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J B Lefkowith

Publications and source records attributed to J B Lefkowith.

At least 55 records · Page 3Linked to original sources
PubMed1991

Role of leukocytes in metabolic and functional derangements of experimental glomerulonephritis.

Nephrotoxic nephritis (NTN) is characterized by an influx of leukocytes into the glomerulus, with accompanying glomerular dysfunction and a marked increase in glomerular eicosanoid production. We examined the relationship between the glomerular inflammatory cell infiltrate and the concomitant metabolic/functional changes in this model of renal disease using a combination of in vivo immunologic strategies to both decrease [X-irradiation and cobra venom factor (CVF)] and increase (preimmunization with rabbit immunoglobulin G or accelerated NTN) the inflammatory cell infiltrate. With the use of these manipulations, a close correlation between glomerular leukocytes and the proteinuria of NTN was observed. The ablative strategies (X-irradiation and CVF) also attenuated the increase in leukotriene B4 (LTB4) generation seen with NTN and virtually completely prevented the increase in thromboxane B2 (TxB2) production (basal and angiotensin II elicited). Accelerated NTN, in contrast, increased and prolonged the rise in glomerular LTB4 production and exacerbated the increase in TxB2 production. Glomerular prostaglandin E2 production was not altered by the induction of nephritis nor any of the aforementioned immunologic manipulations. Regression analysis established that glomerular TxB2 production correlated significantly with the leukocyte influx at both 3 and 24 h. Glomerular LTB4 production correlated only with the presence of leukocytes at 3 h. Both glomerular TxB2 and LTB4 production were closely correlated with the renal dysfunction as assessed by proteinuria. These data suggest that leukocytes play a direct critical role in both the functional and metabolic alterations that occur in the setting of NTN. They further imply that leukocytes are crucial to the observed increase in glomerular eicosanoid production.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Manipulation of the acute inflammatory response by dietary polyunsaturated fatty acid modulation.

Dietary polyunsaturated fatty acid modulation has been used as an anti-inflammatory strategy in experimental models of disease as well as in clinical trials. To elucidate the mechanisms underlying the anti-inflammatory effects of manipulating dietary polyunsaturated fatty acids, the in vivo effects of essential fatty acid (EFA) deficiency and (n-3) fatty acid supplementation were contrasted using a model of acute inflammation induced by the i.p. injection of zymosan into mice. Both diets led to a substantial decrease in tissue (n-6) fatty acid content. EFA deficiency was also characterized by the accumulation of (n-9) fatty acids, particularly 20:3 (n-9), the fatty acid that uniquely characterizes the deficiency state. Dietary (n-3) fatty acid supplementation led instead to marked increases in (n-3) fatty acids, especially 20:5 (n-3). With respect to the antiinflammatory effects of the two diets, EFA deficiency, but not (n-3) fatty acid supplementation, depleted levels of resident peritoneal macrophages. EFA deficiency was also more effective than (n-3) fatty acid supplementation in inhibiting the influx of polymorphonuclear neutrophils in response to zymosan. The effect of the two diets on the in vivo generation of leukotriene(LT)B also differed markedly. EFA deficiency completely inhibited the synthesis of LTB. Dietary (n-3) fatty acid supplementation, in contrast, reduced the production of LTB4 by only 50%. With (n-3) fatty acid supplementation LTB5 was produced. The more modest effect of (n-3) fatty acid supplementation in decreasing LTB4 generation was not due to blockade of the cyclooxygenase pathway. EFA deficiency, but not (n-3) fatty acid supplementation, was associated with the decreased synthesis of thromboxane. Although dietary fatty acid modulation has been shown to diminish platelet activating factor (PAF) synthesis, studies using the PAF receptor blocker, L659989, established that PAF was not a significant factor in the elicitation of leukocytes in this model of inflammation. In summary, the anti-inflammatory effect of EFA deficiency was more marked that that of dietary (n-3) fatty acid supplementation in acute inflammation. This difference in anti-inflammatory potential appeared to be due to either the greater effect of EFA deficiency in decreasing levels of resident peritoneal macrophages or in suppressing the in vivo generation of LTB4.

Acute Disease↗
PubMed1990

Mechanisms underlying the anti-inflammatory effects of essential fatty acid deficiency in experimental glomerulonephritis. Inhibited release of a monocyte chemoattractant by glomeruli.

Injection of nephrotoxic serum into rats results in glomerular inflammation and proteinuria. Rats placed on an essential fatty acid (EFA)-deficient diet are protected from the glomerular macrophage infiltration and the ensuing proteinuria. To account for this protection, we studied EFA-deficient rats to determine if there were defects in macrophage chemotaxis. We also investigated the possibility that EFA deficiency diminishes the production of a glomerular chemoattractant for monocytes. In microchemotaxis assays EFA-deficient macrophages migrated normally. EFA-deficient serum did not appear to contain a chemotactic inhibitor. Cultured glomeruli from control and control nephritic rats were found to elaborate a chemoattractant for monocytes. This chemoattractant activity was markedly enhanced after induction of nephritis, was heat stable, was not altered by inhibition of cyclooxygenase, lipoxygenase, or platelet-activating factor, and did not depend on C or the glomerular inflammatory cell infiltrate. EFA-deficient glomeruli harvested from animals receiving injections with nephrotoxic serum produced markedly less chemoattractant activity than glomeruli from control nephritic animals. Lipid extraction of nephritic glomeruli from control animals yielded chemoattractant activity in the organic phase. Extracts of EFA-deficient nephritic glomeruli had considerably less activity. We propose that EFA deficiency attenuates glomerular inflammation by inhibiting the ability of glomeruli to produce a specific lipid monocyte chemoattractant after exposure to a nephritic stimulus.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1990

Accelerated essential fatty acid deficiency by delta 9 desaturase induction: dissociation between the effects on liver and other tissues.

Essential fatty acid (EFA) deficiency is an important tool in probing the role of arachidonic acid (20:4(n-6] in pathophysiologic processes, but requires stringent and prolonged deprivation of (n-6) fatty acids. The present study investigated whether induction of the delta 9 desaturase, which is responsible for the synthesis of oleate, the precursor of 20:3(n-9) which uniquely accumulates in the deficiency state, might serve to accelerate the biochemical and biological effects of EFA deficiency. By alternately fasting and feeding animals a fat-free diet, it was possible to induce markedly the delta 9 desaturase selectively in liver. This dietary manipulation in consequence led to dramatic and rapid changes in hepatic phospholipid fatty acid composition. Within 2 weeks, 20:3(n-9) to 20:4(n-6) ratios in liver phospholipids were several fold greater than those seen in animals fed a fat-free diet alone. These changes, however, contrasted with those seen in the serum and other tissues. The mol% of 20:3(n-9) in serum was not increased by delta 9 desaturase induction and the 20:3(n-9) to 20:4(n-6) ratio was only modestly increased. The effects of delta 9 desaturase induction were even more attenuated in tissues other than the liver. Desaturase induction led to a doubling in the 20:3(n-9) to 20:4(n-6) ratio in phosphatidylcholine in renal cortex and heart, although the ratio in the other phospholipids was unaffected. The 20:3(n-9) to 20:4(n-6) ratio in peritoneal macrophage phospholipids was unaffected by desaturase induction. Thus, delta 9 desaturase induction greatly augments the synthesis of (n-9) fatty acids within the liver and leads to the rapid and substantial accumulation of the abnormal fatty acid, 20:3(n-9). This markedly augmented synthesis of hepatic 20:3(n-9), however, is not reflected in increased plasma levels of 20:3(n-9), and thus the effects of delta 9 desaturase induction are attenuated in tissues other than the liver. These data underscore the notable ability of the liver to maintain polyunsaturated fatty acid homeostasis.

Animals↗
PubMed1990

Essential fatty acid deficiency ameliorates acute renal dysfunction in the rat after the administration of the aminonucleoside of puromycin.

The administration of the aminonucleoside of puromycin (PAN) to rats causes the nephrotic syndrome that is associated with an acute decline in renal function, and an interstitial infiltrate. We examined whether essential fatty acid deficiency (EFAD), which inhibits macrophage infiltration in glomerulonephritis, affects PAN-induced renal dysfunction. Both control and EFAD rats developed proteinuria that resolved over 28 d. After PAN administration, there was a prominent infiltration of macrophages in rats fed a normal diet. The infiltrate was prevented by the EFAD diet. The absence of a macrophage interstitial infiltrate was associated with a significantly higher Cin in the EFAD rats than in controls at 7 d (5.21 +/- 1.19 versus 0.39 +/- 0.08, P less than 0.002 ml/min/kg BW). In addition, CPAH fell to less than 10 ml/min/kg BW by day 7 in controls, but remained the same as normal in the EFAD. After administration of PAN to control rats, there was no increase in urinary thromboxane excretion or an increase in glomerular thromboxane production. Furthermore, the effect of EFAD could not be mimicked by the administration of a thromboxane synthase inhibitor. Irradiation-induced leukopenia in rats on a normal diet markedly improved glomerular filtration and renal blood flow in acutely nephrotic rats. EFAD prevents the interstitial cellular infiltrate and the renal ischemia associated with experimental nephrosis. The recruitment of mononuclear cells into the kidney following PAN directly contributes to the decline in renal function.

Acute Disease↗
PubMed1990

Essential fatty acid deficiency: probing the role of arachidonate in biology.

EFA deficiency appears to be a uniquely useful tool in probing the role of arachidonate in a variety of physiologic and pathologic processes. Recent studies have clarified the effects of the deficiency state on tissue fatty acid content and on the production of metabolites of arachidonate and related mediators such as PAF. The ability of EFA deficiency to ameliorate a variety of inflammatory states, particularly models of autoimmune disease, is striking. The central mechanism appears to be the ability of EFA deficiency to inhibit leukocyte migration into foci of inflammation. The mechanisms underlying this phenomenon are currently under investigation. Additionally EFA deficiency has the capacity to alter dramatically tissue immunogenicity by affecting the representation of Ia-bearing cells within tissues. The role of arachidonate in the regulation of Ia-bearing cells within tissues is an area of continuing interest.

Animals↗
PubMed1989

The antiinflammatory effects of essential fatty acid deficiency in experimental glomerulonephritis. The modulation of macrophage migration and eicosanoid metabolism.

Dietary polyunsaturated fatty acid modulation exerts a beneficial effect in immune-mediated glomerulonephritis. To elucidate the mechanisms underlying this phenomenon, the effects of essential fatty acid (EFA) deficiency on the heterologous phase of nephrotoxic nephritis in rats (induced by the injection of a rabbit antiglomerular basement membrane antibody) were studied. The heterologous phase of nephrotoxic nephritis was characterized by an invasion of leukocytes into the glomerulus. Polymorphonuclear neutrophils predominated early on (3 h), whereas macrophages predominated at 24 and 72 h. EFA deficiency selectively prevented the influx of macrophages into the glomerulus. The invasion of polymorphonuclear neutrophils, in contrast, was unaffected. The influx of leukocytes into the glomerulus during nephritis was accompanied by a marked enhancement (10- to 40-fold) in glomerular thromboxane and leukotriene B4 production. EFA deficiency largely attenuated this change. Renal dysfunction during the heterologous phase of nephritis was manifested as azotemia, polyuria, sodium retention, and proteinuria. With EFA deficiency, polyuria, azotemia, and sodium retention were not seen. Proteinuria was reduced by approximately 85%. To address whether the lack of macrophage migration into the glomerulus in the context of nephritis with EFA deficiency might be due to a functional defect in macrophage migration, the chemotactic responsiveness of EFA-deficient macrophages was examined. EFA-deficient macrophages displayed normal chemotactic migration toward activated C. In sum, EFA deficiency prevents the invasion of macrophages into the glomerulus in nephrotoxic nephritis and attenuates the accompanying metabolic and functional alterations, but does not affect macrophage chemotactic responsiveness. Alterations in macrophage elicitation and lipid mediator generation by inflamed glomeruli thus appear to be central to the salutary effect of dietary polyunsaturated fatty acid modification on glomerulonephritis.

Animals↗
PubMed1989

Essential fatty acid deficiency inhibits early but not late leukocyte infiltration in rabbit myocardial infarcts.

Essential fatty acid (EFA) deficiency, induced by elimination of the dietary (n-6) fatty acids, has been shown to limit inflammatory cell influx and consequent enhanced eicosanoid production in experimental glomerulonephritis and hydronephrosis. To determine whether EFA-deficiency exerts anti-inflammatory effects following left ventricular myocardial infarction (LVMI), male weanling rabbits were fed EFA-deficient diet for 3 months prior to 60 minutes of distal left circumflex coronary artery occlusion followed by reperfusion. One and 4 days later, corresponding to infiltration of cardiac tissue with polymorphonuclear (PMN) and mononuclear leukocytes respectively, infarcted hearts were buffer perfused and stimulated to produce eicosanoids with f-met-leu-phe or bradykinin. One day following LVMI, the hearts of EFA-deficient rabbits demonstrated a marked suppression of PMN infiltration and eicosanoid production relative to controls. Four days following myocardial infarction, no differences were observed in mononuclear cell invasion, collagen deposition, or eicosanoid production between EFA-deficient and normal hearts. Our data show that EFA-deficiency inhibits PMN influx and consequent enhanced eicosanoid production without affecting the later appearance of mononuclear cells, collagen deposition, or eicosanoid production. Recent studies have shown that suppression of PMN invasion limits the extent of tissue damage following LVMI. Selective inhibition of PMN infiltration is possible and may be useful in the management of acute myocardial infarction.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Essential fatty acid depletion of renal allografts and prevention of rejection.

A central hypothesis in transplantation biology is that resident leukocytes expressing class II histocompatibility antigens may determine the immunogenicity of an organ. By means of a novel method to deplete the kidney of resident leukocytes, essential fatty acid deficiency (EFAD), this hypothesis was tested in an intact, vascular organ. Kidneys subjected to EFAD and thus depleted of resident Ia-positive macrophages survived and functioned when transplanted across a major histocompatibility antigen barrier in the absence of immunosuppression of the recipient. Control allografts were rejected promptly. Allografts from donors subjected to EFAD normalized their lipid composition and were repopulated with host macrophages by 5 days. Administration of Ia-positive cells at the time of transplantation established that the resident leukocyte depletion induced by EFAD was responsible for the protective effect. These observations may provide insights into the mechanisms underlying tissue immunogenicity and the population of normal tissues with resident leukocytes.

Animals↗
PubMed1988

Essential fatty acid deficiency inhibits the in vivo generation of leukotriene B4 and suppresses levels of resident and elicited leukocytes in acute inflammation.

Essential fatty acid (EFA) deficiency exerts an anti-inflammatory effect in several models of inflammation. In an effort to understand underlying mechanisms, the effect of EFA deficiency on the generation of eicosanoids and the elicitation of leukocytes in a model of acute inflammation was examined. Acute inflammation was induced by the i.p. injection of zymosan in mice. The injection of zymosan in normal mice was followed by a short burst of eicosanoid synthesis lasting 2 hr. Leukotriene (LT)B4, LTC4, LTD4, and LTE4, thromboxane B2, and 6-keto-prostaglandin F1 alpha were detected using high pressure liquid chromatography and specific radioimmunoassays. This initial phase of eicosanoid production was followed by a more prolonged infiltration of leukocytes (predominantly polymorphonuclear neutrophils (PMN)) lasting 48 hr with little eicosanoid synthesis. When challenged with zymosan, EFA-deficient mice exhibited a marked decrease in the production of eicosanoids during the early phase. No LTB could be detected at all. The number of resident peritoneal macrophages in EFA-deficient mice was also substantially decreased, and the influx of PMN during the inflammatory response was markedly diminished. In order to establish that the generation of eicosanoids during the early phase of this model of acute inflammation played a causal role in the later infiltration of PMN, the effect of the mixed lipoxygenase/cyclooxygenase inhibitor, BW755C, on LTB formation and PMN influx in this model of inflammation was assessed in control animals. BW755C completely blocked LTB synthesis and inhibited the subsequent influx of PMN. In conclusion, EFA deficiency inhibits eicosanoid generation, depresses levels of resident macrophages, and markedly diminishes the influx of PMN in the acute inflammatory response. The decrease in PMN influx appears to result from the inhibition of the antecedent generation of LTB.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1988

Essential fatty acid deficiency prevents multiple low-dose streptozotocin-induced diabetes in CD-1 mice.

Multiple i.p. injections of low-dose streptozotocin (40 mg/kg) produce insulitis, beta cell destruction, and diabetes in male CD-1 mice. Recent data also suggest that macrophages figure in the low-dose streptozotocin model. Because other recent studies have shown that essential fatty acid deficiency prevents autoimmune nephritis in mice, decreases the number of resident Ia-positive glomerular macrophages, and decreases the elicitation of macrophages into the glomerulus in inflammation, we examined the effect of essential fatty acid deficiency on the incidence and severity of insulitis and diabetes in CD-1 mice treated with low-dose streptozotocin. Streptozotocin-treated mice on the control diet uniformly developed diabetes (19/19). Essential fatty acid-deficient mice treated with streptozotocin did not develop diabetes (1/13). Mean plasma glucose levels for the control and essential fatty acid-deficient mice were 384.5 +/- 23.6 and 129.1 +/- 15.5 mg/dl, respectively, at the end of 1 month. To discern whether essential fatty acid deficiency prevented the streptozotocin-induced beta cell injury or the inflammatory response to injured beta cells, mice were repleted with daily injections of 99% pure methyl linoleate beginning 3 days after the last streptozotocin injection. These mice also quickly developed severe (3/4) or mild (1/4) diabetes. Histologic examination of the pancreata of control mice or repleted mice showed marked insulitis and beta cell destruction; in contrast, the pancreata of essential fatty acid-deficient mice showed preservation of beta cells and only focal mild peri-insulitis. Essential fatty acid deficiency thus prevents the insulitis and resultant diabetes in low-dose streptozotocin-treated CD-1 mice, suggesting a central role for macrophages and lipid mediators in this autoimmunity model.

Animals↗
PubMed1988

Murine glomerular leukotriene B4 synthesis. Manipulation by (n-6) fatty acid deprivation and cellular origin.

Leukotriene (LT) B4 is an important pro-inflammatory autocoid. In order to investigate the potential role of this eicosanoid in renal inflammation, in this study we determined the capability of glomeruli to synthesize this mediator. Glomeruli were able to synthesize LTB4 when provided with exogenous substrate in a dose-dependent fashion in the presence of ionophore A23187. Ionophore, although by itself a weak agonist for LTB4 formation, was required for LTB4 production from exogenous arachidonate. The identity of LTB4 was confirmed by specific radioimmunoassay, high pressure liquid chromatography, and gas chromatography/mass spectrometry. The synthesis of LTB4 was inhibited by BW755C (a lipoxygenase/cyclooxygenase inhibitor) but not indomethacin. Essential fatty acid (EFA) deficiency, obtained by the deprivation of (n-6) fatty acids, is known to exert a protective effect in renal inflammatory states. This dietary manipulation markedly attenuated the ability of glomeruli to synthesize LTB4. In contrast, the synthesis of cyclooxygenase products from exogenous arachidonate was increased by EFA deficiency. Because EFA deficiency has been shown to deplete glomeruli of resident mesangial macrophages, it was hypothesized that this effect accounted for the diminished LTB4 synthesis. To test this hypothesis, glomeruli were depleted of macrophages using x-irradiation. Glomeruli from these animals exhibited a marked decrease in LTB4 synthesis. Glomerular synthesis of cyclooxygenase products was unaffected by irradiation. In sum, glomeruli have the capability to synthesize LTB4, and this capacity is correlated with the presence of glomerular macrophages. EFA deficiency attenuates the ability of glomeruli to synthesize LTB4 by depleting them of macrophages.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1988

Essential fatty acid deficiency reduces the inflammatory cell invasion in rabbit hydronephrosis resulting in suppression of the exaggerated eicosanoid production.

The rabbit hydronephrotic kidney (HNK) is a model of renal inflammation characterized by a marked increase in arachidonic acid metabolism which is temporally associated with an inflammatory cell influx into the injured tissue. The HNK exhibits an exaggerated elaboration of eicosanoids ex vivo in response to inflammatory agonists (bradykinin and the chemotactic peptide, n-formyl-methionyl-leucyl-phenylalanine). Essential fatty acid (EFA) deficiency [i.e., deprivation of (n-6) fatty acids] attenuated markedly the ex vivo elaboration of eicosanoids and prevented the enhancement of the microsomal cyclooxygenase and thromboxane synthase activity associated with 3 days of ureter occlusion. In contrast, postobstructive release prevented the ex vivo elaboration of eicosanoids by the HNK. When the HNK was assessed morphologically by electron microscopy, both EFA deficiency and postobstructive release markedly reduced the population of interstitial macrophages normally seen in the HNK. Apparently, EFA deficiency blocked the influx of macrophages whereas postobstructive release resulted in the efflux of macrophages from the HNK. Because EFA deficiency has been shown to inhibit the synthesis of leukotriene B4, a potential chemotaxin, it was hypothesized that EFA deficiency might prevent the influx of macrophages due to an inhibition of leukotriene B4 synthesis. Indeed, EFA deficiency suppressed the synthesis of this eicosanoid in blood whereas prostaglandin E2 and thromboxane A2 production were unaffected. In summary, this study demonstrates that EFA deficiency prevents the influx of macrophages into the HNK and prevents the enhanced arachidonate metabolism which normally occurs after ureter obstruction. A potential role for leukotriene B4 as a chemotactic agent in this model of renal inflammation also is suggested.

Animals↗
PubMed1987

Metabolic and functional alterations in macrophages induced by essential fatty acid deficiency.

Essential fatty acid (EFA) deficiency has been shown to protect against the glomerulonephritis in a murine model of systemic lupus erythematosus. Since macrophages are an important cellular constituent of the inflammatory lesion, the effects of EFA deficiency on the eicosanoid metabolism and function of these cells were determined. EFA-deficient macrophages exhibited a depletion of phospholipid arachidonate and an accumulation of 20:3(n-9); phosphatidylinositol was the phospholipid most affected. When these macrophages were stimulated with unopsonized zymosan, they produced markedly less leukotriene C4 and B4 than control macrophages. EFA-deficient macrophages also synthesized leukotriene C3 from endogenous 20:3(n-9). No leukotriene B3 was detected. In contrast to the effects on leukotriene production, prostaglandin and thromboxane production were only minimally affected by EFA deficiency. When challenged with zymosan, EFA-deficient macrophages released less arachidonate relative to control macrophages and released half again as much 20:3(n-9) as arachidonate. Release of arachidonate from phosphatidylcholine in the EFA-deficient cells was highly selective for arachidonate; however, release of arachidonate from phosphatidylinositol was depressed relative to control and was not selective. Incubation of macrophages with exogenous arachidonate and 20:3(n-9) established that 20:3(n-9) decreased leukotriene C4 and B4 synthesis from arachidonate but did not affect prostaglandin production. To determine the functional effects of the deficiency state, receptor-mediated pinocytosis and phagocytosis were also examined in EFA-deficient cells. EFA-deficient macrophages exhibited a marked reduction in receptor-mediated pinocytosis. Phagocytosis, however, was unaffected by the deficiency state. These effects on macrophage eicosanoid metabolism and function may comprise a significant component of the anti-inflammatory effect of EFA deficiency.

Animals↗
PubMed1987

Essential fatty acid deficiency depletes rat glomeruli of resident macrophages and inhibits angiotensin II-induced eicosanoid synthesis.

Essential fatty acid (EFA) deficiency exerts a beneficial effect on immune-mediated glomerulonephritis, preventing both the tissue injury and consequent mortality. Because both macrophages and eicosanoids are thought to play pathogenic roles in glomerulonephritis, and because macrophages play an important role in modulating arachidonate metabolism at sites of renal injury, the effects of EFA deficiency on the population of resident glomerular macrophages and on glomerular eicosanoid generation were examined. EFA deficiency led to a striking reduction in the number of resident glomerular macrophages and a corresponding reduction in the number of resident glomerular Ia+ cells. This phenomenon was not strain-specific, was not due to a decrease in circulating monocytes, was not a function of changes in cell surface labeling characteristics, and was not restricted to a specific subset of glomeruli. In addition, EFA deficiency affected other areas of the renal cortex: a comparable depletion of interstitial macrophages and Ia+ cells was also observed. In conjunction with the decrease in glomerular macrophages seen with the deficiency state, a marked decrease in both basal and angiotensin II-stimulated glomerular eicosanoid production was noted. In contrast to angiotensin II, platelet-activating factor-induced eicosanoid production was not significantly affected by the deficiency state. These changes in glomerular eicosanoid production could not be attributed to changes in glomerular cyclooxygenase or reacylation capacity. Dietary (n-6) fatty acid supplementation, but not (n-3) fatty acid supplementation, reversed both the decrease in glomerular macrophages and the diminished eicosanoid metabolism seen with the deficiency state. Understanding the mechanisms behind the changes in the glomerular microenvironment induced by EFA deficiency may provide a basis for elucidating the protective effect of dietary fatty acid manipulation on immune-mediated glomerulonephritis.

Angiotensin II↗
PubMed1986

Glucose-induced phospholipid hydrolysis in isolated pancreatic islets: quantitative effects on the phospholipid content of arachidonate and other fatty acids.

Our recent findings indicate that glucose-induced insulin secretion from isolated pancreatic islets is temporally associated with accumulation of substantial amounts of free arachidonic acid and that arachidonate may serve as a second messenger for intracellular calcium mobilization in islets. In an effort to determine the source of this released arachidonate, the endogenous fatty acid composition of phospholipids from islets has been determined by thin-layer chromatographic separation of the phospholipids, methanolysis to the fatty acid methyl esters, and quantitative gas chromatographic analyses. The relative abundance of phospholipids in islets as judged by their fatty acid content was phosphatidylcholine (PC), 0.63; phosphatidylethanolamine (PE), 0.23; phosphatidylinositol (PI), 0.067; phosphatidylserine (PS), 0.049. Arachidonate constituted 17% of the total islet fatty acid content, and PC contained 43% of total islet arachidonate. Islets incubated with [3H]arachidonate in the presence of 28 mM D-glucose incorporated radiolabel into PC with a considerably higher specific activity than that of PE, PS or PI. The total fatty acid content of PC from islets incubated with 28 mM glucose for 30 min was significantly lower than that of islets incubated with 3 mM glucose, and smaller effects were observed with PE, PS and PI. The molar decrement in PC arachidonate was 3.2 pmol/islet under these conditions, which is sufficient to account for the previously observed accumulation of free arachidonate (2 pmol/islet). A sensitive method involving negative ion-chemical ionization-mass spectrometric analyses of the pentafluorobenzyl esters of fatty acids derived from trace amounts of lysophosphatidylcholine (lyso-PC) was developed, and glucose-stimulation was found to reduce islet lyso-PC content by about 10-fold. These findings indicate that the insulin secretagogue D-glucose induces phospholipid hydrolysis in islets and suggest that PC may be the major source of free arachidonate which accumulates in glucose-stimulated islets.

Animals↗