Human adrenomedullin and its binding protein ameliorate sepsis-induced organ injury and mortality in jaundiced rats

Abstract

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 20 h after CLP. In additional groups of BDL+CLP rats, human AM/AMBP-1 (24/80 µg/kg 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.

Adrenomedullin and Adrenomedullin-Targeted Therapy As Treatment Strategies Relevant for Sepsis

“…Note that in these survival experiments, treatment was started 5 h after CLP surgery. Other studies have also demonstrated beneficial effects coadministration of ADM and AMBP-1 in models of hemorrhagic shock ( 140 – 142 ), ischemia/reperfusion ( 143 , 144 ), endotoxemia ( 98 ), and septic shock ( 145 , 146 ). To what extent complement factor H influences the described ADM-mediated effects remains unclear as the majority of preclinical studies on ADM with AMBP-1 coadministration did not compare ADM/AMBP-1 with ADM alone.…”

Current trends in inflammatory and immunomodulatory mediators in sepsis

“…The effects of AM are mediated by the functional receptor combination of calcitonin receptor-like receptor with receptor activity-modifying protein-2 or -3 [134]. Our group recently revealed that the small intestine is a major source of AM during CLP-induced polymicrobial sepsis in rats, which may account for the increased portal blood flow observed in the early stage of sepsis [69].…”

“…Recently, the understanding of the regulation of AM activity in sepsis has been greatly expanded after the discovery of AMBP-1 in mammalian blood [69,70]. Inflammatory cytokines, particularly IFN-␥, have been recognized as positive regulators of AMBP-1 expression, whereas oxidative stress and NF-B-sensitive microRNA-146a have been shown to down-regulate AMBP-1 [135,136].…”

Neuropeptide receptors as potential drug targets in the treatment of inflammatory conditions

“…Target sites comprise the cardiorespiratory organs and immune cells . Adrenomedullin has been shown to be anti‐inflammatory in animal models of sepsis, pancreatitis, arthritis and colonic inflammation . Adrenomedullin was also reported to inhibit cell proliferation and inflammatory mediator secretion by synovial fibroblasts of rheumatoid arthritis patients .…”

“…Target sites comprise the cardiorespiratory organs and immune cells [116]. Adrenomedullin has been shown to be anti-inflammatory in animal models of sepsis, pancreatitis, arthritis and colonic inflammation [117][118][119][120].…”