Thursday, 19 December 2013

The Effects of Hormone Prostacyclin(3)

Prostacyclin (or PGI2), also known as known as eicosanoids, a member of the family prostaglandins as a metabolite of arachidonic acid, inhibits platelet aggregation, and dilates blood vessels and is released by healthy endothelial cells and performs its function through a paracrine signaling cascade that involves G protein-coupled receptors on nearby platelets and endothelial cells(a).
17. Endothelial dysfunction in sepsis
The endothelium takes part in the regulation of numerous physiological functions and lies at the interface of circulating blood and the vessel wall. Under physiological conditions, it is responsible for anticoagulant and anti-adhesive properties, and it regulates vasomotor tone and vascular homeostasis. According to the study by Hôpitaux Universitaires de Strasbourg, septic shock is associated with hypotension and frequently with disseminated intravascular coagulation contributing to multiple organ failure and a high mortality rate. Impairment of endothelial function leads to phenotypic and physical changes of the endothelium, with deregulated release of potent vasodilators nitric oxide and prostacyclin, reduction of vascular reactivity to vasoconstrictors, associated with leukocytes' and platelets' aggregation, and increase in inducible nitric oxide synthase expression that can exert a negative feedback on endothelial nitric oxide synthase expression, with subsequent deregulation of nitric oxide signaling. Endothelial dysfunction therefore plays a major role in the pathophysiology of septic shock and organ dysfunction, and has been suggested to be a predictor of mortality in sepsis(17).

18. Endothelial dysfunction and coagulation
In the study to  review endothelial properties and to establish how these unperturbed properties contribute to the maintenance of endothelium anticoagulant activity and to better understand the relative contributions of endothelial cells and monocytes in sepsis-induced altered coagulation, showed that Unperturbed endothelial cells provide anticoagulant properties; exposure to inflammatory and/or septic stimuli can rapidly lead to procoagulant behavior. Sepsis alters endothelial cell surface and induces tissue factor synthesis at the endothelial and subendothelial levels. During endotoxemia, endothelial cells generate adhesion molecules that bind leukocytes and monocytes, increasing local procoagulant reactions. Tissue factor expression is also increased at the level of the monocyte; the relative importance of endothelial injury and monocyte activation in coagulation disorders was recently assessed. Endothelium protection before induction of septic shock was not associated with any reduction in monocyte tissue factor expression, suggesting that altered coagulation was present despite normal endothelial cell function. On the other hand, decreased monocyte tissue factor expression was associated with a marked reduction in endothelial injury, increased endothelium-derived relaxation, and improved survival rate in treated animals(18).

19. Endothelial cells and coagulation abnormalities
Endothelial cells have two important anticoagulant systems, heparan sulfate-antithrombin system and thrombomodulin-protein C system. Under physiological conditions, these two systems inhibit activation of coagulation on endothelial cells. According to the study by the Kumamoto University School of Medicine, under inflammatory conditions, tumor necrosis factor(TNF)-alpha or other cytokines produced by monocytes reduce the anticoagulant properties of endothelial cell by downregulating expression of heparan sulfate and thrombomodulin on endothelial cells. Antithrombin stimulates prostacyclin generation from endothelial cells by interacting with heparan sulfate of endothelial cells and generated prostacyclin inhibits TNF-alpha production by monocytes. Activated protein C inhibits TNF-alpha production by monocyte dependent of its protease activity. Thus, antithrombin and activated protein C might inhibit the endothelial perturbation induced by cytokines. Antithrombin regulates TNF-alpha induced tissue factor expression on endothelial cells by an unknown mechanism. Thus, antithrombin and activated protein C might be useful agents for treating coagulation abnormalities associated with sepsis or other inflammation because these agents inhibit not only coagulation but also downregulation of anticoagulant activities of endothelial cells(19).

20. Antithrombin (AT) can promote the endothelial production of prostacyclin
Antithrombin (AT) is an important inhibitor of the coagulation system, acting at many different levels of the coagulation cascade. This inhibitory action is enhanced several-fold by the glycosaminoglycan heparin. According to the study by the Sahlgrenska University Hospital, Göteborg University , data from cell culture and animal experiments have demonstrated that AT can promote the endothelial production of prostacyclin and may therefore have anti-inflammatory actions. This effect is based on the interaction of AT with glycosaminoglycans in the cell membrane, and is independent of heparin. The role of AT in vessel wall antithrombogenicity is being increasingly appreciated. The concept of neointimal hyperplasia following vascular injury involves thrombin as an important mediator and thus, in addition to the anti-inflammatory effects of AT, new horizons in which AT may have an important role in the prevention of post-traumatic hyperplastic response are also evolving(20).

21. The anti-inflammatory properties of antithrombin III
Antithrombin III (AT III) supplementation has proven to be effective in the treatment of disseminated intravascular coagulation. According to the study by the Kumamoto University School of Medicine , administration of AT III is also useful for prevention of organ failure in animals challenged with endotoxin or bacteria and it increases the survival rate of such animals. Since inhibition of coagulation abnormalities failed to prevent organ failure in animals given bacteria, AT III may exert a therapeutic effect independent of its anticoagulant effect. This therapeutic mechanism of AT III has been explored using an animal model of septicemia. AT III prevented pulmonary vascular injury by inhibiting leukocyte activation in rats given endotoxin. This effect is mediated by the promotion of endothelial release of prostacyclin which inhibits leukocyte activation. Interaction of AT III with heparin-like glycosaminoglycans (GAGs) on the endothelial cell surface appears to be important for this effect. Heparin inhibits these therapeutic effects of AT III by preventing AT III from interacting with the cell surface heparin-like GAGs. This activity of AT III may explain why AT III prevents organ failure as well as coagulation abnormalities in patients with sepsis(21).

22. Thrombin and Prostaglandin I2 (PGI2 or prostacyclin
In the study role of blood clotting in the interaction of Platelet and vessel wall interaction found that vascular damage initiates not only the adhesion and aggregation of blood platelets but also coagulation, which is of mixed (intrinsic and extrinsic) origin. Evidence is presented that thrombin, generated as a result of the injury, is a prerequisite for platelet aggregation. Platelets, after activation, in their turn promote coagulation. Prostaglandin I2 (PGI2 or prostacyclin) inhibits coagulation induced by damaged vascular tissue. This effect of PGI2 is mediated by the inhibition of platelets in their participation in the generation of factor Xa and thrombin(22).

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