Acute Toxic Injury Research Articles

In vivo class II transactivator expression in mice is induced by a non-interferon-gamma mechanism in response to local injury.

Tissue injury induces MHC class II expression, which could be important in the recognition of that tissue as an allograft. The class II transcriptional activator (CIITA) is the major regulator of basal and induced MHC class II expression and is essential for antigen presentation. The role of CIITA in the induction of class II by tissue injury is unknown. In this study, we examined CIITA induction in the course of acute ischemic or toxic renal injury in mice, including the role of interferon (IFN)-gamma and of the transcription factor, interferon regulatory factor (IRF)-1. Kidneys were injured by ischemia or by gentamicin toxicity and were then studied for changes in gene expression using Northern blot, reverse transcriptase-polymerase chain reaction, radioimmunoassay, and tissue staining. We compared wild-type (WT) mice to IFN-gamma knockout (GKO) or IRF-1 knockout mice. Ischemic injury induced CIITA and class II expression in the kidney, in WT and GKO mice. Gentamicin injury also induced both CIITA and class II expression, independent of IFN-gamma, in WT and GKO mice. After ischemic injury, the induction of class II protein levels and CIITA and class II mRNA levels were induced, to a lesser degree, in IRF-1 knockout mice. These data indicate that CIITA is induced by tissue injury, and probably accounts for class II induction during tissue injury. CIITA induction by injury is largely IFN-gamma independent but requires IRF-1. The similarities of the pattern of CIITA and class II induction in ischemic and toxic injury suggest that this is a stereotyped response of injured tissue and not a consequence of a particular mechanism of injury.

Advanced life support for acute toxic injury (TOXALS).

The need to consider the problem of acute toxic injury in the prehospital context emphasized by the recent use of highly toxic agents of warfare in terrorist attacks. Toxic agents differ widely in their nature but may be considered to have four distinct properties: toxicity, latency, persistency and transmissibility. Toxicity and latency determine the onset and pathophysiology of the poisoning and therefore the clinical management. Persistency and transmissibility determine the level of hazard to rescue personnel and the evacuation system and therefore the rationale of logistic management. Previously, special emphasis has been given to the importance of isolation and decontamination of the patient before any medical intervention can occur. This approach, however, although essential for the safety of medical responders may not be in the best interests of the patient who may be in a life-threatening situation within a contaminated zone (CONZONE). Toxic injury may require more rapid help than traumatic injury; moreover, traumatic and toxic injury may co-exist, as in the case of explosion with toxic emission. The special skills required are defined in the TOXALS programme and must now become a standard part of the training and practice of prehospital care medical care.

Acute exposure to formaldehyde induces hepatic metallothionein synthesis in mice

Humans risk inadvertent intraperitoneal or intravenous exposure to formaldehyde (HCHO), commonly used for disinfection of implanted or extracorporeal medical devices. Various chemical and physical stresses are known to induce hepatic metallothionein. This study examined the effect of acute parenteral administration of HCHO on induction of hepatic metallothionein synthesis. Adult male CF1 mice were administered HCHO ip and hepatic metallothionein was quantified by the cadmium-radioassay method. HCHO (50 mg/kg) increased hepatic metallothionein as early as 8 hr after dosing with maximal levels (27-fold increase) occurring at 72 hr. Metallothionein concentrations were elevated (15-fold) 24 hr after 50 or 100 mg HCHO/kg but not at lower dosages. Concomitant elevations in hepatic zinc and copper content were observed. No increases in metallothionein were observed in kidney, pancreas, or intestine 24 hr after HCHO administration (100 mg/kg, ip). Induction of metallothionein by HCHO may reflect direct de novo synthesis since the response was abolished by pretreatment with the RNA synthesis inhibitor, actinomycin D. HCHO induction of metallothionein also does not appear to be mediated by stress-induced release of corticosteroids or catecholamines from the adrenal since the response was unaltered in adrenalectomized mice. Interference with the glutathione (GSH)-dependent oxidation of HCHO by reducing hepatic GSH concentrations to 40% of control after a 2-hr pretreatment with phorone decreased the metallothionein induction response to HCHO by 33%. This result suggests that the induction may be partially due to a HCHO metabolite, e.g., formate. Confirmation of metallothionein synthesis was obtained following spectral and chromatographic analysis. Thus, HCHO and/or a metabolite produces a marked increase in hepatic metallothionein and alters hepatic zinc and copper homeostasis, all of which are transient responses. Although HCHO was only mildly hepatotoxic at the highest dose (as evidenced by an increase in plasma alanine aminotransferase activity), such changes in metallothionein synthesis and essential metal homeostasis may be part of a cellular repair mechanism operant after acute toxic cell injury.

Altered glomerular eicosanoid biosynthesis in uranyl nitrate-induced acute renal failure

The present studies were designed (1) to examine the pattern of changes in eicosanoid biosynthesis in isolated rat glomeruli, and (2) to correlate these changes with the previously observed alterations in renal perfusion and glomerular filtration rate which occur after uranyl nitrate administration, a model of toxin-induced acute renal failure. In the first part of this study, the in vitro and the in vivo effects of two cyclooxygenase inhibitors were examined for their ability to inhibit rat glomerular eicosanoid biosynthesis. Inhibition of prostaglandin E 2 and prostaglandin F 2α generation by 1 mM aspirin in vitro was 76 and 82%, respectively. Similar inhibitions of 85 and 72% of biosynthesis of the above-mentioned lipids by 0.1 mM indomethacin were also noted. Intraperitoneal administration of aspirin (150 mg/kg) resulted in a significant inhibition of 88% or greater of prostaglandin E 2, prostaglandin F 2α, 6-keto-prostaglandin F 2α, and thromboxane B 2 biosynthesis. These results indicated that the expected alterations produced under in vivo conditions were detectable by in vitro techniques used in this study. 24 h after the administration of uranyl nitrate (25 mg/kg), significant increases in the biosynthesis of prostaglandin E 2 (124%) and prostaglandin F 2α (88%) were observed when compared to the control values. No significant changes in prostacyclin or thromboxane formation were noted at this time. A further increase in the biosynthesis of prostaglandin E 2 (248%), prostaglandin F 2α (262%), and a significant increase in prostacyclin (120%), measured as 6-keto-prostaglandin F 1α, were noted at 48 h. No changes in thromboxane B 2 biosynthesis were noted. It is concluded that these data are consistent with the hypothesis that the increased glomerular biosynthesis of vasodilator eicosanoids (i.e., prostaglandin E 2 and prostacyclin) may play a significant role in the homeostatic regulation of renal perfusion and glomerular filtration after acute toxic injury to the kidney.

A protective effect of coenzyme Q 10 on the adriamycin-induced cardiotoxicity in the isolated perfused rat heart

Experiments were undertaken to determine if pretreating the animal with coenzyme Q 10 (CoQ) protected the cardiac muscle of the isolated heart from the acute toxic injury induced by perfusion with adriamycin. CoQ (15 mg/kg/day) or vehicle alone was injected intraperitoneally into male rats for 7 days. Two hours after the last injection, the hearts were excised and perfused by Langendorff's technique. Perfusion with various concentrations of adriamycin (5, 10, 20, 30 or 50 μg of adriamycin/ml of perfusate) induced a dose-dependent decline in the contractile tension development and a dose-dependent elevation in the resting tension. When adriamycin in perfusate was 10 μg/ml or less than that, the coronary flow rate remained almost constant during the perfusion. No significant recovery in the contractile tension development and the resting tension was obtained by subsequent perfusion without adriamycin. The contractile tension development of the CoQ-pretreated hearts was significantly greater than that of the vehicle-pretreated hearts both during the perfusion with adriamycin (10 μg/ml) for 60 min and during the subsequent adriamycin-free perfusion for 30 min. After 60 min of perfusion with adriamycin, the cardiac stores of ATP, total adenine nucleotide and nicotinamide adenine dinucleotide in the CoQ-pretreated group were significantly higher than those in the vehicle-pretreated group. These results indicate that exogenous CoQ protects the cardiac muscle from the deterioraion in mechanical function induced by adriamycin. Better mechanical function of CoQ-pretreated hearts was attributable to relatively higher ATP stores presumably due to lesser loss of adenine nucleotide pool from the cardiac cells.

The effect of pregnancy on the sensitivity of the rabbit liver to diethyl nitrosamine.

SummaryBy the analysis of various serum constituents it is concluded that the liver of a pregnant rabbit is considerably more sensitive to acute toxic injury than that of a non‐pregnant rabbit.