thromboxane-a2 and Gastrointestinal-Hemorrhage

Cyclooxygenase (COX) enzymes catalyse the biotransformation of arachidonic acid to prostaglandins which subserve important functions in cardiovascular homeostasis. Prostacyclin (PGI2) and prostaglandin (PG)E2, dominant products of COX activityin macro- and microvascular endothelial cells, respectively, in vitro, modulate the interaction of blood cells with the vasculature and contribute to the regulation of blood pressure. COXs are the target for inhibition by nonsteroidal anti-inflammatory drugs (NSAIDs--which include those selective for COX-2) and for aspirin. Modulation of the interaction between COX products of the vasculature and platelets underlies both the cardioprotection afforded by aspirin and the cardiovascular hazard which characterises specific inhibitors of COX-2.

Topics: Animals; Cyclooxygenase 2 Inhibitors; Eicosanoids; Endothelium, Vascular; Epoprostenol; Gastrointestinal Hemorrhage; Heart Diseases; Humans; Isomerases; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Receptors, Epoprostenol; Receptors, Prostaglandin; Receptors, Thromboxane A2, Prostaglandin H2; Stroke; Thromboxane A2

Selective inhibitors of cyclooxygenase (COX)-2 were developed to improve the safety of anti-inflammatory therapy in patients at elevated risk for gastrointestinal complications which are thought to be caused primarily by depression of COX-1 derived mucosal prostanoids. They were not expected to be more efficacious analgesics than compounds acting on both cyclooxygenases, the traditional (t) non-steroidal antiinflammatory drugs (NSAIDs). While these predictions were generally supported by clinical evidence, an elevated rate of severe cardiovascular complications was observed in randomized controlled trials of three chemically distinct COX-2 selective compounds. The cardiovascular hazard is plausibly explained by the depression of COX-2 dependent prostanoids formed in vasculature and kidney; vascular prostacyclin (PGI2) constrains the effect of prothrombotic and atherogenic stimuli, and renal medullary prostacyclin and prostaglandin (PG) E(2) formed by COX-2 contribute to arterial pressure homeostasis. A drug development strategy more closely linking research into the biology of the drug target with clinical drug development may have allowed earlier recognition of these mechanisms and the cardiovascular risk of COX-2 inhibition. Open questions are i) whether the gastrointestinal benefit of COX-2 selective compounds drugs can be conserved by identifying individuals at risk and excluding them from treatment; ii) whether the risk extends to tNSAIDs; iii) and whether alternative strategies to anti-inflammatory therapy with a more advantageous risk-benefit profile can be developed.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Platelets; Cardiovascular Diseases; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Endothelium, Vascular; Epoprostenol; Gastrointestinal Hemorrhage; Humans; Renal Circulation; Renin-Angiotensin System; Signal Transduction; Thromboxane A2

Topics: Arteriosclerosis; Aspirin; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Drug Interactions; Drug Resistance; Gastrointestinal Hemorrhage; Humans; Male; Myocardial Infarction; Platelet Aggregation Inhibitors; Risk; Stroke; Thrombosis; Thromboxane A2

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Aspirin; Blood Platelets; Cardiovascular Diseases; Celecoxib; Colorectal Neoplasms; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Depression, Chemical; Dinoprostone; Epoprostenol; Gastric Mucosa; Gastrointestinal Hemorrhage; Humans; Incidence; Intestinal Mucosa; Isoenzymes; Lactones; Membrane Proteins; Peptic Ulcer; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pyrazoles; Randomized Controlled Trials as Topic; Substrate Specificity; Sulfonamides; Sulfones; Thromboembolism; Thromboxane A2; Treatment Outcome

Topics: Aspirin; Blood Platelets; Dipyridamole; Epoprostenol; Gastrointestinal Hemorrhage; Humans; Platelet Aggregation Inhibitors; Stomach Diseases; Thromboxane A2

Microbial infections are a relevant problem for patients with liver cirrhosis. Different types of bacteria are responsible for different kinds of infections: Escherichia coli and Klebsiella pneumoniae are frequently observed in spontaneous bacterial peritonitis or urinary tract infections, and Streptococcus pneumoniae and Mycoplasma pneumoniae in pulmonary infections. Mortality is up to 4-fold higher in infected patients with liver cirrhosis than in patients without infections. Key Messages: Infections in patients with liver cirrhosis are due to three major reasons: bacterial translocation, immune deficiency and an increased incidence of systemic infections. Nonparenchymal liver cells like Kupffer cells, sinusoidal endothelial cells and hepatic stellate cells are the first liver cells to come into contact with microbial products when systemic infection or bacterial translocation occurs. Kupffer cell (KC) activation by Toll-like receptor (TLR) agonists and endothelial sinusoidal dysfunction have been shown to be important mechanisms increasing portal pressure following intraperitoneal lipopolysaccharide pretreatment in cirrhotic rat livers. Reduced intrahepatic vasodilation and increased intrahepatic vasoconstriction are the relevant pathophysiological pathways. Thromboxane A2 and leukotriene (LT) C4/D4 have been identified as important vasoconstrictors. Accordingly, treatment with montelukast to inhibit the cysteinyl-LT1 receptor reduced portal pressure in cirrhotic rat livers. Clinical studies have demonstrated that activation of KCs, estimated by the amount of soluble CD163 in the blood, correlates with the risk for variceal bleeding. Additionally, intestinal decontamination with rifaximin in patients with alcohol-associated liver cirrhosis reduced the portal pressure and the risk for variceal bleeding.. TLR activation of nonparenchymal liver cells by pathogens results in portal hypertension. This might explain the pathophysiologic correlation between microbial infections and portal hypertension in patients with liver cirrhosis. These findings are the basis for both better risk stratifying and new treatment options, such as specific inhibition of TLR for patients with liver cirrhosis and portal hypertension.

Topics: Acetates; Animals; Anti-Infective Agents; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Bacterial Translocation; Cyclopropanes; Endothelial Cells; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Gram-Negative Bacterial Infections; Hepatic Stellate Cells; Humans; Hypertension, Portal; Kupffer Cells; Leukotriene Antagonists; Leukotrienes; Liver; Liver Cirrhosis; Portal Pressure; Quinolines; Rats; Receptors, Cell Surface; Rifamycins; Rifaximin; Sulfides; Thromboxane A2; Vasoconstriction

The pathogenesis of intestinal damage caused by bolus intravenous injection of endotoxin (ETX; 3 mg/kg) was investigated. Administration of ETX to rats induced reddish discoloration suggestive of bleeding, increased hemoglobin amounts, and leakage of plasma protein in the intestine. However, light microscopic examination of the intestine demonstrated blood congestion of the microvessels. Plasma accumulation was partially inhibited by combined pretreatment with a histamine H1 antagonist and a serotonin (5-HT) antagonist. Neither a 5-lipoxygenase inhibitor, a soybean trypsin inhibitor, nor atropine was observed to inhibit plasma accumulation. Both the intestinal leakage of plasma and the accumulation of hemoglobin were completely inhibited by indomethacin, a selective thromboxane A synthetase inhibitor (OKY 1581), and a stable PGI2 analogue (beraprost). Intravital microscopic observation of the microvessels of the small intestinal villi demonstrated microthrombus formation within several minutes after the injection of ETX, and pretreatment with OKY 1581 attenuated the formation of microthrombus. Platelet counts decreased significantly 10 min after ETX administration, and the decrease was not inhibited by pretreatment with either OKY 1581 or beraprost. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were not prolonged. These observations thus suggest that microcirculatory disturbances by platelet thrombus, which are mediated by thromboxane A2 at least in part, play an important role in ETX-induced intestinal damage.

Topics: Animals; Capillary Leak Syndrome; Cyclooxygenase Inhibitors; Endotoxins; Enzyme Inhibitors; Epoprostenol; Escherichia coli; Gastrointestinal Hemorrhage; Indomethacin; Intestine, Small; Male; Methacrylates; Microcirculation; Platelet Activation; Rats; Rats, Sprague-Dawley; Shock, Septic; Specific Pathogen-Free Organisms; Thrombosis; Thromboxane A2; Thromboxane-A Synthase