Researchers at Department of Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences found that a plasma protein, histidine-rich glycoprotein (HRG), decreased dramatically in cecal ligation and puncture (CLP)-induced sepsis mice 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, intravascular NETosis, subsequent immunothrombosis, DIC state, lung inflammation, hypercytokinemia and activation of vascular endothelial cells.

The researchers examined the effects of HRG on human neutrophils and found that HRG reversibly induced spherical shape with few microvilli on neutrophils, associated with reduced production of reactive oxygen species. These morphological and functional features maintained the passage of neutrophils through microcapillaries without the tight attachment of neutrophils to vascular endothelial cells. “We identified a very important plasma protein, HRG, that maintains the circulating neutrophils quiescent,” said senior author Masahiro Nishibori, MD, PhD, Professor and Chair of Pharmacology of Okayama University Graduate School. “We found a novel functional role of HRG in the regulation of neutrophil state in the blood stream.”

Affecting more than 20 million patients annually, sepsis has been a main cause of death worldwide. The pathophysiology of sepsis must be very complexed. Septic ARDS, DIC state, hypercytokinemia, and shock condition are usually observed in combination in septic patients. These events may occur as a cascade and mutually related. Therefore, it is very difficult to design a novel strategy for the treatment of sepsis. In fact, many clinical trials have failed for decades so far. “We observed a same extent of decrease in plasma HRG in septic patients compared with septic mice,” said Professor Masahiro Nishibori. “We strongly speculate the existence of a similar cascade of events triggered by the decreased plasma HRG in patients.”

Based on these findings, 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 vascular endothelial cells.
This research article was published in online journal “EBioMedicine” on June 3rd 2016, which is published with editorial support from Cell Press and The Lancet.

< Article>
Wake, H., Mori, S., Liu, K., Morioka, Y., Teshigawara, K., Sakaguchi, M., Kuroda, K., Gao, Y., Takahashi, H., Ohtsuka, A., Yoshino, T., Morimatsu, H. and Nishibori, M. Histidine-rich Glycoprotein Prevents Septic Lethality through Regulation of Immunothrombosis and Inflammation.
EBioMedicine, 2016. Article DOI: 10.1016/j.ebiom.2016.06.003
URL: http://www.sciencedirect.com/science/article/pii/S235239641630247X

< Grant support>
This work was supported by grants from Scientific Research from the Ministry of Health, Labor, and Welfare of Japan (WA2F2547, WA2F2601), Japan Agency for Medical Research and Development, AMED (15lk0201014h0003), the Japan Society for the Promotion of Science (JSPS No. 2567046405, No. 15H0465617), from Secom Science Technology Foundation and from Hokuto Foundation for Bioscience.



< Contact>
Masahiro Nishibori, M.D., Ph.D.
Professor
Department of Pharmacology,
Okayama University Graduate School of Medicine,
Dentistry and Pharmaceutical Sciences
Okayama 700-8558, Japan

Tel/FAX: +81-(0)86-235-7140