Elevated levels of prostaglandin e2 and thromboxane B2 in depression

Plasma prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) levels were measured in 30 depressed outpatients. Plasma PGE2 was increased in all but one of these patients (p<0.001) and all had increased levels of TXB2 (p<0.001). Since monamine oxidase inhibitors inhibit brain prostaglandin synthesis, and tricyclic antidepressants may antagonize prostaglandin actions, these observations suggest new approaches to depression research.     

Plasma thromboxane B2 levels and thromboxane B2 production by platelets are increased in patients during spinal and epidural anesthesia

Concentrations of thromboxane (Tx) B2 in plasma and its production by platelets were measured in 20 spinal and 10 epidural anesthesia patients scheduled for small operations in the lower extremities. The main metabolite of prostacyclin, 6-keto-PGF1 alpha and prostaglandin (PG) E2 in plasma were also determined. Plasma TxB2 and TxB2 production by platelets increased during both spinal and epidural anesthesia. Plasma TxB2 levels also remained elevated 1 h after anesthesia. The plasma concentrations of 6-keto-PGF1 alpha and PGE2 did not change during spinal or epidural anesthesia. In in vitro studies, only low concentrations of lidocaine (0.5-1.0 micrograms/ml) and bupivacaine (0.5-3.0 micrograms/ml) increased platelet TxB2 production. In platelet rich plasma, neither lidocaine nor bupivacaine in concentrations of 0.5-3.0 micrograms/ml caused constant changes in ADP-induced platelet aggregation, but they inhibited it in toxic concentrations (12 micrograms/ml). The results suggest that the increased TxB2 plasma levels and platelet TxB2 production during regional anesthesia are not caused by local anesthetics itself but by other factors, e.g. tissue trauma. In clinically found concentrations, local anesthetics do not cause any constant changes in platelet aggregation.     

Importance of markers of hepatitis B virus in alcoholic liver disease.

To determine the importance of the presence of serological markers of hepatitis B virus infection in patients with alcohol related liver disease we compared cumulative alcohol intake and clinical and histological features in patients with markers of hepatitis B virus infection and in those without. Hepatitis B surface antigen (HBsAg) was detected in five (2%) out of 285 patients studied and antibody to HBsAg (anti-HBs) in 41 (14%); one patient had antibody to hepatitis B core antigen alone. The combined prevalence of markers of hepatitis B virus infection was similar in patients with alcoholic cirrhosis (18%) and precirrhotic liver disease (13%). Two patients positive for HBsAg had histological features of both alcoholic liver disease and chronic active hepatitis, with stainable HBsAg. Patients with anti-HBs were, however, histologically indistinguishable from patients without markers, and the mean cumulative alcohol intake of patients with anti-HBs was similar to or even higher than that of patients with liver disease of comparable severity who had no evidence of previous infection. The presence of markers of hepatitis B virus infection was related to former residence in countries with a high prevalence of the infection and to previous parenteral treatment and blood transfusions. Infection with hepatitis B virus does not enhance the development of chronic liver disease in heavy drinkers, except in the small number who remain positive for HBsAg.     

Increased urinary F2-isoprostane excretion in alcoholic liver disease

Free radical-induced lipid peroxidation (LP) is thought to be important in alcoholic liver disease (ALD), however, direct demonstration of increased LP in patients with ALD has been difficult. Quantification of F2-isoprostanes (F2-isoP), prostanoids produced by peroxidation of arachidonic acid, in plasma and urine are sensitive and specific indices of LP in vivo. To determine if LP is increased in ALD, 24-h urinary excretion of F2-isoPs were measured in 10 patients hospitalized because of ALD. The mean urinary excretion of the F2-isoP in the ALD patients' urine was 9.6+/-3.5 ng/mg creatinine, which was significantly elevated compared to controls' urinary excretion, which was 1.7+/-0.2 ng/mg creatinine (p<.01). The urinary excretion of F2-isoP decreased to 3.6+/-1.1 ng/mg creatinine as the patients improved clinically with abstinence over the 1-month period. These data suggest that lipid peroxidation, as assessed by this noninvasive method, is increased in patients with acute ALD and decreases with time as the patients improve clinically with abstinence.     

Prostaglandin E2 and thromboxane B2 levels in rats subjected to pancreas transplantation

This work undertakes the study of changes in urinary, plasmatic and tissue levels of Thromboxane B2 (TXB2) as well as in tissue Prostaglandin E2 (PGE2) after pancreas transplantation and the effect of superoxide dismutase (SOD) on these changes. For this purpose, streptozotocine induced diabetic rats were subjected to pancreas transplantation. Experimental groups were classified as follows: Group I: Control; Group II: Animals subjected to 15 min of pancreas arterial flow occlusion followed by reperfusion; Group III: Syngenic pancreas transplantation after 12 hours of organ preservation; Group IV: Same as III, but with additional SOD (13 mg/kg) pretreatment. The results indicate that significant increases of PGE2 and TXB2 levels occur as a consequence of the surgical removal, preservation and implantation of the organ. For TXB2 these increases, immediate in plasma and tissue, are not detected in urine until 24 hours after transplantation of the pancreas. The release of TXB2 and PGE2 was effectively prevented in the SOD treated group supporting the role of oxygen free radicals and lipid peroxidation in the processes of ischemia-reperfusion associated to transplantation of the pancreas.     

Recent advances in alcoholic liver disease. IV. Dysregulated cytokine metabolism in alcoholic liver disease

Alcoholic liver disease (ALD) remains a leading cause of death from liver disease in the United States for which there is no FDA-approved therapy. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentration levels of TNF-alpha and TNF-alpha-inducible cytokines/chemokines, such as IL-6, -8, and -18, have been reported in patients with alcoholic hepatitis and/or cirrhosis, and levels correlated with markers of the acute phase response, liver function, and clinical outcome. Studies in animal models support an etiologic role for cytokines in the liver injury of ALD. Cytokines, such as transforming growth factor-beta, play a critical role in the fibrosis of ALD. Multiple new strategies are under investigation to modulate cytokine metabolism as a form of therapy for ALD.     

Immune mechanisms in alcoholic liver disease

Growing evidence indicates that inflammatory reactions play an important role in the pathogenesis of alcoholic liver disease (ALD). The implication of immunity in fueling chronic inflammation in ALD has emerged from clinical and experimental evidence showing the recruitment and the activation of lymphocytes in the inflammatory infiltrates of ALD and has received further support by the recent demonstration of a role of Th17 lymphocytes in alcoholic hepatitis. Nonetheless, the mechanisms by which alcohol triggers adaptive immune responses are still incompletely characterized. Patients with advanced ALD show a high prevalence of circulating IgG and T-lymphocytes towards epitopes derived from protein modification by hydroxyethyl free radicals (HER) and end-products of lipid peroxidation. In both chronic alcohol-fed rats and heavy drinkers the elevation of IgG against lipid peroxidation-derived antigens is associated with an increased production of pro-inflammatory cytokines/chemokines and with the severity of histological signs of liver inflammation. Moreover, CYP2E1-alkylation by HER favors the development of anti-CYP2E1 auto-antibodies in a sub-set of ALD patients. Altogether, these results suggest that allo- and auto-immune reactions triggered by oxidative stress might contribute to fuel chronic hepatic inflammation during the progression of ALD.     

Noncoding RNAs in alcoholic liver disease

Alcoholic liver disease (ALD) is a complex process with high morbitity and can cause liver dysfunction, which contains a wide spectrum of hepatic lesions, including steatohepatitis, fibrosis, cirrhosis, and eventually hepatocellular carcinoma. To date, the molecular mechanisms for ALD have not been fully explored and an effective therapy is still missing. Overwhelming evidence shows dysregulation of noncoding RNAs (ncRNAs), particularly microRNAs (miRNAs), is correlated with etiopathogenesis and progress of ALD including hepatocyte damage, disrupted lipid metabolism, aggressive inflammatory responses, oxidative stress, programmed cell death, fibrosis, and epigenetic changes induced by alcohol. For example, circulating miRNA-122 is a marker of hepatocyte damage, and miRNA-155 is a potential marker of inflammation, indicating their diagnosis therapeutic potential in ALD. In addition, roles for long noncoding RNAs (lncRNAs) and circular RNAs in ALD are being uncovered. Further, circulating ncRNAs and exosome-derived ncRNAs have attracted more attention lately, suggesting a role in the prevention and treatment of ALD. This review covers the roles of ncRNAs in ALD, and the potential uses as markers for diagnosis and therapeutic options.     

Innate immunity in alcoholic liver disease

Excessive alcohol consumption is a leading cause of chronic liver disease in the Western world. Alcohol-induced hepatotoxicity and oxidative stress are important mechanisms contributing to the pathogenesis of alcoholic liver disease. However, emerging evidence suggests that activation of innate immunity involving TLR4 and complement also plays an important role in initiating alcoholic steatohepatitis and fibrosis, but the role of adaptive immunity in the pathogenesis of alcoholic liver disease remains obscure. Activation of a TLR4-mediated MyD88-independent (TRIF/IRF-3) signaling pathway in Kupffer cells contributes to alcoholic steatohepatitis, whereas activation of TLR4 signaling in hepatic stellate cells promotes liver fibrosis. Alcohol consumption activates the complement system in the liver by yet unidentified mechanisms, leading to alcoholic steatohepatitis. In contrast to activation of TLR4 and complement, alcohol consumption can inhibit natural killer cells, another important innate immunity component, contributing to alcohol-mediated acceleration of viral infection and liver fibrosis in patients with chronic viral hepatitis. Understanding of the role of innate immunity in the pathogenesis of alcoholic liver disease may help us identify novel therapeutic targets to treat this disease.     

Oxidative stress in the alcoholic liver disease

Parameters reflecting oxidative stress (OS) have been studied in 37 patients with alcoholic liver disease (ALD) during admission to the hospital and 2 weeks after the beginning of therapy. The patients were divided into 3 groups: alcoholic hepatitis (AH), alcoholic cirrhosis with hepatic insufficiency (the group C by the Child-Paquet scale) and terminal stage patients (subsequently died). All patients were characterized by a significant increase in plasma products of lipid peroxidation (conjugated diene and malondialdehyde) and a decrease of the ceruloplasmin level. The coefficient C OS significantly exceeded normal values both on admission and after the 2-week course of traditional therapy. This suggests an important role of the OS with ALD.     

Plasma thromboxane B2 in haemodialysed patients

Plasma thromboxane B2 (TXB2) concentration was measured in 7 cases of terminal renal failure before and after haemodialysis. The TXB2 levels were higher in the investigated group than in the control group (p less than 0.05). Haemodialysis induced a further increase in the TXB2 concentration. Increased thromboxane production may play a part in the pathogenesis of accelerated atherosclerosis in uraemic patients treated with chronic haemodialysis.     

Prevention of Ca(2+)-induced or thromboxane B2-induced hepatocyte plasma membrane bleb formation by thromboxane receptor antagonists.

Isolated hepatocytes incubated in the presence of either Ca2+ ionophore A23187 or thromboxane B2 develop many plasma membrane blebs which are a characteristic feature of toxic or ischaemic cell injury. When hepatocytes are incubated in the presence of both Ca2+ ionophore A23187 and any one of three thromboxane receptor antagonists (SK and F 88046, B.M. 13505, B.M. 13177), bleb formation is strongly inhibited. Hepatocytes incubated in the presence of both thromboxane B2 and any one of the three thromboxane receptor antagonists are also well protected from the formation of blebs. Treatment of isolated hepatocytes with Ca2+ ionophore A23187 is known to stimulate the production of thromboxanes. The data presented are consistent with thromboxane B2 acting as an intermediary in a proposed mechanism of cell injury and death in which elevated cytosolic free Ca2+ levels activate phospholipase A2 and the arachidonate cascade.     

Enzyme immunoassay of thromboxane B2

An immunoassay for thromboxane B2 was developed in which the hapten molecule was labeled with beta-galactosidase. The immunoprecipitate formed after competition between enzyme-labeled and unlabeled thromboxane B2 was subjected to a fluorometric assay of beta-galactosidase. Thromboxane B2 was detectable in the range of 0.1-30 pmol. Both enzyme immunoassay and radioimmunoassay showed essentially the same cross-reactivities with other prostaglandins and their metabolites when the same antibody was used. Known amounts of thromboxane B2 were added to human plasma, and the sample was applied to an octadecyl silica column. The extract was analyzed by enzyme immunoassay to examine the correlation between the added (x) and measured (y) thromboxane B2 (y = 1.09x + 11.07 pmol/ml, r = 0.99). A satisfactory correlation was observed between radioimmunoassay (x) and enzyme immunoassay (y) (y = 0.92x + 4.64 pmol/ml, r = 0.96). The validity of enzyme immunoassay was also confirmed by gas chromatography-mass spectrometry of a dimethylisopropylsilyl ether derivative of thromboxane B2 methyl ester. The method was applicable to the assay of thromboxane B2 produced from endogenous precursor during thrombin-induced aggregation of human platelets.