An experimental study on hepatotoxicity of sclerosant ethanolamine oleate flowed into portal vein.

Although endoscopic injection sclerotherapy has been a main treatment option for gastroesophageal varices, intraportal inflow of the sclerosant, ethanolamine oleate, induce liver damage. The aim of this study was to clarify the liver damage due to intraportal inflow of ethanolamine oleate. Ethanolamine oleate suspension was injected into livers of male Wistar rats via the portal (ileocolic) vein. Degrees of liver damage were evaluated by serum levels of transaminases and by histological examination. Intraportal injection of ethanolamine oleate led to extensive liver necrosis, which was marked 1 day after the injection and recovered by 7 days after injection. Liver necrosis became severe as the dose of the injected sclerosant increased. Histologically, neither portal thrombosis nor embolism was evident. Carbon powder particles of India ink, which were injected together with ethanolamine oleate, reached and deposited in sinusoids of the necrotic portions of the liver. These findings suggested that the liver damage had not developed simply as a result of impairment of portal blood flow. Ethanolamine oleate may itself have direct hepatotoxic effects.

Strain-dependent cytokine profile and susceptibility to oleic acid anilide in a murine model of the toxic oil syndrome.

The toxic oil syndrome (TOS) was caused by the ingestion of an adulterated rapeseed oil containing oleic acid anilide (OAA). It was characterized by lethal symptoms in the acute phase and by symptoms of idiopathic autoimmune diseases in the chronic phase. The pathogenetic mechanisms remain unclear. In a murine model of TOS we demonstrate strain-dependent effects on the immune system after treatment with OAA intraperitoneally. While C57BL/6 (H-2b) mice develop a polyclonal B cell activation without disease symptoms, most A/J (H-2a) mice suffer an acute lethal wasting disease. These differences are reflected in the splenic cytokine gene expression and secretion and in the Ig production. Increased IgE serum levels and reduced TNF-beta mRNA suggest a Th2 cell response in C57BL/6 mice. In A/J mice, splenocytes express IL-1alpha, IL-10, and IFN-gamma mRNA in vivo and secrete high levels of TNF-alpha in vitro. These observations resemble the human condition in TOS with development of either an acute lethal disease or a chronic autoimmune-like disease. As in other chemical-induced reactions genetic susceptibility seems to be important.

Synergistic vascular toxicity and fatty acid anilides in the toxic oil syndrome.

The underlying etiology of the toxic oil syndrome may be related to any of several toxic contaminants. The hypothesis is made that two or more toxic compounds may act synergistically to cause vascular damage in the toxic oil syndrome. To support this hypothesis, previous studies are reviewed concerning the remarkable synergistic toxic action of allylamine and beta-aminopropionitrile on the media of blood vessels. Although these toxins are not directly related to the toxic oil syndrome, this previous experimental work emphasizes the possibility that unexplored synergistic actions may be important. Furthermore, the hypothesis that contaminating fatty acid anilides in toxic oil undergo alterations during cooking is supported by high pressure liquid chromatographic analysis. The theoretic metabolism of fatty acid anilides is discussed. Recent data concerning the toxic actions of the anilides of oleic and linoleic acid are given. These data suggest that these anilides induce immunologic alterations that may be similar to those seen in the toxic oil syndrome. In addition, the heated anilides appear to have increased toxicity, supporting the concept that the use of toxic oil in cooking may increase its toxicity.

Airway pressure release ventilation in a neonatal lamb model of acute lung injury.

OBJECTIVE: To determine if airway pressure release ventilation (APRV) is feasible in a neonatal animal model with acute lung injury. DESIGN: Nonrandomized, repeated, bracketed measures. SETTING: University research laboratory. SUBJECTS: Seven neonatal sheep (5.6 +/- 0.6 kg), less than 10 days of age. INTERVENTIONS: Acute lung injury was induced by oleic acid infusion and cardiorespiratory profiles were compared during spontaneous ventilation at ambient airway pressure, continuous positive airway pressure (CPAP), APRV, and conventional positive-pressure ventilation (PPV). MEASUREMENTS AND RESULTS: Oleic acid resulted in acute lung injury with stable cardiorespiratory status during the 3-hr study period. Mean airway pressure (Paw) was comparable for all three positive-pressure modes (CPAP 13.4 +/- 1.5, APRV 13.5 +/- 1.4, PPV 13.9 +/- 1.4 cm H2O, NS). After acute lung injury, CPAP increased arterial oxygenation compared with spontaneous ventilation (77.3 +/- 6.9 vs. 57.7 +/- 4.2 torr [10.3 +/- 0.9 vs. 7.7 +/- 0.6 kPa], p less than .05), and this increase was maintained during APRV (73.3 +/- 5.6 vs. 77.3 +/- 6.9 torr [9.8 +/- 0.7 vs. 10.3 +/- 0.9 kPa], NS). Alveolar ventilation was increased by APRV compared with CPAP (PaCO2 29 +/- 1 vs. 41 +/- 2 torr [3.9 +/- 0.1 vs. 5.4 +/- 0.3 kPa], p less than .05) without impairment of cardiovascular performance (cardiac output 1.18 +/- 0.16 vs. 1.20 +/- 0.17 L/min, NS). To achieve ventilation equivalent to APRV during PPV, peak Paw was greater (36.4 +/- 3.2 vs. 19.7 +/- 1.7 cm H2O, p less than .05) and cardiac output (0.94 +/- 0.11 vs. 1.18 +/- 0.16 L/min, p less than .05) and mean arterial pressure (91 +/- 7 vs. 96 +/- 6 mm Hg, p less than .05) were decreased during PPV compared with APRV. CONCLUSIONS: In this neonatal laboratory model of acute lung injury, APRV maintained oxygenation and augmented alveolar ventilation compared with CPAP. Compared with PPV, APRV provided similar ventilation and oxygenation, but at lower peak Paw than PPV, without compromising cardiovascular performance.

Effects of hyperoxia in the presence of acute lung injury.

We employed a multiple-dose, oleic acid (OA) model to evaluate the susceptibility to oxygen toxicity of rabbits with acute lung injury (ALI). The rabbits were partitioned into four groups: ALI group (n = 8) received OA (0.04 ml/kg iv) and again at two consecutive 24-h intervals and breathed room air (RA); hyperoxic O2/ALI group (n = 8) underwent similar OA injection protocol and breathed an FIO2 greater than or equal to 0.96; oxygen group (n = 8) received identical injection protocol with normal saline (NS) and breathed an FIO2 greater than or equal to 0.96; and control (CTR) group (n = 5) received isovolume NS injections and breathed RA. Arterial blood pH and gas tensions were measured before and 24, 48, and 60 h after ALI. Surviving animals were killed at 72 h and body weight (BW) was determined at autopsy; then the lungs were removed and weighed (LW). The mortality for animals exposed to hyperoxia was significantly (p less than or equal to .02) greater than those breathing RA, regardless of the presence or absence of ALI. Blood pH was lower (p less than or equal to .05) in all animals but the CTR group. However, acidemia was significantly greater in both hyperoxic groups compared to animals in the CTR and ALI/RA. Inflation and deflation lung-thorax compliances were lower (p less than or equal to .05) and percent lung weight of terminal body weight (LW/BW) was higher (p less than or equal to .05) after hyperoxia with or without ALI compared to CTR animals regardless of FIO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of hydralazine on intrapulmonary shunt.

We compared the acute effects of bilateral arteriovenous may be related to levels of PvO2. The hydralazine-associated (p less than .05) decrease in resistance. Mixed venous oxygen fistulas to those of hydralazine infusion on hemodynamics and pulmonary gas exchange in dogs with pulmonary edema induced by administration of oleic acid. Oleic acid significantly (p less than .01) increased intrapulmonary shunt (Qsp/Qt) and pulmonary and systemic vascular resistance, and reduced cardiac output. Once the lesion stabilized, both opening the fistula and infusing hydralazine produced a similar and significant (p less than .01) increase in cardiac output, and a significant (p less than .05) decrease in resistance. Mixed venous oxygen tension (PvO2) closely followed the changes in cardiac output; however, PaO2 did not change. Qsp/Qt significantly (p less than .01) increased with the fistulas open and with hydralazine infusion. Closure of the fistulas or bleeding the animal at the end of the experiment reversed the changes in cardiac output and Qsp/Qt. The comparable increases in cardiac output and Qsp/Qt produced by opening the fistulas or infusing hydralazine may be related to levels of PvO2. The hydralazine-associated PvO2 increase indicates that this drug increased oxygen transport to the tissues even as Qsp/Qt became larger.

Mechanisms involved in acute lung edema induced in dogs by oleic acid.

We investigated mechanisms related to the development of acute lung edema, as induced by oleic acid in adult mongrel dogs. The intravenous injection of oleic acid (0.04 ml/kg) was considered to induce a permeability edema, as an enhancement of transvascular protein clearance was observed after the injection. The effects of oleic acid injection on systemic blood pressure (SBP), pulmonary arterial pressure (PAP), pulmonary arterial wedge pressure (PAWP), cardiac output (CO) and airway pressure (AWP) were measured. A significant decrease in CO and increase in AWP were evident after the injection, but there were no changes in SBP, PAP and PAWP. Treatment of the animals with prostaglandin I2 (PGI2) did not alter the induction of edema by oleic acid. However, the decrease in CO and increase in AWP were normalized by treatment with PGI2. Blood platelet count was not affected by oleic acid given in a dose of 0.04 ml/kg. To determine the direct effect of oleic acid on the vascular endothelium, the agent was injected through a catheter placed in the pulmonary artery. Electron microscopic examination revealed severe vacuolation on the endothelium of the pulmonary artery after only 1 min of exposure to oleic acid. Increased permeation of Evans blue into the subendothelial tissue was also observed with oleic acid treatment, compared with findings in the controls. These results indicate that the lung edema induced by oleic acid is due to an increased protein clearance, probably through a direct toxic effect on the vascular endothelium rather than an indirect toxic effect of chemical mediators released from the aggregated platelets.

Hemodynamic effects of positive end-expiratory pressure during high-frequency ventilation.

We studied the intrapleural and hemodynamic effects of positive end-expiratory pressure (PEEP) during high-frequency ventilation (HFV) with a Venturi high-frequency ventilator (Bird). Ten healthy mongrel dogs were anesthetized with sodium pentobarbital, catheterized with intrapleural and thermodilution pulmonary artery lines, and subjected to oleic acid-induced pulmonary edema. A mean PEEP of 16 +/- 6 (SD) cm H2O restored venous admixture to baseline in nine animals. Both mean airway pressure (Paw) and mean intrapleural pressure (Ppl) increased significantly with each increment of PEEP during HFV. Approximately 50% of Paw was transmitted to the intrapleural space. Cardiac index (CI) decreased with increments of PEEP in spite of constant transmural central venous and pulmonary capillary wedge pressures, so that oxygen delivery decreased despite increased PaO2. Possible mechanisms of PEEP-induced depression of CI during HFV are discussed. We conclude that both hemodynamic and intrapleural effects of PEEP during HFV are similar to those during conventional mechanical ventilation.

Pulmonary artery wedge pressure may fail to reflect left ventricular end-diastolic pressure in dogs with oleic acid-induced pulmonary edema.

We investigated the accuracy with which pulmonary artery wedge pressure (WP) reflected left ventricular end-diastolic pressure (LVEDP) in dogs with oleic acid-induced pulmonary edema. We compared hemodynamic variables before and during edema, as measured from a pulmonary artery catheter placed before oleic acid (PA-1) and from a second catheter (PA-2) placed 2 h after oleic acid infusion. Oleic acid decreased arterial oxygen saturation and cardiac output and increased pulmonary vascular resistance and phasic pulmonary artery pressure. LVEDP did not change after oleic acid, although WP measured by both catheters was increased. In addition, WP measured by PA-2 (7.1 +/- 0.7 mm Hg) was greater than that measured by PA-1 (5.6 +/- 0.5 mm Hg) (p less than or equal to 0.037). Using PA-1, we found that WP increased in a linear manner with LVEDP both before and after pulmonary injury (r2 = 0.91, 0.68, respectively). There was no relationship between LVEDP and WP using PA-2 (r2 = 0.07). We conclude that oleic acid-induced pulmonary edema lessens the accuracy with which WP reflects LVEDP, and that WP from a catheter placed after edema less accurately reflects LVEDP than does WP from a catheter placed before edema.

Prevention of Ozonide-Induced Heinz Bodies in human Erythrocytes by Vitamin E.

Methyl oleate ozonide, a proposed intermediary in ozone intoxication, produced Heinz body inclusions in human erythrocytes at concentrations of from 10-4 to 2 x 10-3 M. Daily oral supplementation with either 100 mg or 200 mg of D-alpha-tocopheryl acetate prevented Heinz body formation by methyl oleate ozonide. These observations suggest that the protective effects of vitamin E against ozone-produced toxicants occurs in man as well as in animals.