Prostacyclin
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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Sources
(a) http://en.wikipedia.org/wiki/Prostacyclin
(17) http://www.ncbi.nlm.nih.gov/pubmed/23506494
(18) http://www.ncbi.nlm.nih.gov/pubmed/11445732
(19) http://www.ncbi.nlm.nih.gov/pubmed/10810875
(20) http://www.ncbi.nlm.nih.gov/pubmed/10102492
(21) http://www.ncbi.nlm.nih.gov/pubmed/9515777
(22) http://www.ncbi.nlm.nih.gov/pubmed/6117897
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