Histidine-Rich Glycoprotein Prevents Septic Lethality through Regulation of Immunothrombosis and Inflammation

• A plasma protein HRG decreased markedly in septic mice with high lethality.
• Supplementary treatment with HRG improved the survival of septic mice.
• HRG treatment inhibited immunothrombosis, NETosis, and excessive inflammation.
• HRG kept circulating neutrophils quiescent morphologically and functionally.Although sepsis is a critical disease condition with high mortality and the main cause of death in intensive care units, there is no therapeutic drug for sepsis now. This research found that a plasma protein, histidine-rich glycoprotein (HRG), decreased dramatically in sepsis mouse model and that supplementary treatment of septic mice with purified human HRG remarkably improved the lethality of mice, associated with inhibition of tight attachment of neutrophils to pulmonary vasculatures, subsequent thrombosis, lung inflammation and activation of vascular endothelial cells. Thus, supplementary therapy with HRG may provide a novel strategy for the treatment of septic patients.

Sepsis is a major cause of death worldwide. We show that a plasma protein histidine-rich glycoprotein (HRG) was decreased significantly in septic mice with cecal ligation and puncture (CLP) and supplementary treatment of septic mice with exogenous HRG improved survival, with strong inhibition of tight attachment of neutrophils to pulmonary vasculatures, subsequent immunothrombosis, DIC state, lung inflammation, hypercytokinemia, and activation of vascular endothelial cells (VECs). In contrast, knockdown of HRG by siRNA exacerbated lethality. Purified human HRG reversibly induced morphological changes in human neutrophils in vitro; induction of spherical shape with reduced microvilli and adhesiveness to VECs. HRG maintained the passage of neutrophils through microcapillaries and abolished production of reactive oxygen species. These results suggested that the supplementary therapy with HRG may provide a novel strategy for the treatment of sepsis through suppression of excessive systemic inflammation and immunothrombosis by keeping circulating neutrophils quiescent and preventing uncontrolled activation of VECs.

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