title: Histidine-Rich Glycoprotein Prevents Septic Lethality through Regulation of Immunothrombosis and Inflammation.
abstract: 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.
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Wake
authors.affiliation: Department of Pharmacology, Shujitsu University, School of Pharmacy, Okayama 703-8516, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Mori
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Keyue
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Morioka
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Teshigawara
authors.affiliation: Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sakaguchi
authors.affiliation: Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kuroda
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, Kinki University, Faculty of Medicine, Osakasayama 589-8511, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Human Morphology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Aiji
authors.initials: A
authors.lastname: Ohtsuka
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshino
authors.affiliation: Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Morimatsu
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan. Electronic address: mbori@md.okayama-u.ac.jp.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishibori
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009504:Neutrophils / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D011014:Pneumonia / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018805:Sepsis / Q000209:etiology* / Q000378:metabolism / Q000401:mortality; D015398:Signal Transduction / Q000187:drug effects; D015996:Survival Rate; D013927:Thrombosis / Q000209:etiology / Q000378:metabolism; D000099053:Histidine-Rich Glycoprotein
chemical_list: D016207:Cytokines; D019007:P-Selectin; D011506:Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000099053:Histidine-Rich Glycoprotein; D018799:Intercellular Adhesion Molecule-1
keywords: ARDS; Histidine-rich glycoprotein; Immunothrombosis; Neutrophil; Sepsis