Human adrenomedullin and its binding protein ameliorate sepsis-induced organ injury and mortality in jaundiced rats.
Sepsis is a serious complication for patients with obstructive jaundice. Although administration of adrenomedullin (AM) in combination with its binding protein (AMBP-1) is protective after injury, it remains unknown whether AM/AMBP-1 ameliorates sepsis-induced organ injury and mortality in the setting of biliary obstruction. The aim of this study is, therefore, to test the efficacy of human AM/AMBP-1 in a rat model of obstructive jaundice and polymicrobial sepsis. To study this, obstructive jaundice was induced in male adult rats (275-325g) by common bile duct ligation (BDL). One week after BDL, the rats were subjected to sepsis by cecal ligation and puncture (CLP). Plasma levels of AM and AMBP-1 were measured at 20h after CLP. In additional groups of BDL+CLP rats, human AM/AMBP-1 (24/80microg/kg body weight (BW)) or vehicle (i.e., human albumin) was administered intravenously at 5h after CLP. Blood and tissue samples were collected at 20h after CLP for various measurements. To determine the long-term effect of human AM/AMBP-1 after BDL+CLP, the gangrenous cecum was removed at 20h after CLP and 7-day survival was recorded. Our results showed that plasma levels of AM were significantly increased while AMBP-1 levels were markedly decreased after BDL+CLP (n=8, P<0.05). Administration of human AM/AMBP-1 attenuated tissue injury and inflammatory responses after BDL+CLP. Moreover, human AM/AMBP-1 significantly increased the survival rate from 21% (n=14) to 53% (n=15). Thus, human AM/AMBP-1 ameliorates sepsis-induced organ injury and mortality in jaundiced rats. Human AM/AMBP-1 can be further developed as a novel treatment for sepsis in jaundiced patients.
Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset, NY 11030, United States.
Juntao
J
Yang
Rongqian
R
Wu
Mian
M
Zhou
Ping
P
Wang
D053607:Adrenomedullin / Q000097:blood* / Q000627:therapeutic use*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002432:Cecum / Q000601:surgery; D017242:Complement Factor H / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D041781:Jaundice, Obstructive / Q000097:blood*; D019344:Lactic Acid / Q000097:blood; D008026:Ligation; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D053607:Adrenomedullin; D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D017242:Complement Factor H; D003404:Creatinine; D015850:Interleukin-6; D019344:Lactic Acid; D014409:Tumor Necrosis Factor-alpha; C481978:adrenomedullin-binding protein 1, rat; C493495:CFH protein, human