Recombinant fibrinogenase from Agkistrodon acutus venom protects against sepsis via direct degradation of fibrin and TNF-alpha.
Severe sepsis remains a leading cause of death and disability because of less effective therapy available for this disease. A complex interplay between the inflammatory factors and the coagulation pathways seems to be the fundamental mechanisms for the pathogenesis of sepsis. Here we report that recombinant fibrinogenase II (rF II) from Agkistrodon acutus plasmin-independently degraded the thrombi, and inhibited inflammatory responses by direct and specific degradation of tumor necrosis factor alpha (TNF-alpha) induced by lipopolysaccharide (LPS) without showing proteolytic activities on interleukin-1 (IL-1), cluster of differentiation 68 (CD68) and some other serum proteins. We also report that rF II effectively protected against LPS induced sepsis in a rabbit model. Administration of rF II reduced hepatic and renal damage, decreased the levels of alanine aminotransferase (ALT) and blood urea nitrogen (BUN), and increased survival rate in LPS-induced sepsis rabbits. We further confirmed the rescue effect of rF II on severe sepsis in rat caecal ligation and puncture (CLP) model. Our findings suggest that rF II could effectively protect against sepsis via direct degradation of microthrombi and inflammatory factor TNF-alpha as well as provide a novel strategy to develop a single proteinase molecule for targeting the main pathological processes of this disease.
Wang
Rongrong
R
Department of Pharmacology, Zhong-Shan Medical College, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou, Guangdong 510089, PR China.
Qiu
Pengxin
P
Jiang
Weijian
W
Cai
Xiaofeng
X
Ou
Yanqiu
Y
Su
Xingwen
X
Cai
Jinlian
J
Chen
Jiashu
J
Yin
Wei
W
Yan
Guangmei
G
D017836:Agkistrodon; D000818:Animals; D001483:Base Sequence; D003435:Crotalid Venoms / Q000201:enzymology*; D017931:DNA Primers; D005337:Fibrin / Q000378:metabolism*; D006868:Hydrolysis; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D011817:Rabbits; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000378:metabolism / Q000517:prevention & control*; D012697:Serine Endopeptidases / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D003435:Crotalid Venoms; D017931:DNA Primers; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D005337:Fibrin; D012697:Serine Endopeptidases; C412879:venombin B