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Biomedical subjects

J J Spitzer

Publications and source records attributed to J J Spitzer.

At least 73 records · Page 4Linked to original sources
PubMed1992

Effect of granulocyte colony-stimulating factor on sepsis-induced changes in neutrophil accumulation and organ glucose uptake.

Neutropenia was seen in rats made septic by subcutaneous (sc) injection of Escherichia coli. The sepsis-induced increase in glucose uptake by tissues distant from the site of infection was not associated with increased myeloperoxidase (MPO) activity. Only the skin and muscle at the site of infection demonstrated an increase in both glucose uptake and MPO activity. Granulocyte colony-stimulating factor (G-CSF) attenuated the sepsis-induced decrease in circulating neutrophils. Both glucose uptake and MPO activity of skin and muscle adjacent to the infection site showed a smaller increase in G-CSF treated rats. In contrast, septic rats injected with G-CSF exhibited a greater number of leukocytes and a larger reduction in the number of bacteria in the sc lavage fluid. These results demonstrate that G-CSF is a potent immunomodulator that stimulates neutrophil function and also increases their recruitment to the site of infection, resulting in improved bacterial killing and host defense.

Animals↗
PubMed1992

Acute ethanol intoxication prevents lipopolysaccharide-induced down regulation of protein kinase C in rat Kupffer cells.

Protein kinase (PK) C has been implicated in a number of cellular events, many of which are also known to be affected by ethanol (ETOH). ETOH intoxication is also known to impair immune function, thereby increasing the host's susceptibility to infection. The purpose of this study was to assess the effect of acute ETOH intoxication on PKC activity and its intracellular distribution in nonparenchymal liver cells following an E. coli lipopolysaccharide (LPS) challenge. The liver was chosen for the study because it is the primary site both for metabolism of ETOH and detoxification of gut derived bacterial products. Catheterized conscious rats were administered saline or ETOH (175 mg/100 g body weight as a bolus followed by a continuous, 7 hr infusion of 28 mg/100 body weight/hr). LPS was injected intravenously (100 micrograms/100 g body weight) 3 hr before the end of the saline or ETOH infusion. Kupffer and endothelial cells were isolated by collagenase-pronase digestion followed by centrifugal elutriation. PKC was assayed after extraction with digitonin containing buffer and partial purification on DE-52 cellulose minicolumns. LPS decreased PKC activity by 69% from control values. Although ETOH infusion alone did not affect PKC activity in Kupffer cells, it completely abrogated the LPS effect. A similar trend was observed for the endothelial cells. No significant differences were observed between groups with respect to the intracellular distribution of PKC. The down-regulation of PKC by LPS may represent a mechanism of functional adaptation of the immunocompetent cells to one of the cytokines, i.e., TNF, whose receptors are down regulated by activation of PKC.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholic Intoxication↗
PubMed1992

Modulation of f-met-leu-phe induced chemotactic activity and superoxide production by neutrophils during chronic ethanol intoxication.

Chronic alcohol consumption has been associated with increased migration of neutrophils into liver that could contribute to the development of alcoholic liver disease. Mild endotoxemia may be at least partially responsible for this condition since endotoxemia was shown to be present in virtually all chronic alcoholics. This study examines the release of superoxide anion and chemotactic activity by Kupffer cells and sequestered hepatic as well as blood neutrophils during chronic alcohol intoxication (16 weeks) alone, and following an intravenous injection of Escherichia coli lipopolysaccharide (LPS) (1 mg/kg) 3 hr before cell isolation. Chronic ethanol consumption increased the total neutrophil yield per liver, but did not change the f-met-leu-phe induced chemotactic activity by both hepatic and blood neutrophils. However, the combined insults of ethanol and LPS increased the chemotactic activity and superoxide anion generation by these cells. Plasma from ethanol-fed rats was highly chemotactic to syngeneic normal rat neutrophils. This activity was increased 1.75-fold in the plasma obtained from chronic ethanol plus endotoxin-injected rats. The chemotactic activity of Kupffer cells was not significantly modulated during ethanol intoxication plus endotoxin treatment. The f-met-leu-phe-induced superoxide anion release by Kupffer cells was enhanced after LPS treatment. Chronic ethanol consumption did not induce any effect on this parameter. These observations suggest that functional alterations in neutrophils during chronic ethanol intoxication may contribute to hepatic injury.

Alcoholic Intoxication↗
PubMed1992

Effect of acute alcohol administration on TNF-alpha binding to neutrophils and isolated liver plasma membranes.

The mechanisms underlying the effects of alcohol (ethanol, ETOH) on host defense are poorly understood. ETOH modulation of the cytokine regulatory network is one possible way by which ETOH could alter nonspecific immune function. In this study we examined the ability of acute alcohol intoxication to alter lipopolysaccharide (LPS)-induced changes in tumor necrosis factor (TNF)-alpha binding to neutrophils and isolated liver plasma membranes. Rats were injected intravenously with a primed constant infusion of ETOH for 7 hr to maintain blood ETOH concentration at approximately 35 mM. Four hours after the start of ETOH infusion, the animals received intravenously either sterile saline or LPS (100 micrograms/100 g body weight) and were sacrificed at the end of ETOH infusion. Blood neutrophils and liver plasma membranes were isolated, and TNF-alpha binding characteristics determined using recombinant human [125I]TNF-alpha. ETOH treatment alone induced a significant decrease (51%) of neutrophil Bmax for TNF-alpha, without affecting the cytokine binding to plasma membranes. LPS, with or without ETOH, significantly decreased (61%) neutrophil Bmax for TNF-alpha and increased (115%) its binding to liver plasma membranes. The KD values of binding to either neutrophils or liver plasma membranes were not altered by ETOH or LPS treatment of animals. By decreasing the cytokine binding to neutrophils, ETOH may impair the control exerted by TNF-alpha on cell function, thus damaging host defense.

Alcoholic Intoxication↗
PubMed1992

Attenuation of glucose metabolic changes resulting from TNF-alpha administration by adrenergic blockade.

Administration of tumor necrosis factor (TNF-alpha) increases whole body glucose kinetics and stimulates in vivo glucose uptake by several tissues. Because circulating catecholamines are also increased after TNF-alpha administration, the present study was conducted to examine the potential role of the adrenergic system in eliciting these changes. Rats given 150 micrograms TNF-alpha/kg by intravenous infusion over a 30-min period exhibited an increased rate of glucose appearance (glucose Ra). Combined alpha- and beta-adrenergic blockade (phentolamine and propranolol infusion) prevented the TNF-alpha-induced increase in glucose Ra without influencing plasma glucagon or corticosterone levels. TNF-alpha infusion also increased in vivo glucose utilization (Rg), measured with 2-deoxy-[14C]glucose, in spleen (86%), liver (80%), skin (47%), ileum (71%), lung (53%), and heart (112%). Adrenergic blockade prevented the tissue Rg increase in the spleen, liver, and skin; partially reduced it in the ileum; but did not abrogate it in the lung or heart. The effect of blockade was primarily due to inhibition of the TNF-alpha-induced increase in hepatic glucose output. Whereas the adrenergic system plays a major role on the effect of TNF-alpha on whole body glucose production, its importance in directly mediating TNF-alpha's effect on tissue glucose uptake is minimal.

Animals↗
PubMed1992

Modulation of glucose metabolic response to endotoxin by granulocyte colony-stimulating factor.

The present study examines whether in vivo administration of granulocyte colony-stimulating factor (G-CSF) and the resultant neutrophilia alters basal glucose metabolism or modulates the glucose metabolic response to a subsequent endotoxin [lipopolysaccharide (LPS)] challenge. Rats were injected with human recombinant G-CSF (50 micrograms/kg sc) twice daily for 2 days preceding an injection of LPS. Animals treated with G-CSF showed an eightfold increase in blood polymorphonuclear leukocytes (PMNs) but no detectable changes in hemodynamics or glucose metabolism. In control animals, LPS transiently decreased circulating PMN number, but by 4 h neutrophils had returned to control levels. LPS produced a greater reduction in circulating neutrophils in G-CSF-treated animals, which did not return to pretreatment levels by 4 h. G-CSF also produced marked changes in the glucose metabolic response to LPS. Rates of whole body glucose production and utilization in both control and G-CSF-treated rats were rapidly increased by LPS; however, the increment in glucose flux was 55-100% greater in the latter group. The enhanced rate of hepatic glucose production in this group occurred despite lower plasma levels of lactate and glucagon. The elevated rate of whole body glucose utilization was attributable to the G-CSF-enhanced LPS-induced increase in glucose uptake by the ileum, spleen, liver, and lung. Furthermore, LPS increased glucose uptake by skeletal muscle in G-CSF-treated rats but not in control animals. The enhanced glucose disposal in G-CSF-treated rats was not mediated by increases in plasma glucose or insulin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Sepsis- and endotoxin-induced increase in organ glucose uptake in leukocyte-depleted rats.

Both gram-negative infection and bacterial endotoxin (lipopolysaccharide, LPS) produce a marked neutropenia and increase glucose disposal by peripheral tissues. The purpose of the present study was to determine whether leukocyte depletion before these insults would diminish the commonly observed increases in tissue glucose uptake. Rats were depleted of circulating and marginated leukocytes with cyclophosphamide (CPA). Under basal postabsorptive conditions the subcutaneous injection of live Escherichia coli into control animals enhanced whole body glucose disposal that resulted in part from a stimulation of glucose uptake by the liver, spleen, intestine, and lung. These increases in tissue glucose uptake were not associated with an increase in neutrophil number, as assessed by myeloperoxidase (MPO) activity. CPA-induced leukopenia did not alter the sepsis-induced increase in glucose uptake by these tissues and whole body glucose use remained elevated. In contrast, skin and muscle proximal to the site of infection showed an increase in both glucose uptake and MPO activity. Furthermore, leukocyte depletion attenuated the elevated glucose uptake by skin and muscle near the inflammatory focus. The intravenous injection of LPS also increased whole body glucose disposal and enhanced glucose uptake by the lung, liver, spleen, intestine, and skin in saline-treated rats. Of these tissues the lung, liver, and spleen had a corresponding increase in neutrophil number. The LPS-induced increases in tissue glucose uptake in leukopenic rats were comparable, with the exception of liver and lung. In these tissues the incremental increase in glucose uptake after LPS was reduced 40-50% in leukopenic animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Platelet activating factor stimulates and primes the liver, Kupffer cells and neutrophils to release superoxide anion.

Platelet activating factor (PAF) is considered a key mediator in eliciting the immunologic and metabolic consequences of endotoxic shock and sepsis. Release of oxygen-derived radicals is one of the important and relevant actions of PAF. This study examines the direct and priming effects of PAF on superoxide anion release by perfused liver, isolated Kupffer cells and blood neutrophils. One hour after PAF infusion at a dose of 2.2 micrograms/kg body weight a significant amount of superoxide release (0.71 +/- 0.1 nmol/min/g liver) was measured in the perfused liver compared with the control livers (0.2 +/- 0.01). In the in vitro presence of either phorbol ester or opsonized zymosan, superoxide release following PAF treatment in vivo was significantly increased to 1.36 +/- 0.2 and 4.29 +/- 0.36, respectively. The administration of PAF receptor antagonist (SDZ 63-441) almost completely inhibited the release of this radical. Kupffer cells (KC1, KC2, KC3) and blood neutrophils isolated from PAF-treated rats were also primed for increased production when these cells were challenged in vitro by the activator of protein kinase C, opsonin-coated zymosan as well as the chemotactic factors, complement 5a and F-met-leu-phe. PAF added in vitro to the perfused livers, isolated Kupffer cells or neutrophils from normal animals stimulated the release of superoxide with or without the above agonists. The direct stimulatory effect of PAF on superoxide release was inhibited by the PAF receptor antagonist in vitro. The role of PAF in the LPS-induced superoxide release by the perfused liver was also examined by the administration of PAF antagonist in endotoxic rats. The antagonist inhibited the LPS-mediated superoxide release at 1 hr, but not at 3 hr post-treatment. These results indicate that PAF stimulates and primes the hepatic elements to release superoxide. PAF may be an important factor during the early phase of endotoxemia, while other bioactive substances may take over at a later phase. Therefore, PAF is a key mediator that can directly enhance the release of toxic oxygen-derived radicals which may contribute to organ failure during endotoxemia or sepsis.

Animals↗
PubMed1991

Up-regulation of glucose metabolism in Kupffer cells following infusion of tumour necrosis factor.

Alterations of glucose metabolism and the oxidation of glutamine and palmitate were studied, by using specifically labelled substrates, in freshly isolated Kupffer cells and hepatic endothelial cells after infusion in vivo of human recombinant tumour necrosis factor-alpha (TNF; 7.5 x 10(5) IU/30 min per kg body wt., intravenously). Cells were incubated in a medium containing 5 mM-glucose, 0.4 mM-palmitate, 1 mM-lactate and 0.5 mM-glutamine. Administration of TNF in vivo increased glucose use in Kupffer cells by 70%. Glucose oxidation in the tricarboxylic acid cycle and flux in the Embden-Meyerhof (EM) pathway were elevated by 40 and 80% respectively. Treatment in vitro with 1 microM-phorbol 12-myristate 13-acetate (PMA) resulted in a similar percentage increase in glucose use by Kupffer cells prepared from either saline- or TNF-treated rats. However, PMA increased the activity of the hexose monophosphate shunt (HMS) by 3- and 10-fold in cells isolated from saline- or TNF-infused animals respectively. A phagocyte stimulus in vitro, opsonized zymosan, increased glucose use by 30% and doubled the flux through the HMS in Kupffer cells from saline-infused animals. The activity of the HMS in response to zymosan was increased by 400% after TNF treatment. In endothelial cells, basal glucose utilization was not altered by TNF treatment. PMA increased HMS activity in endothelial cells to a similar degree after saline or TNF infusion. Zymosan, however, increased HMS activity only in endothelial cells from TNF-treated rats. Oxidation of palmitate or glutamine was not affected by TNF treatment either under basal conditions or after challenge in vitro. Our data indicate that, after phagocytosis in vitro or protein kinase C activation, glucose use and flux through the HMS increase in Kupffer cells. This is accompanied by increased glycolytic flux, with no changes in glucose oxidation in the tricarboxylic acid cycle. After TNF exposure, followed by a secondary stimulus, the enhanced glucose use by Kupffer cells is primarily channelled through the HMS pathway. These data suggest that the increased glucose use in vivo by Kupffer cells found after immune-stimulated conditions may subserve primarily the increased need for NADPH and HMS intermediates.

Animals↗
PubMed1991

Tumor necrosis factor increases in vivo glucose uptake in hepatic nonparenchymal cells.

This study aims to elucidate the in vivo metabolic response of different liver cells following a short-term (30 min) infusion of a nonlethal dose of human recombinant tumor necrosis factor (TNF). In vivo glucose uptake of different tissues and isolated liver cells was determined by a sequential double-labeling version of the tracer 2-deoxyglucose technique. Following TNF administration glucose uptake was increased in the liver, lung, spleen, and skin while it was not changed in muscle and testis. In response to TNF infusion neutropenia developed which was sustained for 40 min. The number of lymphocytes in the blood was also decreased after the termination of TNF infusion. This short-term infusion of TNF, however, was not accompanied by marked sequestration of leukocytes into the liver. In vivo glucose uptake in response to TNF was doubled in the Kupffer cells and increased by 56% in hepatic endothelial cells. Glucose uptake of parenchymal cells was not significantly affected. The prompt increase of glucose uptake in the reticuloendothelial cells of the liver, primarily in the Kupffer cells, following TNF administration suggests that a similar metabolic response of these cells to sepsis may be mediated at least in part by TNF. It is suggested that the increased glucose uptake by the hepatic nonparenchymal cells is a reflection of the immunomodulatory effect of TNF.

Animals↗
PubMed1991

Upregulation of glucose metabolism by granulocyte-monocyte colony-stimulating factor.

Alterations of glucose metabolism were investigated for 6 hours following an intraarterial injection of murine recombinant granulocyte-monocyte colony-stimulating factor (GM-CSF) (30 micrograms/kg body weight). GM-CSF resulted in a transient elevation of plasma glucose. The rate of whole body glucose appearance, as measured by infusion of [6-3H] glucose, was increased by about 10% between 0.5 and 3 hours following GM-CSF injection. In vivo glucose utilization of individual tissues was investigated by the tracer 2-deoxyglucose technique. At 30 min, GM-CSF increased glucose utilization by 80-90% in liver and lung, and 50-60% in skin and spleen. At 3 and 6 hours, glucose utilization by these tissues returned toward control levels except for lung. There was a 40-50% increase in glucose utilization by skeletal muscle 30 min after GM-CSF which was sustained for 6 hours. Glucose utilization of testis, ileum and kidney did not change significantly. Plasma concentrations of insulin, glucagon and tumor necrosis factor were not altered in response to GM-CSF. These findings indicate that some of the acute metabolic effects of a short-term administration of GM-CSF are observed in macrophage-rich tissues, and suggest that GM-CSF may be involved in the metabolic upregulation of immunologically active tissues.

Analysis of Variance↗
PubMed1991

Acute ethanol intoxication suppresses E. coli lipopolysaccharide enhanced glucose utilization by hepatic nonparenchymal cells.

During infection or endotoxemia, the immune system is activated and its energy needs increase. Alcohol (ETOH) intoxication on the other hand suppresses the immune system and increases susceptibility to infection. Since the liver is the primary site both for metabolism of ETOH and detoxification of bacterial lipopolysaccharides (LPS), this investigation was directed at studying the effect of acute ETOH intoxication on the LPS-induced enhancement of in vivo glucose utilization in different types of hepatic cells. Rats were given an intravenous (IV) injection of ETOH followed by a constant infusion for 7 hr to maintain blood alcohol levels at about 175 mg/dl. E. coli LPS was administered IV at 4 hr and in vivo glucose utilization by the different types of liver cells was estimated 3 hr later using the 14C-2-deoxyglucose technique. Hepatocytes (HP), Kupffer (KC), and endothelial cells (EC), as well as the sequestered polymorphonuclear leukocytes (PMN), were separated from the liver by collagenase-pronase digestion followed by centrifugal elutriation and Ficoll-Hypaque density gradient centrifugation. The number of PMN in the liver was increased several-fold 3 hr after LPS administration. The presence of ETOH did not inhibit the LPS-induced neutrophil migration into the liver. ETOH depressed the LPS-induced increase in glucose uptake in both EC and KC by 50 to 80%, respectively. It also reduced the LPS-induced increase of plasma tumor necrosis factor activity by 80%. ETOH alone did not produce any significant changes in the parameters studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholic Intoxication↗
PubMed1991

Glucose utilization by Kupffer cells, endothelial cells, and granulocytes in endotoxemic rat liver.

There are several types of glucose-consuming, immunologically active nonparenchymal cells interspersed among the glucose-producing parenchymal liver cells. Combining the in vivo 2-deoxyglucose tracer technique with cell separation methods enabled us to investigate the effect of Escherichia coli endotoxin on the rate of glucose utilization by the nonparenchymal cells. Rats were injected with [14C]deoxyglucose, and intracellular 2-deoxyglucose 6-phosphate was determined in different liver cell fractions. Parenchymal, Kupffer, and endothelial cells as well as polymorphonuclear leukocytes (PMN) were separated from the liver by centrifugal elutriation followed by Ficoll-Hypaque density gradient. The number of PMN obtained from the liver was increased severalfold 3 h after endotoxin and was comparable to the number of Kupffer cells. Glucose utilization by the liver of fasted rats was due predominantly to nonparenchymal cells. Endotoxin enhanced the rate of glucose utilization by Kupffer (6.7-fold) and endothelial (2.7-fold) cells and by the infiltrated hepatic PMN (5.4-fold). Enhanced glucose metabolism of immunologically active cells is part of the hepatic immune response and subserves the antibacterial defense of the body. The activated cells, however, may also have the potential of causing tissue damage by releasing harmful toxic metabolites.

Animals↗
PubMed1991

Endotoxin-induced increases in regional glucose utilization by small intestine: a TNF-independent effect.

The purpose of the present study was to determine whether the lipopolysaccharide (LPS)-induced increase in glucose uptake was a generalized response along the length of the entire gastrointestinal (GI) tract and to assess the relative contributions of the mucosa and muscularis. The putative roles of tumor necrosis factor (TNF) and blood flow in the metabolic response of the intestine to LPS were also examined. In vivo glucose uptake (Rg) was determined for various segments of the GI tract under basal postabsorptive conditions and 3 h after intravenous injection of Escherichia coli LPS using 2-[14C]deoxyglucose. At this time, LPS-treated rats were euglycemic, and Rg was elevated in all sections of the GI tract (52-96%). In control animals, mucosal Rg accounted for 79% of the glucose uptake by the entire small intestine; LPS increased Rg in both the mucosa and muscularis and did not alter this relationship. The LPS-induced increase in intestinal Rg was not attenuated by pretreatment with TNF antibody. Cardiac output (CO) and intestinal blood flow, assessed using radiolabeled microspheres, were not different from control values 3 h after LPS. Blood flow to the muscularis was increased (120%) in all sections of the small intestine from LPS-treated rats. These results indicate that 3 h after a low dose of LPS, glucose uptake by the entire length of the GI tract was elevated, and the majority of increase was due to enhanced uptake by the mucosa, which was blood flow independent. Furthermore, the increased Rg was not dependent on elevations in plasma glucose, insulin, or TNF levels. However, an increased blood flow to the muscularis was associated with an elevated Rg in that region.

Animals↗
PubMed1991

Glutamine and fatty acid oxidation are the main sources of energy for Kupffer and endothelial cells.

This study assessed and compared the rate of glucose utilization, activity of the hexose-monophosphate shunt (HMS), and the oxidation of glutamine, lactate, and palmitate in Kupffer (KC), endothelial (EC), and parenchymal liver cells (PC). Cells were isolated by collagenase and pronase digestion followed by centrifugal elutriation. The freshly isolated cells were incubated in the presence of 5 mM glucose, 0.5 mM glutamine, 1 mM lactate, and 0.4 mM palmitate, and the oxidation rate of individual substrates was determined by the measurement of 14CO2 production. Glucose utilization was assessed by detritiation of [2-3H]glucose. Glucose flux through HMS was 2.6, 1.6, and 0.72 nmol.h-1.mg protein-1 in KC, EC and PC, respectively. The oxidation rate of palmitate in PC (3.5 nmol.h-1.mg protein-1) was about twofold greater than in nonparenchymal cells. Glutamine oxidation was 6.1, 4.2, and 2.1 nmol.h-1.mg protein-1 in KC, EC, and PC, respectively. In contrast, oxidation of exogenous lactate by PC (32.1 nmol.h-1.mg protein-1) was about seven- to eightfold greater than by KC or EC. Presence of prevailing lactate concentrations did not inhibit glucose oxidation in these cells, while it attenuated glucose utilization by PC. Our data show that in the presence of a physiological substrate mixture, less than 20% of the ATP generated from exogenous substrates is derived from glycolysis in KC or EC. Oxidation of glutamine and palmitate are the main sources for energy in these cells. In PC, however, lactate and palmitate oxidation is responsible for approximately 90% for the ATP production derived form the oxidation of exogenous substrates.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Increased glucose uptake by intestinal mucosa and muscularis in hypermetabolic sepsis.

The purpose of the present study was to determine the following: 1) whether the sepsis-induced increase in glucose uptake was a generalized response along the entire length of the gastrointestinal tract; 2) the relative contribution of the mucosa and muscularis to the enhanced uptake; and 3) whether reducing intestinal blood flow would attenuate the elevated rate of glucose uptake. Hypermetabolic sepsis increased in vivo glucose uptake in all sections of the gastrointestinal tract (57-93%) except the stomach. The rates of glucose uptake per gram of tissue by the mucosa and muscularis were not different. However, because the mucosa accounted for the majority of the whole intestine mass, this layer was responsible for 76-78% of the glucose uptake by the entire small intestine. Intestinal blood flow, determined with the use of radiolabeled microspheres, increased by 127% in sepsis. In both groups, approximately 70% of the total intestinal blood flow was distributed to the mucosa. Somatostatin was infused to produce splanchnic vasoconstriction and decreased the sepsis-induced increment in intestinal flow to the mucosa and muscularis (38 and 54%), whereas the enhanced rate of glucose uptake was not altered. Somatostatin also produced a severe insulinopenia. These results indicate that hypermetabolic sepsis increases glucose uptake to a similar extent along the length of the small and large intestine and that the majority of this increase is due to an enhanced uptake by the mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Tumor necrosis factor-alpha stimulates superoxide anion generation by perfused rat liver and Kupffer cells.

Tumor necrosis factor (TNF) has been implicated as one of the mediators of the immunologic and metabolic changes in endotoxemia. Under adverse conditions, TNF can also be cytotoxic, and its effects can ultimately contribute to organ failure. This study shows that a 30-min infusion of a nonlethal dose of TNF induced the release of superoxide anion (0.9 nmol.min-1.g-1) by the in situ perfused rat liver. TNF also primed the liver to generate more superoxide anion (2.0 nmol.min-1.g-1) in response to an in vitro challenge with phorbol 12-myristate 13-acetate (PMA). Kupffer cells are most likely responsible for the superoxide anion production under these conditions, because the isolated Kupffer cells from TNF-infused rats produced increased quantities of superoxide anion (4-8 nmol/10(6) cells) when subsequently treated in vitro with either PMA or opsonized zymosan (control less than 1 nmol/10(6) cells). Thus, under these experimental conditions, TNF in vivo primed the Kupffer cells, but not the hepatocytes, endothelial cells, and the blood or hepatic neutrophils, to release more superoxide anion. These studies indicate that during a short-term nonlethal TNF infusion, Kupffer cells are a major target of TNF action, leading to the release of toxic-oxygen metabolites that may contribute to organ failure.

Animals↗