Interferon regulatory factor-1 is a major regulator of epidermal growth factor receptor gene expression.

Overexpression of the epidermal growth factor receptor (EGFR) occurs in many tumors and in breast cancer correlates with poor prognosis for treatment. Here, we report that interferon regulatory factor-1 (IRF-1) induces EGFR promoter activity up to 200-fold compared to 3-10-fold induction by other regulators. The region of the promoter that is required for this induction was defined using deletion mutants.

Transient inhibition of CD18-dependent leukocyte functions after hemorrhage and polymicrobial sepsis.

Background: The goals were (1) to characterize physiologic changes after a combined insult of hemorrhage plus sepsis in a large animal model and (2) to determine whether transient inhibition of the neutrophil CD18 adherence receptor during fluid resuscitation impairs host defense during recovery from this injury.

Methods: Two series of experiments were performed in anesthetized swine. In the first series (n = 22), the cecum was ligated and incised immediately before 35% hemorrhage.

Granulocyte colony-stimulating factor improves host defense to resuscitated shock and polymicrobial sepsis without provoking generalized neutrophil-mediated damage.

Background: Granulocyte colony-stimulating factor (G-CSF) increases production and release of neutrophil precursors and activates multiple functions of circulating polymorphonuclear neutrophils (PMNs). G-CSF has therapeutic effects in many experimental models of sepsis; its actions with superimposed reperfusion insults are unknown. In traumatic conditions, G-CSF could exacerbate unregulated, PMN-dependent injury to otherwise normal host tissue or, it could partially reverse trauma-induced immune suppression, which may improve long-term outcome.

"In-line" bipolar, steroid-eluting, high impedance, epimyocardial pacing lead.

Recent advances in electrode surface designs have eliminated traditional threshold differences between endo- and epicardial pacing leads. Since the epicardial approach offers the potential of direct left ventricular pacing and the transvenous approach may not be feasible or warranted in all instances, more advanced leads are being designed to optimize epicardial pacing capabilities. This study was conducted to evaluate a bipolar epimyocardial lead.

Effect of transfusion on physiologic changes after resuscitated trauma.

Background: The purpose of this experimental study was to test whether transfusion potentiated physiologic changes associated with fluid resuscitated trauma in controlled conditions.

Methods: Anesthetized and ventilated mongrel pigs were subjected to soft-tissue injury plus 35% hemorrhage and 1 hour shock and then were resuscitated with either autologous (shed) or heterologous (cross-transfused) fresh whole blood. Leukocyte differential counts, T-lymphocyte subsets, neutrophil adherence molecule (CD18) expression, granulocyte oxidative burst, plasma cortisol, and serum chemistries were monitored in awake animals with indwelling catheters on 3 consecutive days.

Unexpected action of platelet activating factor antagonism after fluid resuscitation from traumatic shock.

Background: We have shown that therapy directed at polymorphonuclear neutrophil (PMN) CD18 receptors attenuates sequelae associated with a post-trauma endotoxin (lipopolysaccharide [LPS]) challenge. Platelet activating factor (PAF) stimulates PMNs by CD18-independent pathways, and WEB-2086, a PAF receptor antagonist, blunts septic symptoms in many experimental models. This study tested the hypothesis that the blockade of non-CD18 dependent PMN adherence attenuates trauma- and LPS-evoked pulmonary dysfunction.

Dehydroepiandrosterone, an endogenous immune modulator, after traumatic shock.

Dehydroepiandrosterone (DHEA), an endogenous immune modulator, reduces mortality after endotoxin (lipopolysaccharide (LPS)) administration in rodents. However, there have been no studies in clinically relevant large-animal models. A unique experimental model is used to study the effects of DHEA in resuscitated trauma and to evaluate the protective effect of DHEA on the systemic inflammatory response induced by a delayed LPS challenge.

Actions of acute ethanol intoxication on cardiopulmonary function after an endotoxin challenge.

Background: This study examined whether acute ethanol (EtOH) intoxication could alter the systemic inflammatory response evoked by endotoxin (lipopolysaccharide, LPS).

Methods: Anesthetized (fentanyl) and mechanically ventilated mongrel pigs were administered 20% EtOH (3 gm/kg) or its vehicle (VEH) by means of gastric lavage. After 60 minutes of equilibration, blood levels were 110 to 130 mg/dl, and LPS (1 microgram/kg per 30 minutes) was infused intravenously to mimic the type of sepsis that might be encountered after a penetrating abdominal injury.

Acute ethanol intoxication and endotoxemia after trauma.

To determine actions of acute intoxication on pathophysiologic responses to trauma, anesthetized and ventilated mongrel pigs received a 20% solution of ethanol (EtOH) by an intravenous (IV group; 2 g/kg, n = 8) or an oral (PO group; 3 g/kg, n = 12 x 60 minutes) route of administration, or the lactated Ringer's vehicle (LR group; n = 12). After 60 minutes, all were subjected to soft tissue injury and 30 to 35% hemorrhage, 60-minute shock, and then resuscitation, with shed blood plus supplemental LR. After 3 days, host defense was challenged with Escherichia coli lipopolysaccharide (LPS); (1 microgram/kg x 30-minutes IV).

Acadesine and lipopolysaccharide-evoked pulmonary dysfunction after resuscitation from traumatic shock.

Background: We have reported that the purine precursor acadesine (AICAR) improved the microcirculation, repleted adenosine triphosphate, and attenuated local and lung neutrophil infiltration after intestinal reperfusion and that it quickly improved systemic hemodynamics after resuscitation from hemorrhagic shock. This study evaluated the therapeutic potential of AICAR after fluid resuscitated trauma.

Methods: Anesthetized (fentanyl) mongrel pigs were subjected to tissue injury plus hemorrhage and randomized to receive resuscitation fluids comprised of shed blood plus either lactated Ringer's solution (LR) or AICAR (1 or 10 mg/kg bolus + 0.

Antibiotic pharmacokinetics following fluid resuscitation from traumatic shock.

Objective: To describe the pharmacokinetic profile of aztreonam and vancomycin hydrochloride in a clinically relevant experimental model of hemorrhagic shock and trauma.

Methods: Ten mongrel pigs (mean +/- SD weight, 26.7 +/- 6.

Reduced tumor necrosis factor production in endotoxin-spiked whole blood after trauma: experimental results and clinical correlation.

Background: The overproduction of tumor necrosis factor-alpha (TNF) plays a key role in virtually every experimental model of septic shock, which has led to the development of several therapies that target TNF and other cytokines in clinical sepsis. However, our previous work showed that plasma TNF was reduced, rather than increased, when a septic challenge was administered 3 days after hemorrhagic shock. In this study we compared whole-blood TNF production ex vivo in human beings and animals after trauma.

Actions of prostaglandin E1 on lipopolysaccharide-evoked responses in vivo and in vitro following resuscitated trauma.

Prostaglandins of the E series (PGE1, PGE2) have well-described immunosuppressive (antiinflammatory) as well as vasodilator (pro-inflammatory) actions. The net effect on an acute inflammatory response would depend on the dose, timing, and site of action. Egg phosphatidyl liposomes are novel drug delivery vehicles that can alter the in vivo disposition of PGE1.

Fasting-induced reduction of intestinal reperfusion injury.

Background: Fasting is associated with significant structural, functional, and metabolic alterations in the intestinal mucosa. Before abdominal surgery, patients are usually fasted the night before surgery or for a longer period of time if chronic illness is present. The splanchnic organs may experience varying degrees of ischemia/reperfusion as blood vessels are occluded during the various manipulations.

Gastric and extragastric actions of the histamine antagonist ranitidine during posttraumatic sepsis.

Background: Histamine H2 antagonists (e.g., ranitidine) are generally thought to specifically reduce gastric acid secretion and are commonly used for stress ulcer prophylaxis in critically ill patients because of their efficacy and safety profile.

Improved epimyocardial pacing: initial experience with a new bipolar, steroid-eluting, high impedance lead design.

Epicardial pacing typically is associated with decreased pacing and sensing capabilities compared with the endocardial approach. Since endocardial pacing is neither appropriate nor possible in all instances, this study was conducted to evaluate a new concept in a chronic epimyocardial lead design in six 3-month-old growing dogs. The new bifurcated lead (Medtronic model 10401) is a low current drain, high impedance, steroid-eluting, bipolar design.

Neutrophil CD18 expression and blockade after traumatic shock and endotoxin challenge.

Objective: The expression of the leukocyte CD18 adhesion complex on polymorphonuclear leukocytes (PMNs) was measured, and the physiologic effects of blockade of the complex were studied after trauma and sepsis.

Summary Background Data: Margination of PMNs occurs early during inflammation and depends, in part, on expression of the CD18 adhesion complex. Blockade of this adherence complex can reduce PMN-mediated damage.

Gamma-scintigraphy and early hepatocellular dysfunction during posttraumatic sepsis.

Background: To determine whether the hepatic conjugation-detoxification function was altered during sepsis, the metabolism of bilirubin was measured with gamma-scintigraphy.

Methods: Time-activity curves were generated after a radiolabeled bilirubin analog (technetium 99m-mebrofenin, hepatoiminodiacetic acid [HIDA]) was administered to anesthetized (fentanyl) mongrel pigs in the following conditions: control (n = 16); 30 minutes after 5 micrograms/kg intravenous Escherichia coli endotoxin (LPS; n = 6); 30 minutes after trauma (40% arterial hemorrhage plus soft tissue injury, n = 9); 72 hours after sham trauma (n = 6); 72 hours after fluid resuscitated trauma either before (n = 9) or 30 minutes after (n = 10) LPS administration. All were ventilated with 65% O2 and instrumented with pulmonary artery oximetric catheters.

Splanchnic and systemic hemodynamic responses to portal vein endotoxin after resuscitation from hemorrhagic shock.

Background: Hemorrhagic shock and sepsis are usually studied separately or in rodents. This study combined the two insults in a large animal model.

Methods: Anesthetized pigs were bled, held in shock for 1 hour, and then resuscitated with fluid.

Plasma tumor necrosis factor and post-traumatic hyperdynamic sepsis evoked by endotoxin.

To examine the role of systemic plasma tumor necrosis factor (TNF) in the septic response following trauma, an endotoxin (lipopolysaccharide (LPS)) challenge was administered to anesthetized mongrel pigs 72 h following either hemorrhagic shock/resuscitation or sham shock. For TNF to be considered a mediator, at least two conditions should be satisfied: a TNF increase should precede other manifestations of the septic response and the magnitude of that increase should correlate with the symptoms. Immediately following resuscitation from shock, hemodynamics were stable, but heart rate, cardiac index (CI), and systemic oxygen delivery (DO2) were elevated 20-60%, and systemic vascular resistance (SVR) was decreased 40%, relative to the preshock baseline.

Resuscitation of hemorrhagic shock with hypertonic saline/dextran or lactated Ringer's supplemented with AICA riboside.

Anesthetized and ventilated swine were bled 23 ml/kg (34% of calculated blood volume) to a mean arterial pressure < 50 mm Hg. After 60 min, a bolus of either 7.5% hypertonic saline/6% dextran 70 (HSD, 4 ml/kg x 5 min) or lactated Ringer's (LR, 32 ml/kg x 5 min) was infused i.

Extracellular and intracellular actions of adenosine and related compounds in the reperfused rat intestine.

By using pharmacological tools, the biological actions of adenosine (ADO) were manipulated in rat intestine that had been rendered ischemic for 5 or 15 minutes and reperfused for 1 or 24 hours. With 100 microM ADO topically administered for 30 minutes after ischemia and then washed out, intestinal arteriolar blood flow (BF) and tissue ATP were restored to preocclusion levels, and histological damage was minimal after 1 hour of reperfusion. For comparison, with vehicle treatment after ischemia, BF was reduced by 50%, tissue ATP was reduced by 50%, myeloperoxidase levels in the intestine and lung were increased at least twofold, and mucosal villi were shortened and thickened after 1 hour of reperfusion.

Potentiation of leukotriene B4-mediated inflammatory response by the adenosine antagonist, 8-phenyl theophylline.

Previous in vitro studies have shown that adenosine (ADO)-induced inhibition of granulocyte function is near maximal at the sub-micromolar concentrations that would be anticipated in normal tissues. If this mechanism is operative in vivo, then antagonizing ADO receptors should potentiate granulocyte-mediated inflammatory responses. To unmask the putative inhibition, the antagonist, 8-phenyl theophylline (8pTHEO), was continuously suffused over the hamster cheek pouch microcirculation, which was observed with intravital bright field and fluorescence microscopy.

Activation of brain adenosine receptors evokes vasodilation in skin arterioles.

Metabolically stable adenosine (ADO) agonists were infused into cannulas chronically implanted in the lateral cerebral ventricle intracerebroventricularly (icv) while responses in skin microcirculation of pentobarbital-anesthetized hamsters were observed with intravital microscopy. Cyclohexyladenosine (CHA; A1-receptor selective; 0.0001-1 pmol) and N-ethylcarboxoamidoadenosine (NECA; A2-receptor selective; 0.

Microcirculatory flow changes after initial resuscitation of hemorrhagic shock with 7.5% hypertonic saline/6% dextran 70.

In rabbits, laser Doppler flow probes were placed in the jejunum and on the renal cortex. Pulsed Doppler probes were implanted on the abdominal aorta and superior mesenteric and femoral arteries for measuring blood flow velocity. Cardiac output was measured by thermal dilution.