The role of histidine-rich glycoprotein on immunothrombosis in septic organ failure

[Speaker] Hidenori Wake:1
[Co-author] Shuji Mori:2, Kiyoshi Teshigawara:1, Keyue Liu:1, Dengli Wang:1, Yuan Gao:1, Hideo K Takahashi:3, Masahiro Nishibori:1
1:Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan, 2:Shujitsu University School of Pharmacy, Japan, 3:Department of Pharmacology, Kinki University Faculty of Medicine, Japan

Background: Sepsis definition was updated in 2016. New sepsis definition was focused on multiple organ failure (MOF) instead of systemic inflammatory response syndrome. The pathogenesis of sepsis includes the disturbance of blood-vascular homeostasis, which may cause MOF, circulatory shock, and disseminated intravascular coagulation, leading to high mortality. Recent studies revealed that neutrophil adhesion on vascular wall followed by neutrophil extracellular traps (NETs) release may trigger platelet aggregation and immunothrombus formation in septic organ failure. Therefore, immunothrombosis (including NETosis) may be a crucial role on the progression of septic MOF condition. Histidine-rich glycoprotein (HRG) is a 75 kDa glycoprotein with high histidine contents. HRG is known as the plasma factor to regulate coagulation/fibrinolysis, immune response and angiogenesis. Recent reports suggested that HRG may be associated with regulation of blood vascular function in septic condition. However, the effects of HRG on the immunothrombosis in systemic septic condition is poorly understood.
Methods: Sepsis was induced by cecal ligation and puncture (CLP). We evaluated the beneficial effects of HRG administration on survival rate, lung inflammation, and the state of circulating neutrophils using immunohistochemical staining and in vivo imaging method. Purified neutrophils from human blood were treated with HRG and analyzed with respect to neutrophil shape, adhesiveness to vascular wall, passage through microcapillaries using MC-FAN, and production of ROS. Human plasma HRG levels were assessed by ELISA.
Results: Our recent study indicated that plasma HRG levels significantly decreased in CLP septic mice and administration of HRG dramatically improved the survival rate of CLP mice. We also confirmed that plasma HRG levels in septic patients decreased significantly, compared with those in healthy volunteers. The clinical data suggested that the detection of plasma HRG levels is clinically useful for the diagnosis and predictive indicator for prognosis of sepsis. Moreover, we focused on the role of HRG on NETosis and immunothrombosis in septic condition and showed that HRG inhibited NETs and immunothrombus formation in pulmonary vasculatures by keeping neutrophils quiescent morphologically and functionally.
Conclusion: Consequently, supplementary therapy with HRG may provide a novel strategy for the treatment of septic patients by inhibiting immunothrombosis in blood vessels.
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