Gu-4 suppresses affinity and avidity modulation of CD11b and improves the outcome of mice with endotoxemia and sepsis.
BACKGROUND
Systemic leukocyte activation and disseminated leukocyte adhesion will impair the microcirculation and cause severe decrements in tissue perfusion and organ function in the process of severe sepsis. Gu-4, a lactosyl derivative, could selectively target CD11b to exert therapeutic effect in a rat model of severe burn shock. Here, we addressed whether Gu-4 could render protective effects on septic animals.


RESULTS
On a murine model of endotoxemia induced by lipopolysaccharide (LPS), we found that the median effective dose (ED50) of Gu-4 was 0.929 mg/kg. In vivo treatment of Gu-4 after LPS challenge prominently attenuated LPS-induced lung injury and decreased lactic acid level in lung tissue. Using the ED50 of Gu-4, we also demonstrated that Gu-4 treatment significantly improved the survival rate of animals underwent sepsis induced by cecal ligation and puncture. By adhesion and transwell migration assays, we found that Gu-4 treatment inhibited the adhesion and transendothelial migration of LPS-stimulated THP-1 cells. By flow cytometry and microscopy, we demonstrated that Gu-4 treatment inhibited the exposure of active I-domain and the cluster formation of CD11b on the LPS-stimulated polymorphonuclear leukocytes. Western blot analyses further revealed that Gu-4 treatment markedly inhibited the activation of spleen tyrosine kinase in LPS-stimulated THP-1 cells.


CONCLUSIONS
Gu-4 improves the survival of mice underwent endotoxemia and sepsis, our in vitro investigations indicate that the possible underlying mechanism might involve the modulations of the affinity and avidity of CD11b on the leukocyte. Our findings shed light on the potential use of Gu-4, an interacting compound to CD11b, in the treatment of sepsis and septic shock.
Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Jiangsu Province, China.
TingTing
T
Yan
Qing
Q
Li
HuiTing
H
Zhou
YueTao
Y
Zhao
ShuQin
S
Yu
GuangLin
G
Xu
ZhiMin
Z
Yin
ZhongJun
Z
Li
ZhiHui
Z
Zhao
D000818:Animals; D039481:CD11b Antigen / Q000187:drug effects*; D002448:Cell Adhesion; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000188:drug therapy*; D005973:Glutamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007785:Lactose / Q000031:analogs & derivatives* / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008833:Microcirculation / Q000187:drug effects; D018805:Sepsis / Q000188:drug therapy*; D015996:Survival Rate
D039481:CD11b Antigen; C540504:Gu-4 compound; D005973:Glutamine; D007785:Lactose