Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0012739 (disseminated intravascular coagulation)
 8,673 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sepsis or its synonymously termed "SIRS (systemic inflammatory response syndrome)" is a common cause of individual morbidity and mortality in various clinical situations. In such conditions, high mobility group box-1 DNA binding protein (HMGB1), widely known as a nuclear structural protein, has been identified to act as a late mediator of delayed endotoxin lethality. Once released from necrotic damaged cells or secreted by activated monocytes/macrophage, it participates in the development of lethality and it activates downstream cytokine release. In this review, we describe herein the general features of sepsis focusing on the role of HMGB1 in the mechanism of development of systemic inflammation, and also introduce newly established therapeutic concept "Functional HMGB1 inhibition with thrombomodulin" against sepsis/SIRS/DIC.
 ...
PMID:[Inflammation and its regulatory system]. 1559 89

Thrombomodulin (TM) is a type 1 membrane bound glycoprotein that has a C-type lectin domain at its Nterminus, 6 copies of the epidermal growth factor-like (EGF) motif and serine/threonine rich domain carrying a glycosoaminoglycan external to the membrane. TM binds thrombin changing thrombin's substrate specificity from procoagulant and pro-inflammatory to anti-coagulant and anti-inflammatory because of the activation of protein C (PC) and thrombin-activatable fibrinolysis inhibitor (TAFI). Thrombin's anion binding site 1 binds to TM's EGF domains 5 and 6. EGF4 is required for PC activation and EGF3 and 4 for TAFI activation in addition to EGF56. The X-ray structure of thrombin bound to TM has been solved and shows few major alterations in the active site of thrombin. The lectin domain can bind high mobility group box protein 1 (HMGB1) and a sugar, Lewis Y. TM's lectin domain behaves as an antagonist to HMGB1 endowing it with intrinsic anti-inflammatory activity. Treatment of dendritic cells with TM converts them from immunogenic to tolerogenic. TM is necessary for maintenance of pregnancy as well as prevention of coagulation throughout life. Soluble TM has been developed as an anticoagulant possessing favorable pharmacokinetics that has been approved for treatment of disseminated intravascular coagulation in Japan.
 ...
PMID:Thrombomodulin links coagulation to inflammation and immunity. 2220 50