Biomedical subjects
Publications and source records attributed to Josef E Fischer.
The House of Medicine has been disadvantaged by not being at the table, by believing that society will take care of us, and by believing that economics are not critically important to the practice of medicine. All of these assumptions are incorrect. We must be at the table the next time around and we must be prepared for the crisis of access that will bring about societies' dealings with these important issues.
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Bacterial sepsis is frequently accompanied by increased blood concentration of lactic acid, which traditionally is attributed to poor tissue perfusion, hypoxia and anaerobic glycolysis. Therapy aimed at improving oxygen delivery to tissues often does not correct the hyperlactatemia, suggesting that high blood lactate in sepsis is not due to hypoxia. Various tissues, including skeletal muscle, demonstrate increased lactate production under well-oxygenated conditions when the activity of the Na+-K+ ATPase is stimulated. Although both muscle Na+-K+ ATPase activity and muscle plasma membrane content of Na+, K+-ATPase subunits are increased in sepsis, no studies in vivo have demonstrated correlation between lactate production and changes in intracellular Na+ and K+ resulting from increased Na+-K+ pump activity in sepsis. Plasma concentrations of lactate and epinephrine, a known stimulator of the Na+-K+ pump, were increased in rats made septic by E. coli injection. Muscle lactate content was significantly increased in septic rats, although muscle ATP and phosphocreatine remained normal, suggesting oxygen delivery remained adequate for mitochondrial energy metabolism. In septic rats, muscle intracellular ratio of Na+:K+ was significantly reduced, indicating increased Na+-K+ pump activity. These data thus demonstrate that increased muscle lactate during sepsis correlates with evidence of elevated muscle Na+-K+ ATPase activity, but not with evidence of impaired oxidative metabolism. This study also further supports a role for epinephrine in this process.
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BACKGROUND: Traditionally, elevated blood lactate after hemorrhage is interpreted as tissue hypoperfusion, hypoxia, and anaerobic glycolysis. The severity and duration of the increase in blood lactate correlate with death. Recent in vitro studies indicate that epinephrine stimulates lactate production in well-oxygenated skeletal muscle by increasing activity of the Na+-K+-adenosine triphosphatase (ATPase), which derives a significant amount of adenosine triphosphate from glycolysis. Using in vivo microdialysis, we tested whether inhibiting the Na+-K+ pump with ouabain could reduce muscle lactate production during local exposure, via the microdialysis probe, to epinephrine or during hemorrhage in rats. METHODS: Microdialysis catheters were placed in the muscle of both thighs of pentobarbital-anesthetized male Sprague-Dawley rats (275-350 g) and perfused (1 microL/min) with Krebs-phosphate buffer (pH 7.4) containing ethanol (5 mmol/L) to permit assessment of changes in local blood flow. To inhibit the Na+-K+-ATPase, ouabain (2-3 mmol/L) was added to the perfusate of one leg. In one series of studies, epinephrine was added to the perfusate. In another series, rats were hemorrhaged to a mean arterial pressure of 45 mm Hg for 30 minutes, followed by resuscitation with shed blood and 0.9% sodium chloride. Dialysate fractions were analyzed for lactate and ethanol fluorometrically. RESULTS: Lactate rose during epinephrine exposure or during hemorrhage and resuscitation. Treatment with ouabain reduced dialysate lactate concentration significantly in both series of studies. Local blood flow was reduced by either epinephrine or hemorrhage, but returned toward baseline afterward. Ouabain had no apparent effect on local blood flow. CONCLUSION: Increased Na+-K+ATPase activity during epinephrine treatment or hemorrhage contributes to muscle lactate production. Hypoxia is not necessarily the sole cause of hyperlactatemia during and after hemorrhagic shock.
Recent studies suggest that the stress (heat shock) response protects cells and tissues from inflammatory and other noxious insults. The transcription factor nuclear factor-kappa B (NF-kappaB), normally sequestered in the cytoplasm by its inhibitory protein IkappaB, regulates many genes involved in the inflammatory response to critical illness. Endotoxemia is associated with increased NF-kappaB activity in liver but the effect of the stress response on endotoxin-induced NF-kappaB activation in the liver is not known. We hypothesized that the stress response inhibits NF-kappaB DNA binding activity in liver during endotoxemia. The stress response was induced in mice by hyperthermia (42 degrees C for 3 min) or sodium arsenite (10 mg/kg) and resulted in increased hepatic heat shock protein-72 levels. After induction of the stress response, mice were injected subcutaneously with endotoxin (12.5 mg/kg) or a corresponding volume of sterile saline. NF-kappaB DNA binding activity in the nuclear fraction of liver tissue increased and cytoplasmic IkappaB-alpha levels decreased after endotoxin injection, with a maximal effect seen at 60 min. The endotoxin-induced increase in NF-kappaB DNA binding activity and decrease in IkappaB-alpha levels were inhibited by prior induction of the stress response. In additional experiments, treatment of mice with sodium arsenite after induction of endotoxemia blunted the increase in NF-kappaB activity, indicating a therapeutic potential of sodium arsenite, in addition to its preventive effect. The present results suggest that the protective effects of the stress response in vivo may, at least in part, be due to inhibited NF-kappaB activation.
In previous studies, the heat shock response, induced by hyperthermia or sodium arsenite, increased interleukin (IL)-6 production in intestinal mucosa and cultured human enterocytes. A novel way to induce the heat shock response, documented in other cell types, is treatment with proteasome inhibitors. It is not known if proteasome inhibition induces heat shock in enterocytes or influences IL-6 production. Here we tested the hypothesis that treatment of cultured Caco-2 cells, a human intestinal epithelial cell line, with proteasome inhibitors induces the heat shock response and stimulates IL-6 production. Treatment of Caco-2 cells with one of the proteasome inhibitors MG-132 or lactacystin activated the transcription factor heat shock factors (HSF)-1 and -2 and upregulated cellular levels of the 72-kDa heat shock protein HSP-72. The same treatment resulted in increased gene and protein expression of IL-6, a response that was blocked by quercetin. Additional experiments revealed that the IL-6 gene promoter contains a HSF-responsive element and that the IL-6 gene may be regulated by the heat shock response. The present results suggest that proteasome inhibition induces heat shock response and IL-6 production in enterocytes and that IL-6 may be a heat shock-responsive gene, at least under certain circumstances. The observations are important considering the multiple biological roles of IL-6, both locally in the gut mucosa and systemically, and considering recent proposals in the literature to use proteasome inhibitors in the clinical setting to induce the heat shock response.