Y found inside cells, unless released by damage. Under normal conditions, DAMPs are hidden from recognition 2-(2,4-Dichloro-5-fluorophenyl)oxirane by innate immune cells. However, under conditions of cellular stress or injury, DAMPs can be released into the extracellular space from damaged PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/14960617 cells, activating innate immune cells [46]. Prototypical DAMPs include nuclear proteins such as high mobility group box 1 (HMGB1) [47,48] and histones [49], purine metabolites such as ATP [50,51] and uric acid [52,53], and mitochondrial components such as formyl peptides and mitochondrial DNA [54]. Detection of these DAMPs by PRRs, such as Toll-like receptors and inflammasomes, triggers inflammation, which is important for eradication of invading pathogens, clearance of dead cells, and regeneration of damaged tissue [55]. DAMPs also trigger intravascular thrombus formation [50], possibly by inducing tissue factor expression on monocytes [56], elevating tissue factor procoagulant activity [57,58], and promoting platelet aggregation [59].Immunothrombosis beyond controlAlthough immunothrombosis might be important in early host defense against bacterial dissemination, uncontrolled immunothrombosis might be detrimental to the host.Disseminated intravascular coagulation (DIC) occurs in 25 ?0 of patients with sepsis and is associated with poor outcomes [12,60]. DIC is characterized by widespread microvascular thrombosis with exhaustion of coagulation factors and platelets [61]. Monocyte-associated tissue factor and neutrophil-derived NETs are predisposing factors for DIC [20,32,38,40,62], indicating that DIC might be an advanced stage of immunothrombosis wherein the immune system is no longer able to restrict PAMP/ DAMP spreading and immunothrombosis becomes overwhelmed [13]. As mentioned above, tissue factor-induced coagulation is important for preventing bacterial dissemination [18]. However, excessive coagulopathy can be detrimental [63], and pharmacological inhibition ijms17122034 of tissue factor or genetic reduction of tissue factor expression often rescues (S)-3-(tert-Butoxycarbonyl)-2,2-dimethyloxazolidine-4-carboxylic acid animals from sepsis-associated lethal coagulopathy [32,33,62]. Similarly, elimination of NETs can decrease organ damage [38,40], although NETs are important for preventing bacterial dissemination [40-42]. These findings support the concept that immunothrombosis can be detrimental if it becomes overwhelmed. The same is true for DAMPs. Although DAMPs have beneficial roles in immunity and tissue repair [44,64], excessive DAMPs can be detrimental. Serum and plasma HMGB1 PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/9544797 levels are elevated in patients with sepsis and/or DIC [65,66] and are correlated with DIC scores.Ito Journal of Intensive Care (2014)2:Page 6 ofExtracellular HMGB1 stimulates tissue factor expression on monocytes, inhibits protein C activation, and promotes microvascular thrombosis development [56]. Antibodies or antagonists capable of neutralizing HMGB1 reduce organ damage and improve survival of septic mice [65,67,68], indicating that excessive HMGB1 circulating in the blood is detrimental. Plasma histone levels are also elevated in patients with sepsis and DIC [69,70]. Extracellular histones trigger platelet aggregation, fibrin deposition, thrombotic occlusion of microvessels, and exhaustion of coagulation factors and platelets [70]. Extracellular cell-free DNA (cfDNA) also acts as a DAMP [71]. Plasma cfDNA levels are elevated in patients with severe sepsis, especially in non-survivors and have better prognostic utility than Acute Physiology and Chronic Health Evaluation (APACHE) II.