Biomedical subjects

T C Vary

Publications and source records attributed to T C Vary.

8 recordsLinked to original sources

PubMed1992

Age-dependent decrease in the amount of eukaryotic initiation factor 2 in various rat tissues.

Recent studies have suggested that the decline in protein synthesis that occurs in rat liver and brain during development and aging is associated with a decrease in the activity of eukaryotic initiation factor 2 (eIF-2). One way in which eIF-2 activity could be decreased in tissue extracts would be through a decrease in the activity of the GDP exchange factor, eIF-2B. In the present study, the activity of eIF-2B was measured in tissue extracts and was found to be less in older than in younger rats. Thus a decrease in eIF-2B activity could account for part of the decrease in protein synthesis that occurs during aging. Another way in which eIF-2 activity could be decreased would be through a decrease in amount of the protein. Therefore the amount of eIF-2 in various tissues was quantified by protein immunoblot analysis. We found that the amount of eIF-2 relative to total protein tended to fall with increasing age. Furthermore, eIF-2 content was directly proportional to the rate of protein synthesis in the tissues examined. Finally, slot-blot analysis of polyadenylated RNA revealed no significant change in the relative abundance of eIF-2 alpha mRNA with age. The last-mentioned experiments suggest that the synthesis of eIF-2 may be regulated through changes in the deficiency of translation of eIF-2 alpha mRNA rather than through changes in gene transcription.

Aging↗

PubMed1992

Effects of recombinant monokines on hepatic pyruvate dehydrogenase, pyruvate dehydrogenase kinase, lipogenesis de novo and plasma triacylglycerols. Abolition by prior fasting.

1. The effects of recombinant human tumour necrosis factor alpha (TNF) and murine interleukin-1 alpha (IL-1) on the activation state of the hepatic pyruvate dehydrogenase complex (PDHa), the activity of mitochondrial PDH kinase, hepatic lipogenesis de novo and plasma triacylglycerol (TG) concentrations were studied. 2. Monokine effects depended upon prior nutritional state. In rats fasted for 20 h or 45 h before monokine administration and refeeding (orally or with intravenous glucose), PDHa, TG and hepatic lipogenesis were not increased. In rats fed ad libitum, treatment with TNF plus IL-1 increased the contribution of hepatic lipogenesis to circulating TG to 550% of control values (P = 0.03) and plasma TG concentrations to 159% (P = 0.02), whereas PDHa increased slightly to 120% (P = 0.02) and liver glycogen content fell to 45.8% (P = 0.05) of control values. 3. Intrinsic hepatic PDH kinase activity was not changed by monokine treatment in rats fed ad libitum. 4. The increased lipogenesis de novo showed no correlation (r2 = 0.05, not significant) with hepatic PDHa in individual animals fed ad libitum. 5. In conclusion, these results suggest that monokines increase pyruvate flux through hepatic PDH in vivo in rats fed ad libitum primarily by mechanisms other than covalent modification of PDH. Prior nutritional status exerts a permissive effect for monokine stimulation of PDHa and lipogenesis, consistent with a substrate-mediated action, but the mechanism of this permissive effect remains uncertain.

Animals↗

PubMed1992

Regulation of hepatic protein synthesis in chronic inflammation and sepsis.

The regulation of protein synthesis was determined in livers from control, sterile inflammatory, and septic animals. Total liver protein was increased in both sterile inflammation and sepsis. The rate of protein synthesis in vivo was measured by the incorporation of [3H]phenylalanine into liver proteins in a chronic (5 day) intra-abdominal abscess model. Both sterile inflammation and sepsis increased total hepatic protein synthesis approximately twofold. Perfused liver studies demonstrated that the increased protein synthesis rate in vivo resulted from a stimulation in the synthesis of both secreted and nonsecreted proteins. The total hepatic RNA content was increased 40% only in sterile inflammation, whereas the translational efficiency was increased twofold only in sepsis. The increase in translational efficiency was accompanied by decreases in the amount of free 40S and 60S ribosomal subunits in sepsis. Rates of peptide-chain elongation in vivo were increased 40% in both sterile inflammation and sepsis. These results demonstrate that sepsis induces changes in the regulation of hepatic protein synthesis that are independent of the general inflammatory response. In sterile inflammation, the increase in protein synthesis occurs by a combination of increased capacity and translational efficiency, while in sepsis, the mechanism responsible for accelerated protein synthesis is an increased translational efficiency.

Animals↗

PubMed1992

Sepsis-induced changes in protein synthesis: differential effects on fast- and slow-twitch muscles.

Sepsis is associated with severe muscle wasting. Mechanisms responsible for sepsis-induced alterations in muscle protein metabolism were investigated in vivo and compared with changes induced by nonseptic inflammation. The rate of protein synthesis in mixed hindlimb muscles was not altered in inflammation but was inhibited 50% in sepsis. This inhibition did not result from a decreased RNA content. Instead, the translational efficiency was significantly reduced by 50% in skeletal muscle of septic animals compared with control. The effect of sepsis to lower the rate of protein synthesis was further examined using individual muscles containing different fiber types. Both the protein concentration and protein synthetic rate in fast-twitch muscles were reduced by sepsis, whereas neither of these parameters was affected in slow-twitch muscles or heart. The decreased translational efficiency did not result from a change in the rate of peptide-chain elongation. Instead, the sepsis-induced inhibition of protein synthesis resulted from a restraint in peptide-chain initiation because sepsis caused a 1.6-fold increase in free ribosomal subunits. Overall, sepsis, but not inflammation, caused an inhibition of protein synthesis primarily in muscles composed of fast-twitch fibers. The mechanism involved in the reduced rates of protein synthesis in muscles resulted from an inhibition of peptide-chain initiation, with no change in peptide-chain elongation.

Abscess↗

PubMed1991

Intravascular plastic catheters. How they potentiate tumor necrosis factor release and exacerbate complications associated with sepsis.

We tested the hypothesis that long-term intravascular cannulation exacerbates the harmful effects of an infectious challenge. Four groups of rats were initially studied: rats without intravascular catheters or infection (group 1), rats without catheters with a polymicrobial infection (group 2), rats with catheters but no infection (group 3), and rats with catheters and infection (group 4). Infected animals had an increased mortality and generated a significantly increased tumor necrosis factor response compared with noninfected animals. Animals with catheters and infection generated far less cardiac output than animals from the other three groups. No histologic changes differentiated the four groups. Therefore, the presence of a sterile intravascular catheter significantly increases cardiac dysfunction and mortality rates in rats with chronic bacteremia. These results suggest that intravascular plastic catheters potentiate the destructive cascade of events produced by the host in response to bacteremia.

Abscess↗

PubMed1991

Oxygen debt and metabolic acidemia as quantitative predictors of mortality and the severity of the ischemic insult in hemorrhagic shock.

BACKGROUND AND METHODS: An experimental canine model of hemorrhagic, hypovolemic shock is described that uses oxygen debt and its metabolic consequences of lactic acidemia and metabolic base deficit as independent variables for the prediction of probability of death. RESULTS: Lactic acidemia and metabolic base deficit are compared with the conventional hemodynamic variables of BP and cardiac output (Qt) as predictors of outcome and are shown to be superior using a modified Kaplan-Meier probability statistic. The LD50 for oxygen debt is shown to be 113.5 mL/kg, 12.9 mmol/L for lactate, and -18.8 mmol/L for base excess (BE). Comparison is made between the ability of Qt, BP, shed blood, BE, and lactate to predict oxygen debt. CONCLUSIONS: Of the single-variable predictors, BE shows the highest explained variability. However, a combined prediction from both lactate and BE appears superior to the use of either alone. Using this regression to compute the oxygen debt, it is possible to estimate accurately the actual level of oxygen debt from the BE and lactate values obtained during hemorrhagic hypovolemia. From serial determinations over time of the increase in these biochemical variables above the oxygen debt baseline, it is possible to estimate the rate of oxygen debt accumulation and the time remaining until the LD50 will be reached as indicators of the severity of the total body ischemia resulting from hemorrhagic shock.

Acid-Base Equilibrium↗

PubMed1991

Increased pyruvate dehydrogenase kinase activity in response to sepsis.

The effect of sterile inflammation and sepsis on the proportion of active pyruvate dehydrogenase complex (PDH) in mitochondria isolated from skeletal muscle has been investigated. The proportion of active PDH in mitochondria isolated from septic animals was significantly reduced compared with control under all incubation conditions examined, even in the presence of inhibitors of the PDH kinase. There was no significant difference between control and sterile inflammation in any of the incubations examined. The rate constant for ATP-dependent inactivation of the PDH complex in mitochondrial extracts from control animals was -0.42 min-1 (r = 0.993; P less than 0.001) and was not altered in mitochondrial extracts from sterile inflammatory animals (-0.43 min-1; r = 0.999; P less than 0.001). However, rate constants for inactivation in septic animals was significantly increased over twofold to -1.08 min-1 (r = 0.987; P less than 0.001) (P less than 0.001 vs. control or sterile inflammation). In the presence of inhibitors of the PDH kinase reaction (2.5 mM pyruvate or 1 mM dichloroacetate), inactivation of PDH after addition of ATP was significantly greater in mitochondrial extracts from septic than either control or sterile inflammatory animals. These results suggest that sepsis, but not sterile inflammation, induces a stable factor in skeletal muscle mitochondria that increased PDH kinase activity.

Animals↗

PubMed1979

Relationship between adenine nucleotide metabolism and irreversible ischemic tissue damage in isolated perfused rat heart.

The relationship between energy metabolism and the extent of irreversible ischemic damage was examined in an isolated perfused working rat heart. The amount of cardiac work recovered after reperfusion of hearts exposed to severe global ischemia was dependent upon both the duration of ischemia and the type of substrate provided (either 5 mM glucose or 5 mM glucose + acetate). There appear to be two distinct phases in the ability to recover mechanical function in the reperfused ischemic heart. The second phase corresponds to the onset of severe irreversible tissue damage. Irreversible mitochondrial damage was not found to correspond with the onset of heart failure since the ATP/ADP ratio remained constant in the reperfused myocardium. Furthermore, there does not appear to be a direct correlation between the total ATP content and the extent of irreversible damage, either during ischemia or following reperfusion. However, the total adenine nucleotide content during ischemia showed dramatic changes which correspond temporally with the initiation of the second phase of damage. The observation that the adenine nucleotide pool becomes further depleted during reperfusion suggests that alterations in the salvage pathway for adenine nucleotide synthesis have occurred. Loss of adenine nucleotides appears to be an excellent marker for irreversible heart failure. Acetate provides some protection the the ischemic myocardium. The mechanism by which acetate mediates this protective effect is discussed.

Adenine Nucleotides↗