Secondary Dysfunction of the Intestinal Barrier in the Pathogenesis of Complications of Acute Poisoning.

The last decade has been marked by an exponential increase in the number of publications on the physiological role of the normal human gut microbiota. The idea of a symbiotic relationship between the human organism and normal microbiota of its gastrointestinal tract has been firmly established as an integral part of the current biomedical paradigm. However, the type of this symbiosis varies from mutualism to parasitism and depends on the functional state of the host organism. Damage caused to the organism by external agents can lead to the emergence of conditionally pathogenic properties in the normal gut microbiota, mediated by humoral factors and affecting the outcome of exogenous exposure. Among the substances produced by symbiotic microbiota, there are an indefinite number of compounds with systemic toxicity. Some occur in the intestinal chyme in potentially lethal amounts in the case they enter the bloodstream quickly. The quick entry of potential toxicants is prevented by the intestinal barrier (IB), a set of structural elements separating the intestinal chyme from the blood. Hypothetically, severe damage to the IB caused by exogenous toxicants can trigger a leakage and subsequent systemic redistribution of toxic substances of bacterial origin. Until recently, the impact of such a redistribution on the outcome of acute exogenous poisoning remained outside the view of toxicology. The present review addresses causal relationships between the secondary dysfunction of the IB and complications of acute poisoning. We characterize acute systemic toxicity of such waste products of the normal gut microflora as ammonia and endotoxins, and demonstrate their involvement in the formation of such complications of acute poisoning as shock, sepsis, cerebral insufficiency and secondary lung injuries. The principles of assessing the functional state of the IB and the approaches to its protection in acute poisoning are briefly considered.

Permeability of Intestinal and Blood-Tissue Barriers in Rats for Evans Blue Dye under Conditions of Acute Intoxication with Cyclophosphamide.

Myeloablative therapy was modeled by administration of cyclophosphamide to rats in a dose of 2.1 LD50 for 14 days. Under these conditions, increased accumulation of Evans blue dye given by gavage was observed in the blood, brain, lung, liver, kidney, and ileum (by 34, 1.6, 149, 46, 30, and 6.2 times, respectively). After intravenous injection of the dye, its accumulation was increased only in the lung and ileum. Thus, simulation of myeloablation cytostatic therapy by cyclophosphamide injection to rats is associated with impairment of the intestinal and lung-blood barriers. These alterations predispose to penetration of biologically active substances from the small intestine, gastrointestinal chyme, and lungs to the blood, thus contributing to the development of the early toxic effects of cyclophosphamide.

Effects of cyclophosphamide and lactulose on the release of ammonia and medium-molecular-weight substances from the intestine into blood in rats.

The effects of lactulose on the release of ammonia and medium-molecular-weight substances from the intestine into the blood and on the severity of cyclophosphamide intoxication were studied in rats. The pH and urease-dependent component of ammonia-producing activity of the cecal chyme decreased over 6 h after lactulose administration, while ammonia content in the chyme increased. Cyclophosphamide caused an increase in ammonia and, less so, glutamine level in the portal blood and in the blood collected after decapitation; this drug stimulated release of methylene blue and endogenous substances of medium-molecular-weight to the portal blood. Lactulose was virtually inessential for these changes and for the neurological status, mortality, and medium life span of rats. Hence, lactulose did not prevent cyclophosphamide-induced leakage of ammonia and medium-molecular-weight substances from the gastrointestinal tract into blood and did not reduce the severity of intoxication.

Aggravation of cyclophosphamide-induced acute neurological disorders under conditions of artificial acidification of chyme in rats.

The effect of artificial acidification of the intestinal content on neurological manifestations of acute severe cyclophosphamide intoxication was studied in rats. The animals were gavaged with 20 ml/kg sulfuric (0.05 M), hydrochloric, boric, or lactic acids (0.1 M) 3 h before intraperitoneal injections of the cytostatic in doses of 0, 200, 600, or 1000 mg/kg. The decrease in pH (by.0) and ammonia-producing activity of the cecal chyme developed within 3 h after administration of acids. Cyclophosphamide caused hyperammonemia; glutamine/ammonia and urea/ammonia ratios in the blood decreased. These changes augmented after administration of acids (boric acid produced maximum and lactic acid minimum effects). Acid treatment resulted in greatest elevation of ammonia level in the portal venous blood and a lesser elevation in the vena cava posterior blood. Acid treatment promoted manifestation of cyclophosphamide neurotoxic effect and animal death. Hence, acidification of the chyme inhibited the formation of ammonia in it, while ammonia release from the gastrointestinal tract into the blood increased; the treatment augmented hyperammonemia and aggravated the neurological manifestations of cyclophosphamide intoxication.

Effect of hypoxia on sodium and ammonium acetate toxicity for Daphnia.

Exposure of Daphnia in degassed (boiled) culturing water (hypoxia simulation) led to solitary lethal outcomes after more than 24 h. Before this term, hypoxia had no appreciable effect on the toxicity of sodium or ammonium acetate salts. The sensitivity of daphnias to the lethal effects of the tested chemicals did not change under conditions of normal oxygenation and increased sharply (by two orders of magnitude) under conditions of hypoxia, loosing the linear relationship with toxicant concentration. Ammonium acetate toxicity more markedly increased under conditions of hypoxia than sodium acetate toxicity. These data should be taken into consideration when predicting the results of combined effects of toxicants on water ecosystems and on human organism.

Increase of ammonia pool in the gastrointestinal tract of rats potentiates acute toxicity of cyclophosphamide.

For evaluation of the impact of changes of ammonia pool in the gastrointestinal tract on acute toxicity of cyclophosphamide, the dynamics of blood levels of ammonia and urea of rats was studied after intraperitoneal injection of cyclophosphamide (600 mg/kg) and clinical manifestations of intoxication and lifespan of rate were studied after cyclophosphamide injections in doses of 200, 600, 1000, and 1400 mg/kg alone or in combination with ammonium acetate. Ammonium acetate stimulated the hyperammoniemic and uremic effects of cyclophosphamide. Combined effects of the toxicants were associated with symptoms characteristic of acute poisoning with ammonium salts; these symptoms were not observed under the effect of ammonium acetate alone. Ammonium acetate stimulated the lethal effect of cyclophosphamide injected in doses of 200, 600, 1000, or 1400 mg/kg: the mean lifespan of rats decreased by 1.5, 2.1, 2.8, or 6.1 times, respectively. These data indicate that ammonia redistribution from the gastrointestinal tract into circulating blood is one of the mechanisms of thanatogenesis in acute cyclophosphamide intoxication.

Ammonia potentiates the lethal effect of ethanol on rats.

Blood ammonia concentration increased in the portal vein (by 1.4 times) and inferior vena cava (caudal to the renal vein inflow, by 2.2 times; and cranial to the hepatic vein inflow, by 2.5 times) of rats 3 h after intragastric administration of 16.57 M ethanol solution (446 mmol/kg, approximately 1.4 LD(50)/48 h). Ammonia concentration in mixed blood samples (post-decapitation) increased by 39%. The rate of ammonia accumulation was 3-fold higher in an intraperitoneal lavage solution. Three-hour exposure of ethanol-treated animals to atmospheric ammonia (0.84-1.07 mg/liter, i.e. approximately 1/8LC(50) for intact rats) was followed by a 2.4-fold increase in blood ammonia concentration as compared to specimens of the ethanol group. Ammonia inhalation potentiated the lethal effect of ethanol (dose variation factor 0.81), suppressed external respiration, and decreased oxygen consumption. Our results indicate that kinetic changes in endogenous ammonia have an adverse effect on the outcome of alcohol intoxication in rats.