Abstract
Systemic inflammation as manifested in sepsis is an excessive, life-threatening inflammatory response to severe bacterial or viral infection or extensive injury. It is also a thrombo-inflammatory condition associated with vascular leakage/hemorrhage and thrombosis that is not effectively treated by current anti-inflammatory or anti-thrombotic drugs. Here, we show that MB2mP6 peptide nanoparticles, targeting the Gα13-mediated integrin “outside-in” signaling in leukocytes and platelets, inhibited both inflammation and thrombosis without causing hemorrhage/vascular leakage. MB2mP6 improved mouse survival when infused immediately or hours after onset of severe sepsis. Furthermore, platelet Gα13 knockout inhibited septic thrombosis whereas leukocyte Gα13 knockout diminished septic inflammation, each moderately improving survival. Dual platelet/leukocyte Gα13 knockout inhibited septic thrombosis and inflammation, further improving survival similar to MB2mP6. These results demonstrate that inflammation and thrombosis independently contribute to poor outcomes and exacerbate each other in systemic inflammation, and reveal a concept of dual anti-inflammatory/anti-thrombotic therapy without exacerbating vascular leakage.
Highlights
Systemic inflammation as manifested in sepsis is an excessive, life-threatening inflammatory response to severe bacterial or viral infection or extensive injury
Inflammation, vascular leakage, and thrombosis together lead to multi-organ dysfunction including acute respiratory distress syndrome (ARDS) and kidney failure, disseminated intravascular coagulation (DIC), and circulatory system collapse resulting in morbidity and mortality[1,2,3,4]
THP-1-differentiated macrophages were pretreated with MB2mP6 high-loading peptide nanoparticles (HLPN) or scrambled peptide control for 20 min and loaded onto 48-well plates pre-coated with integrin ligand human (h)ICAM-1 (10 μg mL−1)
Summary
Systemic inflammation as manifested in sepsis is an excessive, life-threatening inflammatory response to severe bacterial or viral infection or extensive injury It is a thromboinflammatory condition associated with vascular leakage/hemorrhage and thrombosis that is not effectively treated by current anti-inflammatory or anti-thrombotic drugs. A repeat clinical trial showed no adverse effect of bleeding and no efficacy, leading to its withdrawal from the market[8,13] These clinical trials suggest a potential benefit for antithrombotic drugs in sepsis treatment, which is consistent with the numerous data showing a close association between inflammation and thrombosis, and with the reported beneficial effects of anti-platelet drugs in treating sepsis in patients and animal models[3,8,14,15,16,17,18,19]. Based on these basic and clinical studies, we hypothesize that inflammation, vascular leakage/
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