Dietary fish oil reduces progression of established renal disease in (NZB x NZW)F1 mice and delays renal disease in BXSB and MRL/1 strains.

Previous studies have shown that dietary marine lipids containing large quantities of n-3 polyunsaturated fatty acids, administered to (New Zealand black X New Zealand white)F1 and MRL-lpr/lpr mice before the development of renal disease, reduce the severity of glomerulonephritis in mice of these strains. The present study demonstrated that delayed administration of a marine lipid diet, 25% menhaden oil (MO) by weight, until after the onset of overt renal disease, also resulted in significant improvement in rates of mortality, proteinuria, and histologic evidence of glomerular injury, compared with control animals fed a diet that contained mostly saturated fatty acids, 25% beef tallow. The MO diet also reduced the histologic severity of renal disease in male BXSB/MpJ and male MRL-lpr/lpr mice. In contrast, necrotizing vasculitis was more frequent in small and medium-sized renal arteries of the MRL-lpr/lpr mice fed MO than in those fed beef tallow (33.4% versus 7.6%, respectively).

The protective effect of dietary fish oil on murine lupus.

Dietary marine lipids markedly reduce the severity of glomerulonephritis and its associated mortality in inbred strains of mice developing autoimmune disease, a model for human systemic lupus erythematosus. We report here the influence of varying the dose of menhaden oil and the timing of its administration on the mortality of female (NZB x NZW) F1 mice. After ingesting 25 wt% menhaden oil (MO) for periods of 1.5 weeks to 12 months, there was a stable content of tissue n-3 fatty acids, with total n-3 fatty acids of 28% and 35% in spleen and liver, respectively. The extent of protection from mortality was dependent on the dose of MO with marked protection at doses of 11 to 25%, marginal protection at 5.5% and no protection at 2.5% MO. Delay in the institution of MO until ages 5 or 7 months still resulted in large reductions of mortality. Conversely, institution of a MO diet from 6 weeks until ages 5 to 7 months followed by a change to beef tallow resulted in little protection. Serum levels of 4 cyclooxygenase products were reduced ranging from 26 to 76% in mice fed MO diets, compared to mice fed beef tallow, based on radioimmunoassay. The degree of reduction of mortality on different doses of MO was correlated best with tissue levels of C22:5, and levels of C20:5 and C22:6 were similar at high and low doses of MO, suggesting that levels of 22:5 may be related to the protective effects of marine lipids on autoimmune disease.

Immunologically induced generation of tetraene and pentaene leukotrienes in the peritoneal cavities of menhaden-fed rats.

The generation of sulfidopeptide leukotrienes and leukotriene B (LTB) in response to an IgG-mediated immune complex reaction in the peritoneal cavities of rats fed either a menhaden oil-supplemented diet or a beef tallow-supplemented diet for 9 to 10 wk was determined with the combined techniques of radioimmunoassay (RIA) and reverse-phase high performance liquid chromatography. Rats on the fish fat diet (FFD) incorporated eicosapentaenoic acid (EPA) into pulmonary and splenic tissues with an EPA:arachidonic acid ratio of approximately 2:1, whereas rats on the beef fat diet (BFD) showed no detectable EPA. The estimated total quantities of immunoreactive sulfidopeptide leukotrienes generated by each group of rats were similar, ranging from 70 to 99 ng/ rat in the FFD groups and 65 to 109 ng/rat in the BFD groups; for rats on the FFD this total included the pentaene products LTC5, LTD5, and LTE5 in quantities ranging from 24 to 39 ng/rat. The total quantities of immunoreactive LTB generated in the two groups of rats were similar, being 6 to 29 ng LTB4/rat for the BFD groups and the sum of LTB4 and LTB5 of 8 to 36 ng/rat for the FFD groups. There was a two- to seven-fold preferential generation of immunoreactive LTB5 over LTB4 in the FFD rats. LTC5 was equipotent with LTC4 in contracting guinea pig pulmonary parenchymal strips and ileal tissues. In contrast, LTB5 was 1/30 to 1/60 as potent and did not reach the same maximum as LTB4 in eliciting neutrophil chemotaxis. The finding that FFD favors the immunologic generation of LTB5, which has attenuated biologic activity when compared to LTB4, suggests that EPA-enriched tissues may produce less pro-inflammatory activity than tissues that are EPA-poor.

Dietary fish oil augments the induction of arthritis in rats immunized with type II collagen.

Certain dietary-induced changes in tissue levels of polyunsaturated fatty acids are known to modify inflammatory reactions, possibly through changes in the synthesis of mediators of inflammation derived from fatty acids, including prostaglandins and leukotrienes. We have therefore examined the effects of a fish oil diet, enriched in highly unsaturated (delta-17) long chain fatty acids, on collagen arthritis. Weanling female Sprague-Dawley rats were maintained on a diet with fat provided by either fish oil (containing 14.5% 5, 8, 11, 14, 17-eicosapentaenoic acid; EPA) or, as a control, beef tallow (containing less than 0.05% EPA). They were immunized with native chick type II collagen emulsified in incomplete Freund's adjuvant 5 to 6 wk later. There was an increased incidence of arthritis in the rats receiving the fish oil compared with the group receiving the beef diet (88 vs 61%, p less than 0.001), but there was no significant difference in the severity of joint inflammation of arthritic rats in the two groups. The mean serum titer of IgG antibodies to type II collagen, measured by an enzyme-linked immunosorbent assay (ELISA), was decreased in the group receiving the fish oil (p less than 0.001), whereas the hemagglutinating antibody titer and delayed-type hypersensitivity to collagen were similar in the two groups. Primary synovial explant cultures from fish oil-treated rats produced only 21 to 24% as much PGE2 as beef tallow-treated controls, and this reduction in the experimental group was not accompanied by any detectable increase in PGE3, the E-prostaglandin derived from the arachidonic acid analogue, EPA, in fish oil. These data demonstrate that inductive mechanisms in collagen arthritis can be altered by diet-induced changes in tissue fatty acid composition without essential fatty acid deficiency. The reason(s) for this effect is unknown, but it is possible that changes in the cyclooxygenase or lipoxygenase products of polyunsaturated fatty acids are involved.

Effects of dietary enrichment with eicosapentaenoic acid upon autoimmune nephritis in female NZB X NZW/F1 mice.

A menhaden oil diet, rich in eicosapentaenoic acid, protected female NZB X NZW/F1 mice from autoimmune nephritis. Only 15% of mice treated with the diet from weaning had died with severe renal disease at 19 months, versus 98% of controls on a beef tallow diet. The menhaden oil also protected these mice from renal disease when instituted at 4 and 5 months of age and, under these conditions, levels of anti-native DNA antibodies were similar in both dietary groups. Our data suggest that the menhaden oil diet may act primarily to reduce inflammation via the ability of eicosapentaenoic acid to alter the production of prostaglandins and leukotrienes.

A diet enriched with eicosapentaenoic acid suppresses autoimmune nephritis in female (NZB x NZW) F1 mice.

A diet containing menhaden oil, rich in EPA, protected (NZB x NZW) F1 mice from developing lupus nephritis. Only 16% of mice treated with this diet from 5-6 weeks of age developed severe renal disease by 19 months of age, as opposed to 100% of controls. The menhaden oil diet, when delayed until mice were 5 months of age, also reduced the incidence of renal disease, and under these conditions anti-n-DNA and anti-ss-DNA antibodies were similar in treated and control groups. We suggest that EPA, an AA analogue, may reduce inflammation by altering the production of PGs and LTs.

Dietary enrichment with the polyunsaturated fatty acid eicosapentaenoic acid prevents proteinuria and prolongs survival in NZB x NZW F1 mice.

Prostaglandins and related compounds are active mediators of inflammation, but data concerning their role in the pathogenesis of the glomerulonephritis of New Zealand Black x New Zealand White (NZB x NZW) F1 mice are conflicting. Dietary eicosapentaenoic acid (EPA, C20:5), a fatty acid analogue of arachidonic acid (C20:4), has been shown to impair platelet aggregation in humans, apparently through inhibition of the synthesis of prostaglandins and thromboxanes from arachidonic acid. We report here the effects of a diet high in EPA on the development of renal disease and survival in female NZB x NZW F1 mice. Animals from 4--5 wk of age were fed diets containing 25% lipid, supplied either as beef tallow or menhaden oil, with fatty acid analysis of less than 0.05 and 14.4% EPA, respectively. In the first experiment, by 13.5 mo of age, mice on the beef tallow diet had all (9/9) developed proteinuria and the majority (6/9) had died, with renal histologic examination revealing severe glomerulonephritis. In contrast, none of 10 menhaden oil-fed animals had developed proteinuria, and all were alive at this time (P less than 0.005 for both proteinuria and survival). In a second experiment using 50 mice in each dietary group, 56% of the beef tallow group vs. none of the menhaden oil group had developed proteinuria at 9 mo of age (P less than 0.005). Native DNA binding at 6 mo of age was 23.9 +/- 14.7 vs. 10.1 +/- 9.7% in the beef and menhaden oil groups, respectively (P less than 0.01). Weights were similar in all groups, and there was no evidence of essential fatty acid deficiency in any group. These results demonstrate that a diet high in EPA protects NZB x NZW F1 mice from the development of glomerulonephritis.