Modification of glomerular immune complex deposition in mice by activation of the reticuloendothelial system.

To determine the effect of activation of the reticuloendothelial system on the localization of immune complexes in the kidney, a model of passive serum sickness nephritis in the mouse was used, with activation of the reticuloendothelial system with Corynebacterium parvum. Groups of mice, control and C. parvum-treated animals, were injected with BSA-125I-anti-BSA complexes containing 3 mg 125I-anti-BSA. Blood was obtained at 5 min, at 3 h, and at 12 h, when the animals were killed. Blood concentrations of BSA-125I-anti-BSA complexes were reduced in C. parvum-treated animals compared with controls. This appeared to be mediated by two effects, increased uptake of complexes in the liver and spleen, and enhanced degradation of immune complexes as measured by TCA-soluble radioactivity. In vitro studies using cultures of peritoneal macrophages also showed enhanced uptake of immune complexes. The amount of immune complexes deposited in the glomeruli of C. parvum-treated animals was reduced as determined by quantitation of radiolabeled material bound to isolated gomeruli and by immunofluorescence techniques. The results of the study emphasize the role of the reticuloendothelial system in the modulation of immune complex localization in the kidney and suggest a potential use of stimulants of the reticuloendothelial system in the therapy of immune complex nephritis.

Fish oil has beneficial effects on lipids and renal disease of nephrotic rats.

The effects of fish oil on serum lipids, eicosanoid production, fibrinolysis, and renal disease of nephrotic rats were studied. Three groups of rats were given adriamycin to induce nephrotic syndrome. They were pair-fed diets containing 14% beef fat, 3%, and 14% fish oil, and killed at 4 weeks. Marked beneficial effects of the fish oil on plasma triglycerides, total cholesterol, and LDL cholesterol were observed. Fish oil suppressed dienoic eicosanoid production. Protection of renal function and morphology was achieved in the fish oil fed groups, as evidenced by lower serum creatinine levels and lesser degrees of tubular dilatation and intraluminal protein in the kidney tubules. We conclude that fish oil, rich in n-3 fatty acids, is beneficial to the plasma lipids and may prevent progression of renal disease in this model of nephrotic syndrome. These two events may be interrelated.

Effect of blood transfusions on immune function. III. Alterations in macrophage arachidonic acid metabolism.

Blood transfusions have been shown to prevent allograft rejection, to increase the rate of tumor growth, and to increase susceptibility to infectious complications. We evaluated the mechanism of this immunosuppression by studying the effect of transfusions on macrophage function in a Lewis rat model. Allogeneic transfusions were found to decrease macrophage migration in response to inflammatory stimuli and to increase their production of the strongly immunosuppressive arachidonic acid metabolite prostaglandin E. Syngeneic transfusions did not alter macrophage migration or arachidonic acid metabolism. The immunosuppression seen following transfusions appears to be related to an increased synthesis of prostaglandin E.

Muscle prostaglandin production in the rat. Effect of abdominal sepsis and different amino acid formulations.

Recent in vitro studies attribute regulatory functions to prostaglandins (PGs) in muscle protein metabolism, particularly enhancing proteolysis. In the present study, the amount of muscle PG production from endogenous precursors was determined in control and septic animals (cecal ligation and puncture) that were infused with 5% dextrose or dextrose with three amino acid formulations differing in their branched-chain amino acid (BCAA) content. We could not detect any differences in prostaglandin E, 6-keto-prostaglandin F1 alpha, and thromboxane B2 production between control and septic animals. Furthermore, the infusion of BCAAs, which have previously been shown to be nitrogen sparing following injury, did not influence the production of any of the PGs studied in either control or septic muscle. It is likely that the effects of the BCAAs on muscle synthesis and degradation are independent of the PGs.

The effect of indomethacin on muscle and liver protein synthesis and on whole-body protein degradation during abdominal sepsis in the rat.

It has been recently suggested that increased muscle protein degradation during injury or infection is at least partially mediated by the increased production of prostaglandin E2 in muscle, and some have suggested that cyclooxygenase inhibitors might decrease protein loss in injured or septic patients. In these experiments, fractional synthesis rates of mixed muscle and liver protein and whole-body tyrosine flux were measured by constant intravenous infusion of tyrosine labeled with carbon 14 in 17 rats with sham operations and 15 severely septic rats with or without indomethacin treatment (20 mg/kg/d). Fractional synthesis rates in muscle and liver were decreased in late sepsis and were lowest in the septic group receiving indomethacin. Unlike the fractional synthesis rate, which was affected by indomethacin in septic rats only, tyrosine flux was significantly lower in indomethacin-treated rats with sham operations and those with sepsis. Although indomethacin reduced total-body protein breakdown during sepsis, it was also associated with lower plasma albumin levels and with decreased protein synthesis in muscle and liver at a time when the survival of the septic host may be dependent on its ability to produce new protein for a variety of vital functions. These results do not support the use of indomethacin in sepsis.

Enhancing effect of dietary supplementation with omega-3 fatty acids on plasma fibrinolysis in normal subjects.

A supplement of MaxEPA oil containing 5 g of omega-3 polyunsaturated fatty acids was given for two weeks to nine normal volunteers. The vascular plasminogen activator (VPA) level increased and there was a fall in the levels of inhibitors of vascular plasminogen activator (IPA) and of plasmin, alpha 2-antiplasmin (alpha 2-AP). No significant changes occur in serum cholesterol, triglycerides, HDL or LDL levels.

Dietary fat in experimental nephrotic syndrome: beneficial effects of fish oil on serum lipids and, indirectly, on the kidney.

Three isocaloric diets with different fat composition were fed to rats for seven weeks after the production of nephrotic syndrome by adriamycin. The effects of feeding 3% and 14% fish oil were compared with those of feeding beef fat. At the fourth week of feeding the levels of triglycerides and cholesterol were lower in both fish oil fed groups. At the seventh week these levels, and the LDL cholesterol, were lower only in the 14% fish oil group. In rats fed beef fat, but not in those fed fish oil, there was a striking positive correlation of the four-week serum triglycerides and cholesterol with the seven-week serum creatinine level and with the degree of glomerular hyalinosis and endothelial swelling. The favorable effects of fish oil feeding on serum lipids may have a protective effect on the development of glomerular damage.

The influence of n-6 and n-3 fatty acids on kidney phospholipid composition and on eicosanoid production in aging rats.

Changes in eicosanoid production may contribute to some of the complications of the aging process such as atherosclerosis and glomerular sclerosis. Polyunsaturated fatty acids of the n-6 and n-3 series are precursors of eicosanoids. We fed diets containing safflower oil as a source of n-6 fatty acids, fish oil as a source of n-3 fatty acids or beef tallow as a source of saturated fats to three groups of normal rats from 2-18 months of age. We demonstrated incorporation of the n-3 fatty acids, 20:5n-3 and 22:6n-3 into kidney phospholipids. Feeding of the diet containing n-3 fatty acids was associated with a markedly decreased glomerular production of PGE, 6-keto-PGF1 alpha and TXB2. It also decreased the aortic production of 6-keto-PGF1 alpha and platelet production of TXB2. No significant effect of n-6 fatty acids on dienoic eicosanoid production was observed. There were no adverse effects on kidney function as measured by urinary protein excretion and serum creatinine levels or on renal morphology by any diet. A diet enriched in n-3 fatty acids for 18 months remains effective in decreasing dienoic eicosanoids in the aging rat.

A diet containing n-3 and n-6 fatty acids favorably alters the renal phospholipids, eicosanoid synthesis and plasma lipids in nephrotic rats.

The nephrotic syndrome was induced in rats by intravenous adriamycin (3 mg/kg). The rats were then divided into four groups which, for six weeks, were pair-fed diets containing beef tallow (BT), fish oil (FO), a source of n-3 fatty acids, evening primrose oil (EPO), a source of n-6 fatty acids, or a combination of evening primrose oil and fish oil, 75:25 (EPO:FO). The fat content of the diets was 15%. Significant incorporation of the fatty acids into kidney phospholipids was demonstrated. Diets containing FO, EPO and EPO:FO lowered plasma triglycerides and total cholesterol levels as compared with diets containing BT. Only EPO:FO raised high density lipoprotein (HDL) cholesterol levels, as compared with BT. The combination EPO:FO prevented the tenfold suppression of aortic 6-keto-PGF1 alpha caused by FO. These changes in plasma lipids and eicosanoid production are potentially antiatherogenic and may prevent glomerular sclerosis. The combination of EPO and FO, containing n-6 and n-3 fatty acids may offer advantages over either family of fatty acids in this model of nephrotic syndrome.

Measurement of prostaglandin E3 and other eicosanoids in biologic samples using high pressure liquid chromatography and radioimmunoassay.

A method to measure PGE3 in biologic samples is described. Complete resolution of PGE3 from PGE1 and PGE2 is achieved by reversephase high pressure liquid chromatography. Quantification is carried out by radioimmunoassay using an antibody directed against PGE2 that has high cross-reactivity with PGE3. Using this method, a marked increase in PGE3 production by mouse kidney tissue and in rat urine was demonstrated after supplemental feeding of omega-3 fatty acids. This method can also be applied to measurement of 6-keto-PGF1 alpha and TXB2 in the same samples.

Effects of dietary linoleic acid enrichment on induction of immune complex nephritis in mice.

In pharmacologic doses E series prostaglandins attenuate the development of immune complex nephritis. We studied the effect of the dietary prostaglandin precursor linoleic acid on murine apoferritin-induced immune complex glomerulonephritis. High, normal, or low linoleic acid diets were fed to mice for 4 weeks prior to and during the intraperitoneal apoferritin administration. A high linoleic acid diet feeding was associated with less proteinuria, less renal histologic damage, and prevented a rise in serum creatinine. We conclude that linoleic acid has a protective effect on the development of murine apoferritin-induced immune complex nephritis.

Prostaglandins and thromboxanes in the bronchoalveolar lavage fluid: possible immunoregulation in sarcoidosis.

Prostaglandins are known to be secreted into body fluids. Arachidonic acid cyclooxygenase metabolites (AACM), including prostaglandin E (PGE), prostacyclin, and thromboxane, were measured in the bronchoalveolar lavage (BAL) fluid in 11 patients with active pulmonary sarcoidosis and 7 healthy volunteers. Using a quantitative technique, we found no difference in the amount of PGE per milliliter lung fluid between the sarcoid group (1,950 +/- 1,507.4 pg/ml lung fluid, mean +/- SD) and the control group (2,112 +/- 932.3 pg/ml lung fluid). In patients with sarcoidosis, there was a positive correlation between the number of lymphocytes in the BAL fluid and the amount of PGE and prostacyclin per milliliters of lung fluid (r = 0.71 and r = 0.81, p less than 0.01), but not thromboxane.

Effects of a dietary prostaglandin precursor on the progression of experimentally induced chronic renal failure.

The effect of increasing a dietary PG precursor on the progression of chronic renal failure was studied in the partially nephrectomized rat. NLA or HLA diets were pair-fed to groups of 3/4-nephrectomized and sham-operated rats. Serum creatinine and urinary protein excretion were measured serially. Nephrectomized rats on the NLA diet had progressive deterioration of renal function, the serum creatinine level rising to 1.55 mg/dl by week 20. At week 20, by contrast, nephrectomized rats on the HLA diet maintained stable renal function; the serum creatinine level was 0.97 mg/dl at week 20. Urinary protein excretion was significantly lower and glomerular sclerosis was prevented in the rats fed the HLA diet. No changes were observed in the levels of blood pressure, serum cholesterol, or serum triglycerides as an effect of the diet. Increased PGE2 production, measured by radioimmunoassay in the renal cortex of rats on the HLA diet, suggested that the protective effect upon renal function in this model of chronic renal failure may be mediated by increased renal cortical PG formation.

High linoleic acid diets ameliorate diabetic nephropathy in rats.

The value of high polyunsaturated fatty acid (PUFA) diets in preventing diabetic nephropathy in rats was studied. Diabetes was induced by intravenous injection of streptozotocin (SZ), 65 mg/kg. Rats were divided in four groups fed diets containing 11% fat for 38 weeks. Dietary fat derived from four sources: beef tallow (BT; rich in saturated fatty acids), evening primrose oil (EPO; rich in gamma linolenic [GLA] and linoleic acids [LA]), safflower oil (SO; rich in LA), and fish oil (FO; rich in eicosapentaenoic [EPA] and docosahexaenoic [DHA] acids). Ultralente insulin was administered every other day to maintain the blood glucose levels between 11.1 and 22.2 mmol/L (200 and 400 mg/dL). The diets prepared with EPO and SO had a clear beneficial effect on proteinuria, glomerular sclerosis, and tubular abnormalities, as compared with BT. Both diets also increased the ratio of renal cortical production of 6-keto-PGF1 alpha to thromboxane B2 (TXB2), the stable metabolites of PGI2 and TXA2, respectively. They did not induce significant changes in plasma lipid composition. The FO diet did not have an effect on renal disease, but decreased plasma lipids and inhibited eicosanoid synthesis by platelets and kidney cortex. FO feeding was associated with a lowered 6-keto-PGF1 alpha/TXB2 ratio. It is concluded that high LA diets are protective in this model of diabetic nephropathy. The effect may be secondary to modifications of the eicosanoid balance. Diets containing FO have a beneficial effect on plasma lipids in this model.

A low protein-high linoleate diet increases glomerular PGE2 and protects renal function in rats with reduced renal mass.

Renal function deteriorates progressively in partially nephrectomized rats. This deterioration of renal function may be ameliorated by a diet either low in protein or high in linoleic acid. In the present experiment, partially nephrectomized rats were pair fed diets low in protein, high in linoleic acid or both low in protein and high in linoleic acid. Survival of renal function was most prolonged in rats fed a diet with both a low protein and high linoleic acid content; glomeruli from these animals demonstrated increased glomerular PGE2 production. This additive effect may be mediated by increased production of the vasodilatory PGE2 by glomeruli.