Human adrenomedullin and its binding protein attenuate organ injury and reduce mortality after hepatic ischemia-reperfusion.
OBJECTIVE
To determine whether administration of a vasoactive peptide, human adrenomedullin (AM), in combination with its binding protein (ie, AMBP-1), prevents or minimizes hepatic ischemia-reperfusion (I/R) injury.


BACKGROUND
Hepatic I/R injury results from tissue hypoxia and subsequent inflammatory responses. Even though numerous pharmacological modalities and substances have been studied to reduce I/R-induced mortality, none have been entirely successful. We have shown that administration of AM/AMBP-1 produces significant beneficial effects under various pathophysiological conditions. However, it remains unknown if human AM/AMBP-1 has any protective effects on hepatic I/R-induced tissue damage and mortality.


METHODS
Seventy percent hepatic ischemia was induced in male adult rats by placing a microvascular clip across the hilum of the left and median lobes for 90 minutes. After removing the clip, human AM alone, human AMBP-1 alone, human AM in combination with human AMBP-1 or vehicle was administered intravenously over a period of 30 minutes. Blood and tissue samples were collected 4 hours after reperfusion for various measurements. In additional groups of animals, the nonischemic liver lobes were resected at the end of 90-minute ischemia. The animals were monitored for 7 days and survival was recorded.


RESULTS
After hepatic I/R, plasma levels of AM were significantly increased, whereas AMBP-1 levels were markedly decreased. Likewise, gene expression of AM in the liver was increased significantly, whereas AMBP-1 expression was markedly decreased. Administration of AM in combination with AMBP-1 immediately after the onset of reperfusion down-regulated inflammatory cytokines, decreased hepatic neutrophil infiltration, inhibited liver cell apoptosis and necrosis, and reduced liver injury and mortality in a rat model of hepatic I/R. On the other hand, administration of human AM alone or human AMBP-1 alone after hepatic I/R failed to produce significant protection.


CONCLUSIONS
Human AM/AMBP-1 may be a novel treatment to attenuate tissue injury after an episode of hepatic ischemia.
Yang
Juntao
J
Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset, New York 11030, USA.
Wu
Rongqian
R
Qiang
Xiaoling
X
Zhou
Mian
M
Dong
Weifeng
W
Ji
Youxin
Y
Marini
Corrado P
CP
Ravikumar
Thanjavur S
TS
Wang
Ping
P
D053607:Adrenomedullin / Q000008:administration & dosage*; D000818:Animals; D017242:Complement Factor H / Q000008:administration & dosage*; D004195:Disease Models, Animal; D008099:Liver / Q000098:blood supply*; D008107:Liver Diseases / Q000401:mortality / Q000517:prevention & control*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000401:mortality / Q000517:prevention & control*; D014665:Vasodilator Agents / Q000008:administration & dosage*
D053607:Adrenomedullin; D017242:Complement Factor H; D014665:Vasodilator Agents; C507862:ADM protein, human; C493495:CFH protein, human