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J J Spitzer

Publications and source records attributed to J J Spitzer.

At least 91 records · Page 5Linked to original sources
PubMed1991

Alcohol-induced downregulation of superoxide anion release by hepatic phagocytes in endotoxemic rats.

Bacterial endotoxins [lipopolysaccharide (LPS)] are potent immunomodulators, and ethanol is known to depress certain immune defense mechanisms. Thus the combined impact of these two agents on the generation of superoxide anion (O2(-).) by isolated hepatic phagocytic cells was investigated. Ethanol was infused intravenously into rats for 7 h, and Escherichia coli LPS was injected intravenously at 4 h after ethanol administration. Control groups received an equal volume of saline or ethanol alone. Nonparenchymal cells that were composed of endothelial and Kupffer cells and few polymorphonuclear neutrophils (PMN; less than 1%) were obtained after collagenase-pronase digestion. In the LPS-treated rats, the total number of PMN per liver increased significantly. Histological sections of the liver showed PMN infiltration and areas of necrosis after LPS treatment with or without ethanol. In the presence of either phorbol 12-myristate 13-acetate or opsonized zymosan in vitro, Kupffer cells and hepatic PMN from LPS-treated rats generated large amounts of O2(-).. Ethanol intoxication in vitro by these cells to 50%. Ethanol alone (without LPS) had no effect on the production of O2(-).. These studies demonstrate that ethanol intoxication was associated with the downregulation of the LPS-enhanced in vivo priming of hepatic phagocytes to generate O2(-). in vitro and may thus contribute to the enhanced susceptibility of alcoholic subjects to develop an infection.

Animals↗
PubMed1991

Ethanol oxidation is not required to attenuate endotoxin-enhanced glucose metabolism.

Previous studies from our laboratory demonstrated that acute ethanol (EtOH) intoxication, through an unknown mechanism, blunts the endotoxin-enhanced carbohydrate metabolism. The purpose of the present study was to determine whether oxidation of the ethanol moiety is required for the inhibition of the endotoxin-induced changes in carbohydrate metabolism. In vivo glucose kinetics were assessed by the intravenous administration of D-[3-3H]glucose in catheterized conscious unrestrained rats. Escherichia coli endotoxin (200 micrograms/100 g body wt) increased glucose rate of appearance (Ra) and metabolic clearance rate (MCR) by 75 and 50%, respectively. A primed-constant infusion of EtOH (275 mg/100 g + 25 mg.100 g-1.h-1) initiated 2 h before endotoxin challenge attenuated the endotoxin-enhanced glucose kinetics. EtOH intoxication did not prevent endotoxin-induced hyperglycemia but delayed the hyperlactacidemic response. The importance of EtOH metabolism in suppressing the glucose metabolic response to endotoxin was studied by administering 4-methyl-pyrazole (4-MP; 8 mg/100 g), an inhibitor of alcohol dehydrogenase activity. After administration of 4-MP and a bolus injection of EtOH (275 mg/100 g), the plasma EtOH concentration remained constant and matched the level of EtOH in rats receiving a primed-constant infusion of EtOH. Inhibition of EtOH metabolism with 4-MP did not abrogate the ability of EtOH to suppress endotoxin-induced increases in glucose Ra or MCR. Furthermore, the injection of the nonmetabolized alcohol tert-butanol abolished the endotoxin-induced increase in glucose Ra and MCR without preventing the endotoxin-induced hyperglycemia and hyperlactacidemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Dehydrogenase↗
PubMed1991

Superoxide generation by Kupffer cells and priming of neutrophils during reperfusion after hepatic ischemia.

The objective of this study was to identify the cellular source of the vascular oxidant stress in hepatic ischemia-reperfusion injury in male Fischer rats. Nonparenchymal cells (Kupffer cells, endothelial cells) and neutrophils were isolated from postischemic liver lobes by collagenase-pronase digestion followed by centrifugal elutriation. The spontaneous and stimulated generation of superoxide by these cells were subsequently quantified in vitro. Large Kupffer cells from the postischemic lobes spontaneously generated 300% more superoxide than similar cells from control animals. No difference in spontaneous superoxide formation was found when the small Kupffer cells were compared. No other cells isolated from the postischemic lobes or control liver including neutrophils released any detectable superoxide spontaneously. In contrast, small Kupffer cells and neutrophils from the postischemic liver generated significantly more superoxide after stimulation with phorbol ester or opsonized zymosan than the controls. The considerably higher response with zymosan stimulation compared to phorbol ester indicates a particular priming for a receptor-mediated signal transduction pathway during reperfusion. These studies demonstrate that Kupffer cells are the principal source of the oxidant stress during the initial reperfusion phase after hepatic ischemia. The priming of neutrophils during this time may be an important factor for the later neutrophil-induced injury phase.

Animals↗
PubMed1991

Metabolic response of isolated liver cells to in vivo phagocytic challenge.

This study elucidates the in vivo metabolic response of different liver cells after a single phagocytic challenge. In vivo glucose uptake of different tissues and isolated liver cells was determined by a sequential double labeling version of the 2-deoxyglucose technique. After latex administration, glucose uptake more than doubled in the liver, increased by about 50% in the spleen and lung and was not changed in muscle and testis. Within 10 min after intravenous injection of latex beads, neutropenia developed, with no change in the number of lymphocytes. This was accompanied by a marked influx of polymorphonuclear leukocytes into the liver. Latex was found in 52%, 35%, and 14% of the isolated Kupffer cells, polymorphonuclear leukocytes and endothelial cells, respectively. In vivo glucose uptake increased by 111%, 142%, and 43% in these cells. Glucose uptake by the latex-free hepatocytes was also elevated, presumably by way of intercellular signals between parenchymal and non-parenchymal liver cells. Indomethacin pretreatment resulted in the delay of neutrophil immigration into tissues without any change in the glucose response of different liver cells. Thus phagocytic stimulation in vivo results in marked neutropenia, migration of neutrophils into the liver, increased glucose uptake by phagocytic cells of the liver and enhanced glucose metabolism by the non-phagocytic parenchymal cells.

Animals↗
PubMed1990

Superoxide anion generation in the liver during the early stage of endotoxemia in rats.

Infiltration of polymorphonuclear neutrophils (PMN) in the rat liver 3 hr after an intravenous (IV) injection of a sublethal dose of Escherichia coli lipopolysaccharide (LPS) was observed without any significant alteration in the total number of Kupffer and endothelial cells. Since previous studies have demonstrated that phagocytic cells in the liver were in a state of metabolic activation under similar experimental conditions, we investigated the in vitro generation of superoxide anion (O2-) by this cell type following the administration of LPS. Kupffer cells from normal rats did not release O2-, in contrast to those obtained from LPS-treated rats. The generation of O2- by Kupffer cells from endotoxic rats was elevated from 3.0 +/- 1.9 nmol/10(6) cells/60 min (mean +/- SD) in the absence of macrophage (M phi) activators, to 5.0 +/- 2.36, 11.33 +/- 5.40, and 4.33 +/- 0.90 in the presence of opsonized zymosan, phorbol myristate acetate (PMA), and the calcium ionophore A23187, respectively. Hepatocytes from normal or endotoxic rats did not produce detectable O2-. Endothelial cells from LPS-treated rats generated less than 0.8 nmol/10(6) cells in the presence of zymosan. PMN that accumulated in the livers of endotoxic rats released O2- only in the presence of zymosan (8.12 +/- 5.40), PMA (15.43 +/- 5.84), or A23187 (1.70 +/- 0.12). The O2- generation by blood monocytes and PMN increased significantly after endotoxin administration and in the presence of activators. These results suggest that the hypermetabolic state of phagocytic cells in the liver shortly after LPS treatment may be correlated with the increased generation of O2-. The latter may subsequently contribute to the induction of hepatic injury in endotoxemia.

Animals↗
PubMed1990

The effect of ethanol infusion on the altered glucose turnover during bacterial infection.

The increased glucose turnover seen during the hypermetabolic, hyperdynamic phase of sepsis is part of the body's defense mechanisms. In contrast, the metabolism of ethanol (ETOH) is known to compromise hepatic gluconeogenesis under certain conditions. This study tested the hypothesis that acute infusion of ETOH inhibits the elevated glucose production that is manifested during infection and thereby alters the normal responses to sepsis. In catheterized conscious rats, ETOH or saline infusion was started 24 hours before the induction of sepsis, and continued throughout the experiment. In vivo glucose kinetics were assessed by the infusion of [6-3H, U-14C]-glucose 24 hours after the induction of sepsis. The characteristic sepsis-induced hyperthermia was prevented in ETOH-infused animals. Sepsis increased the plasma lactate concentration (100%), as well as the rates of glucose appearance ([Ra] 77%), recycling (213%), and metabolic clearance ([MCR] 82%) in saline-infused control animals. In contrast, ETOH infusion prevented the sepsis-induced increase in glucose Ra and markedly attenuated the increase in plasma lactate (49%) and glucose recycling (97%). The infusion of ETOH increased the lactate/pyruvate and beta-hydroxybutyrate (BHBA)/acetoacetate (AcAc) ratio in both septic and nonseptic rats. These results indicate that ETOH administration attenuates the increased glucose production, utilization, and elevated arterial lactate, and prevents the hyperthermic response seen during the hypermetabolic phase of sepsis. Thus, ethanol intoxication alters the normal metabolic responses to sepsis, thereby contributing to the compromised host defenses against the challenging bacteria.

3-Hydroxybutyric Acid↗
PubMed1990

Role of insulin in the blunted glucose metabolic response of septic rats to epinephrine.

Epinephrine produces smaller incremental increases in plasma glucose concentration and rate of glucose appearance (Ra) in septic rats compared with nonseptic animals. In the present study, we investigated the role of insulin in the diminished response of septic rats to epinephrine-induced increases in glucose turnover. Glucose kinetics were assessed by the infusion of [6-3H]-glucose in conscious catheterized rats made septic by subcutaneous injections of live Escherichia coli. Epinephrine was infused at 1 micrograms/min/kg for 2 hours in the presence and absence of somatostatin and mannoheptulose (SRIF + MH). In comparison to nonseptic control animals, epinephrine-induced increases in plasma glucose concentration and glucose Ra were blunted by more than 50% in the septic rats. Infusion of SRIF + MH with epinephrine restored the blunted response to normal. During the infusion of epinephrine alone, the plasma insulin concentration in the septic rats was 2.8-fold higher than the nonseptic controls. SRIF + MH lowered the plasma insulin concentrations in both the nonseptic and septic rats to less than 10 microU/mL. SRIF + MH reversed the sepsis-induced hyperglucagonemia, but did not prevent a slight increase in glucagon levels during the epinephrine infusion in the nonseptic rats. In a second study, septic rats infused with SRIF + MH and replacement insulin showed a smaller increase in glucose concentration and glucose production in response to epinephrine than did septic animals administered SRIF + MH and no insulin. These results indicate that insulin plays an important role in the diminished response of septic rats to epinephrine.

Animals↗
PubMed1990

Superoxide anion generation by in situ perfused rat liver: effect of in vivo endotoxin.

A simple method is described to monitor the superoxide dismutase (SOD)-inhibitable production of superoxide anion (O2-.) in the liver. The isolated rat liver was perfused in situ with ferricytochrome c, and the reduction of this substrate during perfusion was determined. Within 30 s after the introduction of the substrate, significant reduction of ferricytochrome c was observed and stabilized at 2-4 min. A marked reduction of the substrate was observed in the livers of rats that received Escherichia coli lipopolysaccharide (LPS, 1 mg/kg) in vivo 3 h before liver perfusion. Ferricytochrome c reduction was inhibited by SOD, but not significantly with allopurinol or deferoxamine mesylate in the livers of LPS-treated rats. Control livers exhibited only a small reduction of the substrate, and this was not significantly inhibited by SOD. After in vivo LPS administration, O2-. production peaked in the liver at 3 h (6.6 nmol/min) and returned toward normal at 6 h (1 nmol/min) after endotoxin. The amount of O2-. generated by the endotoxic livers was dose related. At 3 h post-LPS, neutrophil infiltration and necrotic areas were found in the histological sections of the liver with concomitant elevation of serum aminotransferases, indicating hepatic abnormalities during the early stage of endotoxemia. Phorbol myristate acetate in the perfusion system markedly enhanced O2-. generation in the endotoxic liver. These results show that the perfused rat liver can be used to measure O2-. generation following in vivo stimuli. The data also demonstrate that O2-. release after LPS treatment in vivo is a short and early event and may have an important role in hepatic injury in endotoxemic conditions.

Alanine Transaminase↗
PubMed1990

Ethanol attenuates endotoxin-enhanced glucose utilization.

Ethanol (EtOH) is known to alter various aspects of cellular metabolism. Among these, the blunting of the increased rate of glucose production and utilization by the host after the administration of endotoxin may be an important factor in the increased susceptibility to infections. Therefore the present study was conducted to determine which tissues are responsible for the attenuation of the endotoxin-induced increase in whole body glucose utilization after acute EtOH administration. In vivo glucose metabolic rate (Rg) of different organs was investigated in conscious rats by the tracer 2-deoxy-D-glucose technique. Rats received a slow intravenous bolus injection of EtOH (275 mg/100 g body wt of a 20% wt/vol solution) followed by a continuous infusion (25 mg/100 g body wt) that was maintained throughout the experimental period. Thirty minutes after initiation of the EtOH treatment, Escherichia coli endotoxin (100 micrograms/100 g body wt) was administered intravenously. Time-matched control animals received an equal volume of saline. EtOH alone affected Rg only in gastrocnemius muscle (30% decrease) and adipose tissue (twofold increase). Endotoxin alone increased Rg in all tissues examined except in heart and brain. Prior administration of EtOH inhibited the endotoxin-induced increased Rg in skeletal muscle (regardless of fiber type), ileum, liver, adipose tissue, and kidney, blunted the increase in spleen and lung, and did not alter the increased Rg in skin. Brain showed a 20% decrease in Rg in response to EtOH and endotoxin administration. The EtOH-attenuated increase in glucose utilization in the macrophage-rich tissues of endotoxin-treated rats may be a reflection of an impaired capacity of these tissues to respond to infection.

Animals↗
PubMed1990

Diaphragmatic fatigue after endotoxemic shock in rats: in vitro function and metabolism.

A rat model was used to study the effects of endotoxemic shock in vivo on diaphragmatic tension generation and diaphragmatic metabolism in vitro. Animals were injected with E. coli lipopolysaccharide (30 mg/kg) and killed at fixed times after injection. The hemidiaphragms were isolated in an organ bath, and tension generation was measured during electrical stimulation of the phrenic nerve or diaphragmatic muscle. Diaphragmatic oxygen consumption was measured in vitro during rest and during in vivo stimulation. Adenosine triphosphate and glycogen concentrations were measured in vivo before the animals were killed and in vitro. Tension generation was reduced in a time-dependent fashion after endotoxin at all stimulation frequencies. Both contractile fatigue and transmission fatigue were present. Glycogen stores were reduced but not depleted. ATP concentration was reduced in vivo but recovered in vitro. Diaphragmatic oxygen consumption was reduced in vitro at rest and during stimulation. The results suggest that endotoxemic shock results in diaphragmatic fatigue in a time-dependent fashion, that impaired neural or neuromuscular transmission is present in vitro, and that impaired oxygen consumption in the shocked diaphragm is associated with reduced high-energy-phosphate stores.

Adenosine Triphosphate↗
PubMed1989

Epinephrine-induced increase in glucose turnover is diminished during sepsis.

The responsiveness of septic rats to epinephrine-induced alterations in carbohydrate metabolism was studied. Nonlethal sepsis was produced by subcutaneous injections of live Escherichia coli over 18 hours in conscious catheterized rats. Glucose kinetics were assessed by IV infusion of [6-3H]-glucose. After two hours of tracer infusion, blood samples were taken for basal values. Thereafter, epinephrine was infused at 0, 0.05, 0.2, or 1.0 microgram/min/kg for an additional four hours. Compared with nonseptic rats, septic animals had increased basal values for glucose rate of appearance (Ra, 63%), glucose clearance (86%), and plasma lactate concentration (133%). Infusion of epinephrine resulted in dose-dependent increases in glucose Ra, as well as plasma glucose and lactate concentrations, and decreases in glucose clearance and muscle glycogen content. At each dose of epinephrine, the increases in response from basal of plasma glucose and glucose Ra in septic rats were 50% or less of that observed in nonseptic animals. There were no differences between septic and nonseptic rats in plasma lactate and glucose clearance responses from basal or in circulating levels of catecholamines achieved during the epinephrine infusion. The present results indicate that septic rats are less responsive than control animals to epinephrine-induced increases in glucose turnover.

Animals↗
PubMed1989

Acute alcohol infusion suppresses endotoxin-induced serum tumor necrosis factor.

Tumor necrosis factor (TNF) is suggested to play an important role in host defense as well as in eliciting some of the metabolic alterations in endotoxemia. Bacteria and their products are involved in triggering the production and release of TNF. Alcohol consumption is known to suppress the immune system and increase susceptibility to infections. The present study was undertaken to investigate the effect of acute ethanol administration on the ability of endotoxin to increase circulating TNF levels and to determine the relationship between blood ethanol levels and endotoxin-induced serum TNF. A 50% decrease in serum TNF levels was seen 1-1.5 h after endotoxin challenge in conscious rats with blood alcohol levels between 75-175 mg/dl. A dose-related depression of serum TNF was observed with increasing blood alcohol levels. This was accompanied by a markedly diminished hyperlactacidemia seen following endotoxin administration. These data suggest that impaired TNF release may have a role in the altered immune response of alcoholics to infection.

Animals↗
PubMed1989

Ethanol administration diminishes the endotoxin-induced increase in glucose metabolism.

The metabolism of ethanol (ETOH) is known to increase the cytosolic NADH/NAD ratio and consequently impairs hepatic glucose output in the fasted state. In contrast, one of the characteristic alterations in glucose metabolism produced by the administration of endotoxin is an increase in the de novo synthesis of glucose. Therefore, the present study tests the hypothesis that the acute administration of ETOH will prevent the endotoxin-induced increase in glucose production. In vivo glucose kinetics were determined by the infusion of [6-3H, U-14C]glucose in catheterized conscious rats. The intravenous infusion of tracer glucose, and ETOH (100 mg/100 g b.w./hr) or saline were started at the same time and both continued throughout the experiment. Two hours later the ETOH infusion rate was decreased to maintain the blood ETOH levels between 100 and 160 mg/dl. At 140 min, endotoxin (100 micrograms/100 g b.w.) was injected. ETOH alone did not alter basal values of plasma glucose (5 mM), glucose rate of appearance (Ra; 35 mumols/min/kg) or metabolic clearance (MCR; 7 ml/min/kg). Endotoxin alone increased plasma glucose (80%) and lactate (140%) concentrations, glucose Ra (60%) and recycling (40%) in saline-infused rats, whereas in ETOH-infused animals, plasma glucose and lactate levels were only elevated 40% and glucose Ra and recycling were unchanged. The results show that acute ETOH administration diminishes the increased glucose production and utilization seen in endotoxemia. The attenuation of the endotoxin effect by ethanol is due to inhibition of hepatic glucose production and peripheral glucose utilization.

Animals↗
PubMed1989

Tissue glucose utilization during epinephrine-induced hyperglycemia.

The aim of this study was to investigate glucose utilization by individual tissues during epinephrine infusion. First, the applicability of the 2-deoxyglucose (2-DG) tracer technique during in vivo hyperglycemia was investigated in model systems in vitro. Epitrochlearis muscle and spleen cells were incubated with 1.25-20 mM glucose. The discrimination against 2-[14C]DG in glucose metabolic pathways, expressed by the lumped constant, remained unchanged over this wide range of glucose concentrations. It was concluded that in vivo hyperglycemia does not preclude the application of the 2-DG method. In a series of in vivo experiments, chronically catheterized conscious rats fasted for 24 h and were infused with epinephrine (0.2 microgram.kg-1.min-1), which produced a two-fold increase in plasma glucose concentration. 2-[14C]DG was injected 30 min after starting the epinephrine infusion and glucose utilization rates of individual tissues were calculated based on the concentration of phosphorylated 2-DG in samples excised at 70 min. The epinephrine infusion increased glucose utilization rates by 40-160% in hindlimb muscles, skin, ileum, liver, spleen, lung, epididymal fat, and kidney, although no change was found in the brain. Mass action of the increased plasma glucose is likely to play an important role in the enhanced rate of glucose utilization.

Animals↗
PubMed1989

Importance of hyperglucagonemia in eliciting the sepsis-induced increase in glucose production.

The plasma concentration of various catabolic hormones, including glucagon and catecholamines, is elevated in sepsis. Furthermore, the infusion of these hormones into control animals increases the rate of glucose production. Previous studies by our laboratory have demonstrated that adrenergic blockade alone is not able to reverse or prevent the sepsis-induced increase in glucose metabolism. Therefore, the purpose of the present study was to determine whether the sepsis-induced hyperglucagonemia was important to maintain the elevation in glucose metabolism. Hypermetabolic sepsis was produced in chronically catheterized conscious rats by repeated subcutaneous injections of Escherichia coli. Glucose kinetics, assessed by the constant i.v. infusion of [6-3H]- and [U-14C]-glucose, were determined in septic and nonseptic rats prior to and for 3-4 hr after the infusion of somatostatin with or without insulin replacement. Sepsis increased the rate of glucose appearance (80%), recycling (276%), and metabolic clearance (88%), as well as the plasma lactate concentration (140%), compared to nonseptic rats. Lowering both the insulin and glucagon concentration with somatostatin did not attenuate the sepsis-induced increases in glucose metabolism. However, when the hyperglucagonemia was selectively reduced by replacing insulin, and euglycemia was maintained by a glucose infusion, the elevated rate of endogenous glucose production returned to levels not different from nonseptic animals. In contrast, the sepsis-induced elevation of glucose clearance was unaltered under these conditions. These results indicate that during hypermetabolic sepsis the elevated glucagon level is an important mediator of the enhanced rate of gluconeogenesis.

Animals↗
PubMed1989

Altered control of carbohydrate metabolism in endotoxemia.

Based on our data, we envisage the following sequence of events to occur after the administration of a moderately severe dose of endotoxin: Sympathetic stimulation due to hypotension, and possibly other factors, increases plasma concentration of catecholamines. Increased hepatic phosphorylase a activity depletes existing glycogen stores and causes transient hyperglycemia. Lactate release from skeletal muscle is also enhanced, due to the more sustained activation of muscle phosphorylase a and increased uptake of plasma glucose. Stimulation of the immunologically active tissues by endotoxin with the participation of mononuclear phagocytes and TNF results in elevated glycolysis in these tissues as well, thus further enhancing the hyperlactacidemia. The increased precursor concentration and their delivery to the liver stimulate gluconeogenesis, in spite of endotoxin-induced suppression of PEPCK activity. Thus, an elevated precursor supply accelerates gluconeogenesis which is primarily responsible for the increased glucose Ra when hepatic glycogen stores are depleted. It appears that both an increase in blood lactate and catecholamines are important in maintaining the increased gluconeogenesis. This is illustrated schematically in Fig. 4. We postulate that in the fasted nutritionally nonsupported rat, endotoxin enhances glucose utilization in immunologically active tissues as well as in muscle. The presence of catecholamines and the glycolytically produced lactate stimulates gluconeogenesis. These events support the mounting of an effective immune response and aid the body to maintain the immune response by conserving glucose carbon.

Animals↗