomerular LT synthesis is suppressed, macrophages replace PMNs, and glomerular generation of 15-S-hydroxyeicosatetraenoic acid [15-(S)-HETE], a 15-lipoxygenase derivative of arachidonic acid and a precursor molecule for lipoxin (LX) biosynthesis, increases progressively over the ensuing days to weeks. Here, we summarize evidence supporting the notion that the activation of the 15-LO pathway in the wake of early 5-LO activity is a specific counter-inflammatory signal which limits and antagonizes the proinflammatory actions of leukotrienes.

Topics: Animals; Arachidonate 15-Lipoxygenase; Glomerulonephritis; Humans; Hydroxyeicosatetraenoic Acids; Kidney Glomerulus; Leukotriene Antagonists; Leukotrienes; Lipoxins; SRS-A