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 (275-325. g) 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 20. h after CLP. In additional groups of BDL. +. CLP rats, human AM/AMBP-1 (24/80μg/kg body weight (BW)) or vehicle (i.e., human albumin) was administered intravenously at 5. h after CLP. Blood and tissue samples were collected at 20. h 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 20. h 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.