Biomedical subjects
D Traber
Publications and source records attributed to D Traber.
Differential effects of prolonged septicemia on isolated pulmonary arteries and veins from sheep.
Isolated third-order pulmonary arteries and veins from sheep were examined for the effects of septicemia on norepinephrine-induced contractions, nitric oxide (NO)-mediated dilation, and basal cyclic GMP levels. The groups studied were as follows: control sheep (n = 7); sheep given live Pseudomonas aeruginosa (Ps, n = 6) for 48 h; and sheep given NG-mono-methyl-L-arginine during the last 24 h of Ps infusion (Ps-L-NMMA, n = 4). The norepinephrine-induced contractions were significantly greater (p < .05) in arteries from septic (Ps and Ps-L-NMMA) sheep. Basal cyclic GMP levels were similar in all of the arteries. The norepinephrine-induced contractions were significantly depressed (p < .05) in veins from septic (Ps and Ps-L-NMMA) sheep. Basal cyclic GMP levels in veins from Ps sheep were markedly elevated (p < .01). N omega-nitro-L-arginine methyl ester (L-NAME) ex vivo decreased cyclic GMP in both arteries and veins. Removal of endothelium enhanced contractions and decreased cyclic GMP in arteries and veins only from control sheep. The results show that septicemia differently affects the pulmonary artery and vein. The enhanced vasoconstriction of the artery is due to decreased endothelium-dependent NO release; the attenuated vasoconstriction of the vein is associated with NO-mediated increased cyclic GMP levels.
Does positive end-expiratory pressure significantly reduce airway blood flow?
Nutritive (systemic arterial) airway blood flow (mL/min/100 grams tissue) was studied in various size airways at four randomized levels of positive end expiratory pressure (PEEP) in smoke injured and normal lungs. Seven sheep were studied 24 hours after an isolated injury to the left lung using cotton smoke. Radioactive 15-microns microspheres were utilized to measure this airway blood flow. These data demonstrated a marked increase in systemic arterial blood flow to the airways in the injured left lung. Increasing levels of PEEP significantly reduced this hyperemic response. PEEP did not significantly affect the uninjured right lung. Systemic airway blood flow was never reduced to below normal control levels (uninjured) in either lung despite PEEP of up to 20 cm H2O. Severe reduction in airway nutritive flow, and the possibility of airway necrosis, does not appear to occur at PEEP levels of up to 20 cm H2O.
Bronchial blood flow during changes in inhaled oxygen and carbon dioxide concentrations in conscious sheep.
Bronchial artery blood flow index (BFI) was measured in an unanesthetized sheep model using a chronically implanted ultrasonic flow probe. The bronchial circulation was monitored during changes of the concentrations of oxygen and carbon dioxide in inhaled air. Control BFI was 15.9 +/- 3.8 ml/min/m2 during normoxic breathing with 0% CO2 (n = 6) and 18.0 +/- 1.6 ml/min/m2 while breathing 28% O2 and 0% carbon dioxide (n = 6). Hypoxia (FIO2 = 0.10) significantly increased BFI to 25.8 +/- 4.9 ml/min/m2 with a decrease in the bronchovascular resistance index (BVRI) from a baseline of 7.85 +/- 1.73 to 4.75 +/- 0.86 mm Hg/(ml/min)/m2. Hyperoxia (FIO2 = 1.0) raised BFI to 30.5 +/- 10.1 ml/min/m2 without a significant decrease in BVRI. Changing the inhaled carbon dioxide concentration from 0 to 10% resulted in a significant increase in BFI from 18.0 +/- 1.6 to 43.6 +/- 10.3 ml/min/m2 and a decrease in BVRI from 5.56 +/- 0.44 to 4.63 +/- 2.18 mmHg/(ml/min)/m2 (not significant). The change in BFI varies directly with lymph flow for hypoxia and hypercarbia. This is consistent with changes in cardiac index, indicating probable changes in surface area being perfused in the lung. Changes in BFI with hyperoxia did not follow changes in systemic vascular resistance or cardiac index. Similarly, lymph flow elevation did not occur during hyperoxia. These data suggest that BFI changes with hyperoxia are not related to changes in total systemic vascular resistance, or cardiac index, and a different mechanism may control bronchovascular flow for this condition.
Endotoxin-induced alterations in contractility of isolated blood vessels from sheep.
The present study examined reactivity to norepinephrine (NE) and KCl in isolated, suffused blood vessels from the systemic and pulmonary circulations of endotoxin-treated and control sheep. A possible mechanism underlying an endotoxin-induced alteration in vascular reactivity was also investigated. Chronically instrumented sheep were given Escherichia coli endotoxin (1.5 micrograms/kg). Eight to 12 h later these endotoxin-treated animals exhibited a significantly increased cardiac output and decreased systemic vascular pressure and resistance. The pulmonary vascular pressure and resistance were not changed. The isolated superficial femoral artery from the endotoxin sheep exhibited depressed contractions in response to KCl (75 mM) and to NE (10(-7)-10(-5) M), whereas the pulmonary artery (tertiary branch) did not exhibit altered reactivity. The decreased sensitivity to NE in the femoral artery from endotoxin sheep did not appear to involve an alteration of alpha- or beta-adrenoceptors, or an increased release of vasodilator prostanoids, or endothelium-derived relaxing factor.
Bronchial blood flow and eicosanoid blockade following airway acid aspiration.
The systemic circulation to the lung is thought to be an important microvascular exchange region which may contribute to pulmonary edema resulting from airway injury. In a chronic sheep model, we have evaluated the flow through the bronchial artery after airway injury caused by the aspiration of 2.5 ml/kg of 0.1 N hydrochloric acid with and without inhibition of thromboxane synthetase and cyclooxygenase. Cyclooxygenase inhibition with ibuprofen resulted in no rise in bronchial artery blood flow associated with airway acid aspiration (9.8 +/- 1.72 ml/min to 63.7 +/- 8.9 ml/min in the control group versus 11.3 +/- 2.5 ml/min to 10.3 +/- 3.4 ml/min in the ibuprofen group). No difference in bronchial artery blood flow was noted between control acid aspiration and acid aspiration with thromboxane synthetase inhibition. Significant early reduction in lung lymph flow was noted in the cyclooxygenase inhibition group compared to control. These data suggest that inhibition of the cyclooxygenase pathway of eicosanoid production may lessen the injury caused by airway acid aspiration. The decrease in airway blood flow with associated reduction in lymph flow suggests that airway blood flow may be important in the generation of pulmonary edema in this model.
Conjugated diene production after airway acid aspiration.
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Beta endorphin, a vasoconstrictor during septic shock.
UNLABELLED: A relationship between increased peripheral resistance (TPRI) and decreased cardiac index (CI) and mortality from sepsis has been suggested. The relationship between endogenous opiates and this response was evaluated. METHODS: Chronically instrumented sheep were given E. coli endotoxin (LPS, 1.5 mcg/kg x 30 minutes). In one study, survivors (n = 9) and nonsurvivors (n = 11) of LPS were compared along with survivors (n = 8) of half the dose of LPS. In a second study, two groups of animals received naloxone: one (n = 11) had a bolus of 2 mg/kg followed by a 2 mg/kg/hr continuous infusion started 30 minutes before LPS while the other had the bolus and infusion started 1 hour after LPS was begun. RESULTS: Both vasoconstrictive and vasodilative phases were seen. Vasoconstriction was associated with elevated beta endorphin levels, a pattern sustained until death in the nonsurvivors. Both pre- and posttreatment with naloxone lessened the maximum increase in total peripheral resistance index compared with untreated sheep. DISCUSSION: The vasoconstrictive aspects of the response to LPS correlated with elevated beta endorphin levels and with mortality. This vascular response is attenuated with naloxone blockade.
Cardiopulmonary changes with intermittent endotoxin administration in sheep.
Chronic sepsis was induced by administering endotoxin (lipopolysaccharide--LPS) at 12-hr intervals to sheep. The animals (n = 7) responded to the first dose of LPS with increased pulmonary arterial pressure (PAP), systemic vascular resistance, plasma and lymph thromboxane B2 (TxB2) concentrations, and lung lymph flow rate concurrent with a reduction in the cardiac index (CI). Subsequent doses of LPS produced an elevation of PAP and TxB2 which was progressively attenuated and eventually disappeared. With LPS the lung lymph flow was markedly elevated and CI increased. This latter was transient and associated with a reduction in systemic vascular resistance. Concomitant with the cardiopulmonary changes prekallikrein levels were not diminished, but there was a statistically significant reduction in C1-esterase inhibitor. The administration of LPS was discontinued after 5 days and the cardiopulmonary variables rapidly returned to baseline levels. Chronic endotoxemia appears to be associated with an elevated pulmonary microvascular permeability and a tendency toward a hyperdynamic circulation but with an appreciable degree of refractoriness associated with regional hemodynamics and eicosanoid biosynthesis.
Airway acid injury following smoke inhalation.
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A model of ovine endotoxemia characterized by an increased cardiac output.
High cardiac output sepsis is a major clinical problem. We have designed a sheep endotoxin model to simulate this condition and have evaluated how closely it approximates the clinical situation. The animals were prepared for chronic study by the implantation of cardiopulmonary catheters. One week later, endotoxin (0.75 microgram/kg/30 min) was administered following baseline measurements, and the animals were studied for an additional 15 hr. From 6-15 hr after the administration of endotoxin, there was a statistically significant twofold increase in cardiac output. Simultaneously, the total peripheral vascular resistance and mean arterial pressure was reduced. Eicosanoid measurements made at this time indicated that the vasodilator prostanoid, prostacyclin, was not elevated. A high cardiac output (hyperdynamic) model of sepsis has thus been established by the 30 min infusion of a small quantity of endotoxin. Prostacyclin is not a mediator of this response.
Contamination of caudal mediastinal node efferent lymph in sheep.
Many investigators have used the chronic sheep lung lymph preparation to collect caudal mediastinal node (CMN) efferent lymph. These investigators have assumed that the lymph collected with the preparation is almost pure lung lymph. We examined 17 sheep for possible systemic contamination to the lymph, and in each sheep we found one to five lymph vessels that ran from the diaphragm to the CMN. Contamination from these vessels would not be eliminated in the chronic sheep preparation. We estimated the flow rate from these vessels to be 3.0 +/- 2.6 (SD) ml/h in anesthetized sheep. This represents 25-60% of the lymph flow rate in the chronic lymph preparation. In five sheep, we also located 1-4 esophageal lymph vessels that entered th CMN. These results show that lymph collected with the chronic sheep lung lymph preparation contains a significant nonpulmonary contamination.
The 1996 Moyer Award. Effects of endotoxin on the Th1/Th2 response in humans.
Monocyte/T-cell interactions play a critical role in the systemic response to infection. Distinct patterns of cytokines are produced by two different types of T-helper cells (Th). Th1 cells secrete interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), whereas Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13. In volunteers systemic endotoxin administration initiates many features of gram-negative sepsis including cytokine release, but the patterns (i.e., Th1/Th2 patterns) have not yet been studied. In this institutional review board-approved study we investigated the effect of an intravenous bolus of endotoxin from Escherichia coli (4 ng/kg body weight) on the Th1/Th2 response in four female and four male volunteers (mean age 27.1 +/- 0.8 years). Plasma cytokine levels for IL-2, IL-4, IL-10, IL-12, and IFN-gamma and heart rate, mean arterial pressure, temperature, white blood cell, and differential blood count were determined before and hourly for 5 hours after endotoxin administration. All volunteers had tachycardia, decreased mean arterial pressure, fever, and leukocytosis. IL-10 was significantly (p < 0.05) elevated (9.4 +/- 3.9 pg/ml vs 60.9 +/- 19.3 pg/ml) 3 hours after endotoxin was administered, whereas IL-2 levels were decreased (69 +/- 26 U/ml vs 30.6 +/- 14.9 U/ml). IL-4 and IFN-gamma were not detectable in plasma. No changes were seen in the plasma levels of IL-12. Systemic responses did not correlate with changes in cytokine levels. Cytokine patterns found in this study suggest that after low-dose endotoxin administration the T-cell immune response is shifted towards the Th2 cell type response. This early shift towards a Th2 cell response may contribute to the depressed cell-mediated immune response associated with sepsis.