6-ketoprostaglandin-f1-alpha and Liver-Diseases

To examine whether dalteparin, a low molecular weight heparin, prevents hepatic damage by inhibiting leukocyte activation, we analyzed its effect on ischemia/reperfusion (I/R) injury of rat liver in which activated leukocytes play a critical role.. Prospective, randomized, controlled study.. Research laboratory at a university medical center.. Male Wistar rats weighing 220-280 g.. Hepatic damage was evaluated by changes in serum transaminase concentrations after I/R. Coagulation abnormalities were evaluated by changes in serum concentrations of fragment E of fibrin and fibrinogen degradation products after I/R. Hepatic tissue blood flow was measured by laser-Doppler flow meter. Hepatic edema was evaluated by determination of the change in the wet/dry tissue weight ratio. Rats were intravenously injected with dalteparin or unfractionated heparin (300 units/kg) and subcutaneously injected with DX9056a, a selective inhibitor of activated factor X (3 mg/kg). To determine whether dalteparin inhibits leukocyte activation, we examined the effect of dalteparin on hepatic concentrations of interleukin-12, tumor necrosis factor-alpha, and hepatic myeloperoxidase activity after I/R in vivo. In addition, we examined increases in tumor necrosis factor-alpha production in rat monocytes and in intracellular calcium concentrations in neutrophils in vitro. We also examined the effect of dalteparin on endothelial production of prostacyclin using isolated rat hepatic sinusoidal cells in vitro.. Intravenous administration of dalteparin inhibited increases in serum levels of both transaminases and serum concentrations of fragment E of fibrin and fibrinogen degradation products in animals subjected to hepatic I/R. Hepatic tissue blood flow after reperfusion was increased by dalteparin. Dalteparin inhibited hepatic edema, increases in hepatic tissue levels of interleukin-12 and tumor necrosis factor-alpha, and accumulation of neutrophils in animals subjected to hepatic I/R. Neither DX9065a nor unfractionated heparin showed any therapeutic effects, despite potent inhibition of increases in serum levels of fragment E of fibrin and fibrinogen degradation products. Neither monocytic tumor necrosis factor-alpha production nor neutrophil activation was inhibited by dalteparin in vitro. Dalteparin enhanced the hepatic I/R-induced increases in hepatic tissue levels of 6-keto-prostaglandin (PG) F1alpha, a stable metabolite of prostacyclin, which is capable of inhibiting monocytic tumor necrosis factor-alpha production. Pretreatment with indomethacin completely reversed both of the therapeutic effects of dalteparin, whereas pretreatment with NS-398, a selective inhibitor of cyclooxygenase-2, did not. Dalteparin did not directly increase the endothelial production of prostacyclin in vitro.. Dalteparin might reduce I/R-induced liver injury in rats by attenuating inflammatory responses. These therapeutic effects might be independent of its anticoagulant activity but dependent on its capacity to enhance endothelial production of prostacyclin via cyclooxygenase-1 activation. Furthermore, the mechanism or mechanisms by which dalteparin promotes the endothelial production of prostacyclin in vivo might involve unknown factors other than endothelial cells.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anticoagulants; Calcium; Cyclooxygenase 2 Inhibitors; Dalteparin; Edema; Endothelium; Epoprostenol; Fibrin Fibrinogen Degradation Products; Heparin; In Vitro Techniques; Indomethacin; Inflammation; Interleukin-12; Leukocytes; Liver; Liver Diseases; Male; Monocytes; Naphthalenes; Nitrobenzenes; Peroxidase; Propionates; Prospective Studies; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury; Sulfonamides; Transaminases; Tumor Necrosis Factor-alpha

We previously reported that antithrombin (AT) reduced ischemia/reperfusion (I/R)-induced liver injury in rats by increasing endothelial production of prostacyclin (PGI2). However, the mechanism(s) underlying this phenomenon remains to be fully elucidated. We also demonstrated that activation of capsaicin-sensitive sensory neurons increased endothelial production of PGI2 by releasing calcitonin gene-related peptide (CGRP) in rats subjected to hepatic I/R. In the present study, we investigated whether AT increases endothelial production of PGI2 through activation of the sensory neurons in rats subjected to hepatic I/R. AT significantly enhanced the I/R-induced increases in hepatic tissue levels of CGRP in rats. Increases in hepatic tissue levels of 6-keto-PGF1alpha, a stable metabolite of PGI2, the increase in hepatic-tissue blood flow, and attenuation of both hepatic local inflammatory responses and liver injury in rats administered AT were completely reversed by administration of capsazepine, an inhibitor of sensory neuron activation and CGRP(8-37), a CGRP antagonist. AT did not show any protective effect on liver injury in animals undergoing functional denervation by administration of a large amount of capsaicin. AT significantly increased CGRP release from cultured dorsal root ganglion neurons isolated from rats in the presence of capsaicin. Taken together, these observations strongly suggested that AT might increase hepatic tissue levels of PGI2 via enhancement of hepatic I/R-induced activation of capsaicin-sensitive sensory neurons, thereby reducing liver injury in rats. In this process, CGRP-induced activation of both endothelial nitric oxide synthase and cyclooxygenase-1 might be critically involved.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antithrombin III; Calcitonin Gene-Related Peptide; Capsaicin; Cells, Cultured; Disease Models, Animal; Epoprostenol; Humans; Liver Diseases; Male; Neurons, Afferent; Rats; Rats, Wistar; Reperfusion Injury

The plasma levels of thromboxane B2 (TxB2) and 6-keto-prostaglandin F1alpha (6-KF) in the peripheral and portal blood increase after an extensive hepatectomy, and even more so in cases with complications. In this cell biological study, we estimated the prostanoids in the portal system to clarify which organ produces them, while also evaluating the effect of a splenectomy in conjunction with an extensive hepatectomy. Our results showed that the level of TxB2 in the splenic vein was significantly higher than that in the mesenteric vein. Furthermore, the TxA2 produced by splenic macrophages after an extensive hepatectomy was significantly more than after a sham operation. We also observed the hepatocyte damage to be less in the group that underwent an 84% hepatectomy and splenectomy than in the group that underwent the same hepatectomy without a splenectomy. It therefore appears important both to suppress the splenic macrophages from producing TxA2 and to prevent remnant hepatic dysfunction after an extensive hepatectomy.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cell Survival; Dogs; Female; Hepatectomy; Liver Diseases; Macrophages; Male; Portal System; Spleen; Splenectomy; Thromboxane A2; Thromboxane B2

A beneficial effect of flavonoids in Cl(4)C-induced hepatoxicity in rats has been reported. In this communication we have evaluated the protective effect of astilbin, an active flavonoid isolated from a crude extract of Hymenaea martiana, as well as its action on liver arachidonate metabolism in Cl(4)C-treated rats. The following groups of rats were studied: Group I = controls; Group II = Astilbine-treated animals (40 mg/Kg); Group III = Cl(4)C-treated at 1 ml/kg; Group IV = Astilbine + ClC4 and Group V = Vitamine E (50 mg/Kg) + Cl(4)C-treated animals. Histological findings, superoxide dismutase activity, lipoperoxides and prostanoid profiling studies revealed that the hepatoprotective effect of astilbine was higher than that of vitamin E. Astilbine was capable to restore lipoperoxides and tissue prostanoids to basal values.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antioxidants; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Dinoprostone; Female; Flavonoids; Flavonols; Free Radicals; Lipid Peroxidation; Liver; Liver Diseases; Malondialdehyde; Molecular Structure; Phospholipases A; Prostaglandins; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Thromboxane B2; Vitamin E

Studies indicate that hepatocellular dysfunction occurs at 2 h after cecal ligation and puncture (CLP, i.e., sepsis model) despite the increased cardiac output (CO) and hepatic perfusion. It, however, remains unknown whether hepatocellular function is depressed earlier than the onset of hyperdynamic circulation in sepsis. To determine this, rats were subjected to sepsis by CLP. At .5, 1, 1.5, or 2 h after CLP, CO was measured by dye dilution. Hepatocellular function (i.e., maximum velocity of indocyanine green clearance and the efficiency of the active transport) was determined using an in vivo indocyanine green clearance technique. Microvascular blood flow was measured by laser Doppler flowmetry. To determine whether there is any association between hemodynamics and prostaglandins (PGs), plasma levels of PGE2 and PGI2 were measured by radioimmunoassay. The results indicate that hepatocellular function decreased significantly as early as 1.5 h after CLP. Cardiac output and microvascular blood flow in the liver and small intestine, however, increased and vascular resistance decreased at 2 h after CLP. Thus, hepatocellular dysfunction occurs earlier than the occurrence of hyperdynamic circulation during sepsis. Although circulating PGE2 levels were not altered, plasma PGI2 increased significantly at 2 h after CLP. The elevated circulating PGI2 levels, therefore, may be partially responsible for the decreased vascular resistance and increased tissue perfusion at 2 h after CLP. Our findings also suggest that cellular dysfunction, observed in the very early stage of sepsis, is not due to any hyperdynamic circulation/hypermetabolism-related events, but may be associated with the release of proinflammatory cytokines.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Cardiac Output; Cell Hypoxia; Dinoprostone; Female; Hemodynamics; Indocyanine Green; Intestinal Perforation; Intestine, Small; Liver; Liver Diseases; Microcirculation; Rats; Rats, Sprague-Dawley; Sepsis; Time Factors; Tumor Necrosis Factor-alpha

The multiple parameters of 3 Subtypes: Ganyang Huafeng Syndrome (GYHFS), Xuexu Shengfeng Syndrome and Yinxu Fengdong Syndrome of Ganfeng Neidong Syndrome were determined for the 1st time. It was found that there were several characteristics in GYHFS. (1) Disturbance of the cerebral blood flow and the damage of brain tissue was manifested by the abnormality of the bulbar conjunctival microcirculation, carotid Doppler ultrasonic determination and brainstem auditory and visual pathway, high blood viscosity, dysmnesia, free radical and lipid peroxidation injury and the changes of Zn, Cu, K and Mg after brain damage. (2) Stress status were expressed by the high plasma levels of cortisol, norepinephrine and epinephrine, decreased serum triiodothyronine level and hyperfunction of sympathetic nerve. (3) The marked changes of the regulating substance of the vessel smooth muscle function including the increased plasma levels of TXB2, TXB2/6-k-PGF1 alpha, and calmodulin, as well as decreased SP, ANP, CGRP. Other 2 subtypes had about the same changes of these parameters, but of milder disorders.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Blood Viscosity; Cerebral Hemorrhage; Cerebral Infarction; Conjunctiva; Diagnosis, Differential; Female; Humans; Liver Diseases; Male; Medicine, Chinese Traditional; Microcirculation; Middle Aged; Thromboxane B2; Trace Elements

We measured blood platelet count and plasma beta-thromboglobulin concentration in 67 patients with acute or chronic liver diseases. Plasma TXB2 and 6-keto-PGF1a concentration were also measured in these patients. The results showed that blood platelet count of less than 100 x 10(9)/L was found in 14% of the patients with acute hepatitis, 23% with chronic hepatitis, 67% with hepatic cirrhosis but without splenectomy and 40% with primary liver carcinoma. Platelet count is lowest in patients with hepatic cirrhosis without splenectomy but normal in patients with hepatic cirrhosis after splenectomy. Plasma beta-TG concentration increased in patients with acute or chronic liver diseases. A negative correlation was found between beta-TG concentration and platelet count in chronic liver diseases. It is suggested that platelet is in activated state in vivo and this may be one of the important reasons for both decrease of platelet count and impairment of platelet function. Plasma TXB2 concentration increased in chronic liver diseases, while plasma 6-keto-PGF1a concentration decreased. The balance between TXA2 and PGI2 is upset; this may be an important mechanism for activation of platelets in vivo.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; beta-Thromboglobulin; Female; Hepatitis, Viral, Human; Humans; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Platelet Count; Thromboxane B2

Interleukin-2 (IL-2) produces toxicity characterized by generalized edema within 24 hours. This study tests whether the rate of IL-2 administration modulates the onset of edema and examines thromboxane (Tx) and neutrophils as possible mediators of this event. Recombinant human IL-2, 10(5) U (n = 7), 10(6) U (n = 9), or vehicle (n = 8) were given to anesthetized rats intravenously during a period of 1 hour. At 6 hours edema, as measured by increase in wet to dry weight (w/d) ratio, was present in the heart, liver, and kidney, with 10(5) U IL-2 and in the lung, heart, liver and kidney, with 10(6) U IL-2, relative to values with vehicle-infused controls (all p less than 0.05). With a 1-hour infusion of 10(6) U IL-2, there was an increase in plasma thromboxane (Tx)B2 level to 1290 +/- 245 pg/mL, higher than 481 +/- 93 pg/mL in control rats (p less than 0.05); lung polymorphonuclear leukocyte (PMN) sequestration of 53 +/- 7 PMN/10 higher-power fields (HPF) relative to 23 +/- 2 PMN/10 HPF in controls (p less than 0.05); and increased bronchoalveolar lavage (BAL) fluid protein concentration of 1970 +/- 210 micrograms/mL relative to 460 micrograms/mL in controls (p less than 0.05). When 10(6) U IL-2 was given as a 1-minute intravenous bolus (n = 9), edema was not demonstrated, plasma TxB2 levels were similar to controls, there was no leukosequestration, and BAL protein levels were normal. These data indicate that a constant infusion but not the rapid bolus administration of IL-2 produces in rats multiple-system organ edema, increased plasma TxB2, sequestration of PMNs, and microvascular permeability. These findings may explain the early toxicity seen in patients given high-dose IL-2 in cancer treatment.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bronchoalveolar Lavage Fluid; Edema; Heart Diseases; Infusions, Intravenous; Injections, Intravenous; Interleukin-2; Kidney Diseases; Liver Diseases; Male; Neutrophils; Pulmonary Edema; Rats; Rats, Inbred Strains; Recombinant Proteins; Thromboxane A2; Thromboxane B2

This paper reports on investigations of the formation of PGI2 and TXA2 using their stabile products 6-keto-PGF1 alpha and TXB2 (RIA) in liver biopsy specimens of 46 patients suffering from fatty liver (n = 19), chronic hepatitis B (n = 11), liver cirrhosis (n = 13), and miscellaneous diseases (n = 3). The measured formation rates in chronic liver disease were evaluated in comparison to a reference group (n = 19) consisting of minimal liver lesions. The 6-keto-PGF1 alpha formation correlating to the degree of the portal inflammation in the liver (morphometric evaluation). The same trend existed in relation to the intralobular inflammation. The results presented suggest in respect of analogous data in animal experiments that PGI2 is predominantly generated in mesenchymal cells of the liver and, presumably influences the course of liver diseases.

Topics: 6-Ketoprostaglandin F1 alpha; Chronic Disease; Epoprostenol; Female; Humans; Liver; Liver Diseases; Male; Thromboxane A2; Thromboxane B2

Eighteen patients with fulminant liver failure were studied, 10 with normal renal function (group A) and eight with renal failure (group B, plasma creatinine greater than 200 mumol/l). Renal function was assessed by standard clearance techniques and patients in group B had a marked reduction compared with group A in both renal plasma flow and glomerular filtration rate. Raised plasma renin activity was observed in both groups, but levels in group B were significantly higher than in group A. Renal prostacyclin production was estimated by radioimmunoassay (RIA) of 6-keto-prostaglandin F1 alpha in urine, and the excretion rate was markedly increased in group A as compared with nine healthy controls, but was low in group B. The plasma concentrations of 6-keto-prostaglandin F1 alpha and thromboxane B2 were similar in groups A and B and were both significantly higher than in controls. Haemodynamic measurements showed a high cardiac output with low vascular resistance and mean arterial pressure within normal limits in both groups. The pulse pressure, however, was significantly higher in group B than in group A. In conclusion, patients in FHF with renal failure have marked renal vasoconstriction with increased plasma renin activity and reduced renal prostaglandin excretion indicative of an imbalance between vasoactive forces.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Adolescent; Adult; Female; Hemodynamics; Humans; Kidney Function Tests; Liver Diseases; Male; Middle Aged; Renin; Thromboxane B2

To explore the possible vasoregulatory role of renal prostaglandins during liver disease, excretory rates of PGE2, PGF2 alpha, and a metabolite of PGI2, 6k-PGF1 alpha, were determined before and after chronic ligation of the common bile duct in 23 dogs. Bile duct ligation for 50 +/- 3.7 days (mean +/- SEM) significantly increased serum bilirubin and alkaline phosphatase. PGE2, PGF2 alpha, and 6k-PGF1 alpha excretion rates were significantly (p less than 0.01) increased following chronic bile duct ligation, by approximately 100%, 80%, and 500%, respectively, with similar increments in both ascitic and nonascitic animals. In 10 sham-ligated animals, PGE2, PGF2 alpha, and 6k-PGF1 alpha excretion rates were unchanged. In 6 dogs sequential measurements of urine prostaglandins indicated that PGE2 and 6k-PGF1 alpha excretion were significantly increased at 2, 4, and 6 weeks after ligation, whereas the increase in PGF2 alpha excretion was not significant until 6 weeks. Indomethacin (2 mg/kg) reduced prostaglandin excretion by 65% to 90% and significantly increased arterial pressure, decreased glomerular filtration rate and renal blood flow, and increased renal vascular resistance from 0.53 +/- 0.09 to 0.90 +/- 0.13 mm Hg/ml/min. Fractional renal blood flow, assessed by microspheres, was disproportionately reduced in the inner cortex after prostaglandin inhibition in the chronic bile duct ligation group. Indomethacin did not significantly alter renal function in sham animals, despite comparable reductions in prostaglandin excretion. These data demonstrate that, in dogs with experimental liver disease produced by chronic bile duct ligation, renal prostaglandin synthesis is increased, and the enhanced synthesis of vasodilatory prostaglandins serves to maintain renal blood flow and glomerular filtration rate.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Chronic Disease; Common Bile Duct; Dogs; Female; Kidney; Ligation; Liver Diseases; Prostaglandins; Prostaglandins E; Prostaglandins F