Resuscitation of uncontrolled traumatic hemorrhage induced by severe liver injury: the use of human adrenomedullin and adrenomedullin binding protein-1.
BACKGROUND
The liver is a major organ that is susceptible to injury after blunt or penetrating trauma to the abdomen. No specific nonoperative treatment exists for traumatic hepatic injury (THI). Adrenomedullin (AM), a vasoactive peptide, combined with its binding protein, AM protein (AMBP-1), is beneficial in various disease conditions. In this study, we propose to analyze whether human AM combined with human AMBP-1 provides benefit in a model of THI in the rat.


METHODS
Male adult rats were subjected to trauma hemorrhage by resection of ∼50% of total liver tissues and allowed bleeding for 15 minutes. Immediately thereafter, human AM (48 μg/kg birth weight) plus human AMBP-1 (160 μg/kg birth weight) were given intravenously over 30 minutes in 1-mL normal saline. After 4 hours, the rats were killed, blood was collected, and tissue injury indicators were assessed. A 10-day survival study was also conducted.


RESULTS
At 4 hours after THI, plasma AMBP-1 levels were markedly decreased. Plasma levels of liver injury indicators (i.e., aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase) were significantly increased after THI. Similarly, lactate, creatinine, and tumor necrosis factor-α levels were significantly increased after THI. Administration of human AM/AMBP-1 after THI produced significant decreases of 64%, 23%, and 19% of plasma aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase levels, respectively. Similarly, plasma levels of lactate, creatinine, and tumor necrosis factor-α were also decreased by 42%, 28%, and 46% after human AM/AMBP-1 treatment, respectively. In a 10-day survival study, although vehicle treatment produced 41% survival, human AM/AMBP-1 treatment improved the survival rate to 81%.


CONCLUSIONS
Administration of human AM/AMBP-1 significantly attenuated tissue injury and inflammation and improved survival after THI. Thus, human AM/AMBP-1 can be developed as a novel treatment for victims with uncontrolled traumatic hemorrhage.
Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset, New York, USA.
Kavin G
KG
Shah
Asha
A
Jacob
Derry
D
Rajan
Rongqian
R
Wu
Ernesto P
EP
Molmenti
Jeffrey
J
Nicastro
Gene F
GF
Coppa
Ping
P
Wang
D053607:Adrenomedullin / Q000097:blood / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D017242:Complement Factor H / Q000378:metabolism / Q000494:pharmacology*; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D006470:Hemorrhage / Q000188:drug therapy* / Q000209:etiology; D007124:Immunoenzyme Techniques; D007773:Lactates / Q000097:blood; D008099:Liver / Q000293:injuries*; D008297:Male; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation / Q000379:methods*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D053607:Adrenomedullin; D017242:Complement Factor H; D003404:Creatinine; D007773:Lactates; D014409:Tumor Necrosis Factor-alpha; C493495:CFH protein, human