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C S Deutschman

Publications and source records attributed to C S Deutschman.

At least 19 recordsLinked to original sources
PubMed1998

Intrahepatic STAT-3 activation and acute phase gene expression predict outcome after CLP sepsis in the rat.

Interleukin-6 (IL-6) regulates hepatic acute phase responses by activating the transcription factor signal transducer and activator of transcription (STAT)-3. IL-6 also may modulate septic pathophysiology. We hypothesize that 1) STAT-3 activation and transcription of alpha2-macroglobulin (A2M) correlate with recovery from sepsis and 2) STAT-3 activation and A2M transcription reflect intrahepatic and not serum IL-6. Nonlethal sepsis was induced in rats by single puncture cecal ligation and puncture (CLP) and lethal sepsis via double-puncture CLP. STAT-3 activation and A2M transcription were detected at 3-72 h and intrahepatic IL-6 at 24-72 h following single-puncture CLP. All were detected only at 3-16 h following double-puncture CLP and at lower levels than following single-puncture CLP. Loss of serum and intrahepatic IL-6 activity after double-puncture CLP correlated with mortality. Neither intrahepatic nor serum IL-6 levels correlated with intrahepatic IL-6 activity. STAT-3 activation following single-puncture CLP inversely correlated with altered transcription of gluconeogenic, ketogenic, and ureagenic genes. IL-6 may have both beneficial and detrimental effects in sepsis. Fulminant sepsis may decrease the ability of hepatocytes to respond to IL-6.

Acute-Phase Proteins↗
PubMed1997

Sepsis-induced depression of rat glucose-6-phosphatase gene expression and activity.

Sepsis in rats decreases the hepatic expression of the gluconeogenic enzyme glucose-6-phosphatase (G6Pase). The aim of this study was to investigate the relationship among G6Pase transcription, mRNA, enzymatic activity, and serum glucose levels at different intervals during mild or fulminant sepsis. Both fulminant and mild sepsis immediately decreased hepatic G6Pase mRNA levels. In mild sepsis, levels began to recover late in the time course. Serum glucose levels were maintained in mild sepsis but decreased markedly in fulminant sepsis. G6Pase transcription after fulminant sepsis decreased and never recovered. A similar transcriptional decrease was noted in mild sepsis, but some recovery occurred in this state. Histochemistry after mild sepsis revealed a decrease in G6Pase protein and enzymatic activity that paralleled transcription. These studies suggest that changes in G6Pase transcription and activity are early markers for sepsis-induced alterations in hepatic function. Mechanisms other than gene expression and enzymatic activity serve to maintain glucose levels in mild sepsis, but in the fulminant disorder, compensatory mechanisms fail and hypoglycemia develops.

Animals↗
PubMed1997

Altered hepatic gene expression in fecal peritonitis: changes in transcription of gluconeogenic, beta-oxidative, and ureagenic genes.

Sepsis alters energy production and utilization by the liver. Changes in both metabolic pathways that produce substrate (gluconeogenesis or ketogenesis) for organism-wide consumption or provide an alternative source of fuel for the liver (beta-oxidation and amino acid metabolism) have been identified. In this study, we test the hypothesis that these changes occur via an alteration in the transcription of key enzymes within each pathway. Male Sprague-Dawley rats were made septic using cecal ligation and single puncture with sham operated animals serving as controls. Hepatic tissue was harvested at 0, 3, 6, 16, 24, 48, and 72 h had either total RNA or hepatic nuclei were isolated. Using Northern blot hybridization analysis, the steady-state levels of phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, carnitine palmitoyl transferase II, acetyl coenzyme A-acyltransferase, and ornithine transcarbamylase mRNAs were determined. Using transcript elongation analysis, the rate of transcription of each gene was investigated. Relative to control, steady-state mRNA levels and rates of transcription for all five genes were decreased by ligation and single puncture. These decreases were persistent, with only partial recovery of either mRNA levels or transcription rates at 72 h. These findings could explain in part the long-term alterations in gluconeogenesis, beta-oxidation, and ureagenesis observed in sepsis. More importantly, decreased transcription of certain genes seems to be a characteristic of sepsis-induced changes in hepatic function. Understanding the mechanisms that decrease transcription also may explain other aspects of sepsis in the liver and other organ systems.

Administration, Cutaneous↗
PubMed1996

Acute-phase gene expression correlates with intrahepatic tumor necrosis factor-alpha abundance but not with plasma tumor necrosis factor concentrations during sepsis/systemic inflammatory response syndrome in the rat.

OBJECTIVES: To test the hypothesis that after cecal ligation and puncture in the rat, there is increased expression of the tumor necrosis factor (TNF)/interleukin-1-dependent, acute-phase reactant alpha 1-acid glycoprotein in the liver, and that this change correlates temporally with increased abundance of TNF-alpha in the hepatic parenchyma but not with circulating concentrations of TNF-alpha. DESIGN: Prospective, randomized, controlled study. SETTING: Research laboratory at the University of Pennsylvania School of Medicine. SUBJECTS: Male, adolescent Sprague-Dawley rats, weighing 200 to 300 g. INTERVENTIONS: The procedure of cecal ligation and single puncture with an 18-gauge needle was performed in one group of animals. Control animals underwent sham operation. At 0, 3, 6, 16, 24, 48, and 72 hrs after either procedure, blood was collected and the liver was isolated and perfusion-fixed with 2% paraformaldehyde. In a second group of animals, liver tissue was harvested for isolation of total hepatic RNA. MEASUREMENTS AND MAIN RESULTS: Northern blot hybridization analysis demonstrated an increase in steady-state concentrations of alpha 1-acid glycoprotein messenger RNA that peaked at 16 hrs after cecal ligation and puncture. The alpha 1-acid glycoprotein messenger RNA was not detected in control animals. TNF-alpha concentrations in the plasma, as determined by enzyme-linked immunosorbent assay, were detected 3 and 6 hrs after cecal ligation and puncture. However, TNF-alpha concentrations were undetectable in the plasma at other time points after cecal ligation and puncture and at all time points in the sham-operated animals. Immunohistochemical staining of 7-micron hepatic sections demonstrated a progressive increase in TNF-alpha abundance, with a peak at 16 hrs. Alterations in alpha 1-acid glycoprotein gene expression correlated in time with intrahepatic TNF-alpha abundance, but not with plasma TNF-alpha concentrations. CONCLUSIONS: The changes in TNF-alpha-dependent hepatic gene expression that accompany an animal model of the systemic inflammatory response syndrome correlate with intrahepatic, and not circulating, TNF-alpha concentrations and reflect paracrine, and not endocrine, activity. Therefore, plasma concentrations of TNF-alpha do not appropriately reflect hepatocellular responses during the systemic inflammatory response syndrome.

Animals↗
PubMed1996

Increased expression of cytokine-induced neutrophil chemoattractant in septic rat liver.

Hepatocellular dysfunction in sepsis may be neutrophil mediated. We therefore tested the hypothesis that sepsis-induced neutrophil accumulation is associated with increased expression of the chemokine, cytokine-induced neutrophil chemoattractant (CINC). In Sprague-Dawley rats made septic by cecal ligation and puncture, we demonstrate a time-dependent increase in CINC mRNA, which returns to baseline by 48 h. By in situ hybridization, this mRNA is present in hepatocytes and nonparenchymal cells. CINC protein levels in septic animals parallel mRNA levels and resolve by 48 h. Because CINC expression is induced by cytokines including tumor necrosis factor-alpha (TNF- alpha), we show, by immunohistochemistry, that sepsis elevates intrahepatic TNF-alpha. Finally, because the CINC promoter is transactivated by the transcription factor, nuclear factor kappa B (NF-kappa B), we determined that hepatic NF-kappa B DNA binding increases dramatically, peaking 16 h after cecal ligation and puncture. Thus activated NF-kappa B may mediate CINC induction in sepsis. This constellation of findings suggests a mechanism by which sepsis may induce neutrophil accumulation in the liver and may have implications regarding sepsis-induced hepatic dysfunction.

Animals↗
PubMed1995

Reciprocal expression of phosphoenolpyruvate carboxykinase and acute phase genes during acute inflammation.

Part of the hepatic response to injury is mediated by the expression of a gene family known as acute phase genes. Expression of acute phase genes is induced by the presence of cytokines in the circulation such as tumor necrosis factor alpha, interferon gamma, and interleukins-1 and -6. Simultaneous with the transcription of acute phase genes, there is a decrease in the expression of other genes such as albumin. In the present study, we report the decrease in transcription of the gene coding for phosphoenolpyruvate carboxykinase (PEPCK), a key regulatory enzyme in the gluconeogenic pathway, in rat liver during an acute inflammatory state induced by bacterial endotoxin. Steady-state mRNA levels of PEPCK decrease 3 h after endotoxin injection, returning to 70% of normal levels after 24 h. This decrease in PEPCK mRNA levels was due to a decline in the rate of transcription of the gene, most likely mediated by an increase in the circulating levels of insulin. However, expression of the PEPCK gene was not induced by an increase in the cellular levels of cAMP during inflammation. Such a lack of response to cAMP may be due to the inactivation of, or decrease in, the levels of the transcriptional factor(s) responsible for PEPCK transcription.

Animals↗
PubMed1995

Sepsis-induced attenuation of glucagon and 8-BrcAMP modulation of the phosphoenolpyruvate carboxykinase gene.

Sepsis is associated with alterations in hepatic gluconeogenesis. We have previously demonstrated that this change is associated with reduced expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene, despite an endogenous hormonal milieu that should favor increased expression of the gene. To further elucidate the mechanisms involved, we induced sepsis in fasted Sprague-Dawley rats via cecal ligation and single puncture, with sham-operated animals serving as controls, and we performed two sets of experiments. First, liver tissue was obtained from septic and sham-operated animals at 2, 6, 16, and 24 h after the induction of sepsis. Northern blot hybridization analysis revealed a progressive, sepsis-induced decrease in expression of PEPCK and an increase in the expression of beta-fibrinogen, an acute-phase reactant. In the second set of experiments, we tested whether this reduced expression resulted from an attenuated response to 1) glucagon and 2) 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP). Twenty-four hours after the induction of sepsis, the liver was isolated and perfused with either Krebs buffer with substrate only (unstimulated controls), Krebs buffer + substrate + 10(-8) M glucagon, or Krebs buffer + substrate + 10(-5) M 8-BrcAMP. In sham-operated animals, perfusion with glucagon increased PEPCK mRNA levels and activity, whereas perfusion with buffer alone did not change mRNA levels and decreased activity. Glucagon perfusion of septic livers did not change either PEPCK mRNA levels or activity. Perfusion of sham-operated animals with 8-BrcAMP increased PEPCK mRNA levels and activity, whereas perfusion with buffer alone resulted in a decrease in mRNA levels and activity.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1994

Changes in heart rate variability under propofol anesthesia: a possible explanation for propofol-induced bradycardia.

We propose to study the bradycardia associated with propofol anesthesia. Ten women undergoing laparoscopy for benign disease were studied using ambulatory electrocardiogram monitoring. Anesthesia was induced with an intravenous bolus of propofol and maintained with an infusion. After ventilation using positive pressure via a mask for 5 min, relaxants (succinylcholine or vecuronium) and opioids (alfentanil or fentanyl) were administered and the trachea was intubated. Approximately 15 min later, the laparoscopic trocar was placed and carbon dioxide insufflated. Heart rate variability spectra using a fast Fourier transformation technique were determined from the recordings in four separate time periods (preinduction, postinduction, postintubation, and posttrocar placement). Total, high-frequency, and low-frequency power in each time period was determined. Induction of anesthesia with propofol was associated with a significant reduction in total, low-frequency, and high-frequency power. Maintenance of anesthesia with propofol alone resulted in further reductions in total and low-frequency, but not high-frequency, power. Placement of the laparoscopic trocar and insufflation of carbon dioxide resulted in a decrease in heart rate and an increase in high-frequency power. We conclude that high-frequency variability reflects parasympathetic tone. Propofol anesthesia reduces parasympathetic tone to a lesser degree than sympathetic tone. This autonomic milieu predisposes the patient to developing bradycardia in response to parasympathetic stimuli.

Adult↗
PubMed1993

Substance abuse-related admissions to adult intensive care.

The frequency of adult surgical and medical intensive care unit (ICU) admissions related to substance abuse was determined at a large community, trauma, and tertiary referral hospital. Of 435 ICU admissions, 14 percent (95 percent confidence interval [CI], 5 to 23 percent) were tobacco related generating 16 percent of costs, 9 percent (95 percent CI, 0 to 18 percent) were alcohol related generating 13 percent of costs, and 5 percent (95 percent CI, 0 to 14 percent) were illicit drug related generating 10 percent of costs. In all, 28 percent (95 percent CI, 20 to 36 percent) of ICU admissions generating 39 percent of costs were substance abuse related. Substance abuse-related admissions were significantly longer and more costly than admissions not related to substance abuse (4.2 days vs 2.8 days, p = 0.004; $9,610 vs $5,890, p = 0.001). Frequency of substance abuse-related admission was linked with the patient's insurance status (Medicare, private insurance, uninsured). In the uninsured group, 44 percent of admissions were substance abuse related (95 percent CI, 35 to 52 percent), significantly higher than in the private insurance and Medicare groups, and generating 61 percent of all ICU costs in the uninsured group. Large fractions of adult ICU admissions and costs are substance abuse related, particularly in uninsured patients.

Adult↗
PubMed1993

Sepsis-induced alterations in phosphoenolpyruvate carboxykinase expression: the role of insulin and glucagon.

Sepsis is associated with a decrease in the intrinsic gluconeogenic capacity of hepatocytes. The mechanism underlying this depression is unknown. This study sought to investigate whether decreased expression of phosphoenolpyruvate carboxykinase (PEPCK), a rate limiting enzyme in hepatic gluconeogenesis, might contribute to the decreased gluconeogenesis in sepsis. Therefore, we determined the effects of sepsis on the steady-state level of PEPCK mRNA and on PEPCK activity. Further, levels of insulin and glucagon, which modulate PEPCK expression under normal conditions, were also measured. Rats were subjected to either cecal ligation and puncture, or sham operation. Twenty-four hr later, the steady-state level of PEPCK mRNA was determined by Northern Blot hybridization analysis, and PEPCK activity was measured by 14C incorporation into phosphoenolpyruvate. Insulin and glucagon levels were determined by radioimmunoassay, and the insulin/glucagon ratio calculated. The steady-state levels of PEPCK mRNA were significantly decreased in septic animals relative to sham-operated animals. The specific activity of PEPCK in sham-operated animals was 1.67 +/- 0.25 U/mg protein, compared to 0.93 +/- 0.18 U/mg protein in septic animals (P < 0.05). The insulin/glucagon ratio was lower in septic animals than in sham-operated controls. To investigate the specific effect of the insulin-glucagon ratios observed in septic and sham operated rats on hepatocytes under non-septic conditions, cultures of primary rat hepatocytes were used. These cells were incubated with levels of insulin and glucagon equivalent to those found following cecal ligation and puncture or sham operation. Hormonal conditions designed to mimic sepsis were associated with an increase in PEPCK expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

The role of anesthetic induction agents and neuromuscular blockade in the endotracheal intubation of trauma victims.

Management of extensive trauma often requires immediate tracheal intubation and mechanical ventilation. The role of anesthetic induction agents and neuromuscular blockade in the airway management of the trauma victim is disputed. To better define the role of these agents in the acute management of trauma, the adult trauma registry of The Johns Hopkins Hospital was reviewed to determine the frequency of use of these agents in acute airway management and to assess the effect of these agents on the incidence of complications. Ninety-seven patients were reviewed. Thirty-one patients were intubated because of cardiopulmonary arrest. Of the remaining 66 patients, oral intubation was initially attempted in 54. When drugs were used to facilitate intubation (n = 36), the success rate was 92 per cent on the first attempt, and 100 per cent on the second attempt. When drugs were not used (n = 18), 39 per cent could not be intubated (n = 7). Subsequent drug administration resulted in successful intubation of five of seven of these patients. Nasal intubation (no drugs) was only successful in 60 per cent of the patients (50 per cent on first attempt). Four patients required a cricothyrotomy. Two other patients vomited, and one patient aspirated. None of these patients received drugs prior to the first attempt at intubation. No hemodynamic or neurologic complications, related to relaxant or induction agent use, were observed. These findings suggest that oral intubation with drugs to facilitate airway management is most likely to result in successful intubation on the first attempt and that drug use in the trauma setting is safe.

Adult↗
PubMed1990

Molecular biology of circulatory shock. Part II. Expression of four groups of hepatic genes is enhanced after resuscitation from cardiogenic shock.

Despite an initially successful resuscitation from circulatory shock, multiple organ failure (MOF) develops in some patients. The marked biochemical alterations associated with shock and MOF include clinically important changes in gene expression, such as altered rates of albumin and procoagulant synthesis. To characterize the MOF-associated changes at the cellular level, sequential liver biopsies were obtained from a swine model of cardiogenic shock associated with MOF. Preshock and postresuscitation biopsies were used not only to create a complementary DNA (cDNA) library but also to screen, to confirm, and, in nine out of 12 cases, to specifically identify genes whose expression is enhanced at least fivefold after resuscitation. The twelve genes thus characterized can be separated according to function into distinct groups, including the acute-phase genes and the heat-shock genes. Expression of acute-phase genes is liver specific and is essential for systemic homeostasis; heat-shock gene expression is generic to all cells and important for intracellular homeostasis.

Acute-Phase Proteins↗
PubMed1990

Failure of endotoxic shock to elicit superoxide anion production in pig brain.

Endotoxin shock in pigs alters cerebral blood flow regulation. This study sought 1) to evaluate global cerebral electrical function using somatosensory evoked potential and 2) to determine if superoxide anion free radical (O2-) is generated in brain following endotoxin infusion. Five female pigs received E. coli endotoxin (0.1 mg/kg i.v.) and supplemental fluid to maintain cardiac output at control levels. Somatosensory evoked potential was generated before and after endotoxin infusion, and nitroblue tetrazolium (NBT) precipitation in cranial windows was used to determine O2- production by brain. Following endotoxin infusion, mean arterial blood pressure, cerebral perfusion pressure, and systemic vascular resistance fell by 50% and cerebral oxygen extraction increased. The amplitude and the latency of somatosensory evoked potential performed 60 min after endotoxin were unchanged from that generated at control. No precipitation of NBT in cranial windows was observed, indicating that O2- was not generated. Since endotoxin shock did not alter cerebral electrical function and O2- was not generated by brain, we conclude that alterations in cerebral blood flow regulation observed in fluid-resuscitated endotoxic shock do not result from inadequate cerebral oxygen consumption, nor is the extracellular production of O2- involved in the pathogenesis of this disorder.

Animals↗