title: ANGIOGENESIS INHIBITOR ENDOSTATIN PROTECTS MICE WITH SEPSIS FROM MULTIPLE ORGAN DYSFUNCTION SYNDROME.
abstract: Endostatin is an endogenous inhibitor of vascular endothelium. It can inhibit endothelial cell migration, proliferation, and vascular angiogenesis and is mainly used for anticancer therapy. We have previously found that endostatin is an important node protein in the pathogenesis of sepsis. However, its impacts on sepsis have not yet been reported. We established a septic mouse model using cecal ligation and puncture (CLP) and gave the mice either endostatin or placebo (saline). The effects of endostatin on serum enzyme, Evans blue leakage, lung wet-to-dry weight ratio, and cytokine (tumor necrosis factor α, interleukin 1β [IL-1β], and IL-6) production were assessed. Survival rates were observed for up to 3 days. In addition, we examined the effects of endostatin on serum vascular endothelial growth factor A (VEGF-A), VEGF-C, and pathological changes and scores of lung tissues as well as the phosphorylation of JNK, p38, and ERKl/2 proteins in lung tissues of mice with sepsis. We found that endostatin can increase the survival of septic mice in a time- and dose-dependent manner probably by reducing multiorgan dysfunctions shown by serum indicators, morphologic changes, Evans blue leakage, wet-to-dry weight ratio, and inflammation of lung tissues. In addition, endostatin could reduce serum tumor necrosis factor α, IL-1β, IL-6, and VEGF-C levels in septic mice as well as inhibit phosphorylation of p38 and ERK1/2 in lung tissues of septic mice. This is the first study demonstrating the protective effect of endostatin on sepsis and its possible underlying mechanisms from the aspects of inhibiting inflammatory responses, blocking VEGF receptor, attenuating VEGF-C expression, and reducing vascular permeability. Overall, the study revealed the potential protect role for endostatin in the treatment of sepsis.
authors.affiliation: *Translational Medicine Center of Sepsis †Department of Critical Care Medicine, The Third Xiangya Hospital ‡Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Peng
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
authors.forename: Kangkai
authors.initials: K
authors.lastname: Wang
authors.forename: Huali
authors.initials: H
authors.lastname: Zhang
authors.forename: Zihui
authors.initials: Z
authors.lastname: Xiao
authors.forename: Hao
authors.initials: H
authors.lastname: Ou
authors.forename: Bingchang
authors.initials: B
authors.lastname: Yang
authors.forename: Mingshi
authors.initials: M
authors.lastname: Yang
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Xiao
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D043169:Endostatins / Q000008:administration & dosage / Q000627:therapeutic use*; D018836:Inflammation Mediators / Q000097:blood; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D009102:Multiple Organ Failure / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D018805:Sepsis / Q000150:complications* / Q000378:metabolism; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D020533:Angiogenesis Inhibitors; D016207:Cytokines; D043169:Endostatins; D018836:Inflammation Mediators; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse