The role of platelets in heat-related illness and heat-induced coagulopathy

Disseminated intravascular coagulation (DIC) has a common pathogenesis in terms of persistent widespread activation of coagulation in the presence of underlying disease, but the degree of fibrinolytic activation often differs by DIC type. DIC with suppressed fibrinolysis is a DIC type usually seen in sepsis. Coagulation activation is severe, but fibrinolytic activation is mild. DIC with enhanced fibrinolysis is a DIC type usually seen in acute promyelocytic leukemia (APL). Both coagulation activation and fibrinolytic activation are severe. DIC with balanced fibrinolysis is a DIC type usually seen in solid tumors, with an intermediate pathogenesis between the above two types. In animal DIC models, lipopolysaccharide (LPS)-induced models are similar to suppressed-fibrinolytic-type DIC, whereas tissue factor (TF)-induced models are similar to enhanced fibrinolytic/balanced fibrinolytic DIC. Appropriate diagnosis and treatment may also differ depending on the DIC type.

Liver injury is a common complication of heat stroke (HS), and often constitutes a direct cause for patient death. The cellular and molecular mechanism underlying HS-induced liver injury remains unclear. Recent evidence indicates that inflammasome plays an important role in mediating sterile inflammation triggered by tissue damage. Using a rat HS model, we identified a novel mechanism by which inflammasome-dependent interleukin-1β (IL-1β) activation and hepatocyte pyroptosis mediate HS-induced liver injury.

The damage borne by the endothelial cells (ECs) forming the blood-brain barrier (BBB) during ischemic stroke and other neurological conditions disrupts the structure and function of the neurovascular unit and contributes to poor patient outcomes. We recently reported that structural aberrations in brain microvascular ECs-namely, uncontrolled actin polymerization and subsequent disassembly of junctional proteins, are a possible cause of the early onset BBB breach that arises within 30-60 min of reperfusion after transient focal ischemia. Here, we investigated the role of heat shock protein 27 (HSP27) as a direct inhibitor of actin polymerization and protectant against BBB disruption after ischemia/reperfusion (I/R). Using in vivo and in vitro models, we found that targeted overexpression of HSP27 specifically within ECs-but not within neurons-ameliorated BBB impairment 1-24 h after I/R. Mechanistically, HSP27 suppressed I/R-induced aberrant actin polymerization, stress fiber formation, and junctional protein translocation in brain microvascular ECs, independent of its protective actions against cell death. By preserving BBB integrity after I/R, EC-targeted HSP27 overexpression attenuated the infiltration of potentially destructive neutrophils and macrophages into brain parenchyma, thereby improving long-term stroke outcome. Notably, early poststroke administration of HSP27 attached to a cell-penetrating transduction domain (TAT-HSP27) rapidly elevated HSP27 levels in brain microvessels and ameliorated I/R-induced BBB disruption and subsequent neurological deficits. Thus, the present study demonstrates that HSP27 can function at the EC level to preserve BBB integrity after I/R brain injury. HSP27 may be a therapeutic agent for ischemic stroke and other neurological conditions involving BBB breakdown.