Adrenomedullin and its binding protein attenuate the proinflammatory response after hemorrhage.
OBJECTIVE
The neuroendocrine response to hemorrhage is to maintain perfusion to the heart and brain, often at the expense of other organ systems. Systemic inflammation and tissue injury are important components of pathophysiologic consequences of hemorrhage. We have recently shown that administration of adrenomedullin (AM, a potent vasodilator peptide) and adrenomedullin binding protein-1 (AMBP-1) prevented the transition from the hyperdynamic to the hypodynamic stage in the progression of sepsis. However, the effect of AM/AMBP-1 on the inflammatory response after hemorrhage remains unknown. We therefore hypothesized that administration of AM/AMBP-1 during fluid resuscitation in hemorrhaged animals (i.e., posttreatment) attenuates tissue injury and the proinflammatory response.


METHODS
Prospective, controlled, and randomized animal study.


METHODS
A research institute laboratory.


METHODS
Male adult rats.


METHODS
Rats were bled, and then a mean arterial pressure was maintained at 40 mm Hg for 90 mins. They were then resuscitated by infusion of four times the volume of shed blood using Ringer's lactate solution for 60 mins.


RESULTS
Fifteen minutes after the beginning of resuscitation, AM (12 microg/kg of body weight) in combination with AMBP-1 (40 microg/kg of body weight) was administered via a femoral venous catheter for 45 mins. Blood samples were collected 4 hrs postresuscitation and assayed for levels of liver enzymes (i.e., alanine aminotransferase and aspartate aminotransferase), lactate, creatinine, proinflammatory cytokines tumor necrosis factor and high mobility group box 1, and anti-inflammatory cytokine interleukin-10. The results indicate that levels of alanine aminotransferase, aspartate aminotransferase, creatinine, lactate, tumor necrosis factor, and high mobility group box 1 markedly elevated after hemorrhage and resuscitation, and AM/AMBP-1 treatment significantly attenuated these increases. In contrast, the serum concentration of anti-inflammatory cytokine interleukin-10 was increased by the treatment of AM/AMBP-1. Moreover, AM/AMBP-1 treatment significantly improved the survival rate from 35% in vehicle-treated animals to 73% in AM/AMBP-1-treated animals in a low-volume resuscitation model of hemorrhage.


CONCLUSIONS
The combined administration of AM and AMBP-1 effectively suppresses hemorrhage-elicited organ injury and reduces hemorrhage-induced mortality, partly through down-regulation of proinflammatory cytokines (tumor necrosis factor and high mobility group box 1) and up-regulation of the anti-inflammatory cytokine interleukin-10.
Cui
Xiaoxuan
X
Division of Surgical Research, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset, NY, USA.
Wu
Rongqian
R
Zhou
Mian
M
Dong
Weifeng
W
Ulloa
Luis
L
Yang
Huan
H
Wang
Haichao
H
Tracey
Kevin J
KJ
Simms
H Hank
HH
Wang
Ping
P
D053607:Adrenomedullin; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D017242:Complement Factor H / Q000494:pharmacology*; D003404:Creatinine / Q000378:metabolism; D024002:HMGB Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D019344:Lactic Acid / Q000097:blood; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000378:metabolism* / Q000628:therapy; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*
D053607:Adrenomedullin; D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D017242:Complement Factor H; D003404:Creatinine; D024002:HMGB Proteins; D018836:Inflammation Mediators; D016753:Interleukin-10; D019344:Lactic Acid; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; C493495:CFH protein, human