Inflammation, sepsis, and coagulation. Export

@article{citeulike:238993, abstract = {The molecular links between inflammation and coagulation are unquestioned. Inflammation promotes coagulation by leading to intravascular tissue factor expression, eliciting the expression of leukocyte adhesion molecules on the intravascular cell surfaces, and down regulating the fibrinolytic and protein C anticoagulant pathways. Thrombin, in turn, can promote inflammatory responses. This creates a cycle that logically progresses to vascular injury as occurs in septic shock. Most complex systems are regulated by product inhibition. This inflammation-coagulation cycle seems to follow this same principle with the protein C pathway serving as the regulatory mechanism. The molecular basis by which the protein C pathway functions as an anticoagulant is relatively well established compared to the mechanisms involved in regulating inflammation. As one approach to identifying the mechanisms involved in regulating inflammation, we set out to identify novel receptors that could modulate the specificity of APC in a manner analogous to the mechanisms by which thrombomodulin modulates thrombin specificity. This approach led to the identification of an endothelial cell protein C receptor (EPCR). To understand the mechanism, we obtained a crystal structure of APC (lacking the Gla domain). The crystal structure reveals a deep groove in a location analogous to anion binding exosite 1 of thrombin, the location of interaction for thrombomodulin, platelet thrombin receptor and fibrinogen. Thrombomodulin blocks the activation of platelets and fibrinogen without blocking reactivity with chromogenic substrates or inhibitors. Similarly, in solution, EPCR blocks factor Va inactivation without modulating reactivity with protease inhibitors. Thus, these endothelial cell receptors for the protein C system share many properties in common including the ability to be modulated by inflammatory cytokines. Current studies seek to identify the substrate for the APC-EPCR complex as the next step in elucidating the mechanisms by which the protein C pathway modulates the response to injury and inflammation.}, address = {Oklahoma Medical Research Foundation Cardiovascular Biology Research, 825 N.E. 13th Street, Oklahoma City, Oklahoma 73104, USA. esmonc@omrf.ouhsc.edu}, author = {Esmon, C. T. and Fukudome, K. and Mather, T. and Bode, W. and Regan, L. M. and Stearns-Kurosawa, D. J. and Kurosawa, S.}, citeulike-article-id = {238993}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/10189392}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=10189392}, issn = {0390-6078}, journal = {Haematologica}, keywords = {coagulation, sepsis}, month = {March}, number = {3}, pages = {254--259}, posted-at = {2005-06-27 21:08:00}, priority = {0}, title = {Inflammation, sepsis, and coagulation.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/10189392}, volume = {84}, year = {1999} }

TY - JOUR ID - citeulike:238993 L3 - citeulike-article-id:238993 N2 - The molecular links between inflammation and coagulation are unquestioned. Inflammation promotes coagulation by leading to intravascular tissue factor expression, eliciting the expression of leukocyte adhesion molecules on the intravascular cell surfaces, and down regulating the fibrinolytic and protein C anticoagulant pathways. Thrombin, in turn, can promote inflammatory responses. This creates a cycle that logically progresses to vascular injury as occurs in septic shock. Most complex systems are regulated by product inhibition. This inflammation-coagulation cycle seems to follow this same principle with the protein C pathway serving as the regulatory mechanism. The molecular basis by which the protein C pathway functions as an anticoagulant is relatively well established compared to the mechanisms involved in regulating inflammation. As one approach to identifying the mechanisms involved in regulating inflammation, we set out to identify novel receptors that could modulate the specificity of APC in a manner analogous to the mechanisms by which thrombomodulin modulates thrombin specificity. This approach led to the identification of an endothelial cell protein C receptor (EPCR). To understand the mechanism, we obtained a crystal structure of APC (lacking the Gla domain). The crystal structure reveals a deep groove in a location analogous to anion binding exosite 1 of thrombin, the location of interaction for thrombomodulin, platelet thrombin receptor and fibrinogen. Thrombomodulin blocks the activation of platelets and fibrinogen without blocking reactivity with chromogenic substrates or inhibitors. Similarly, in solution, EPCR blocks factor Va inactivation without modulating reactivity with protease inhibitors. Thus, these endothelial cell receptors for the protein C system share many properties in common including the ability to be modulated by inflammatory cytokines. Current studies seek to identify the substrate for the APC-EPCR complex as the next step in elucidating the mechanisms by which the protein C pathway modulates the response to injury and inflammation. IS - 3 JF - Haematologica SN - 0390-6078 AD - Oklahoma Medical Research Foundation Cardiovascular Biology Research, 825 N.E. 13th Street, Oklahoma City, Oklahoma 73104, USA. esmonc@omrf.ouhsc.edu EP - 259 TI - Inflammation, sepsis, and coagulation. VL - 84 SP - 254 KW - coagulation KW - sepsis AU - Esmon, CT AU - Fukudome, K AU - Mather, T AU - Bode, W AU - Regan, LM AU - Stearns-Kurosawa, DJ AU - Kurosawa, S PY - 1999/03// UR - http://view.ncbi.nlm.nih.gov/pubmed/10189392 ER -