1. Adrenomedullin and its binding protein attenuate the proinflammatory response after hemorrhage
- Author
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Haichao Wang, Rongqian Wu, H. Hank Simms, Weifeng Dong, Mian Zhou, Ping Wang, Luis Ulloa, F. Huan Yang, Kevin J. Tracey, and Xiaoxuan Cui
- Subjects
Male ,Mean arterial pressure ,medicine.medical_specialty ,Resuscitation ,Vasodilator Agents ,Adrenomedullin binding ,Shock, Hemorrhagic ,Critical Care and Intensive Care Medicine ,Systemic inflammation ,Proinflammatory cytokine ,Rats, Sprague-Dawley ,Sepsis ,Adrenomedullin ,HMGB Proteins ,Intensive care ,Internal medicine ,medicine ,Animals ,Aspartate Aminotransferases ,Lactic Acid ,Tumor Necrosis Factor-alpha ,business.industry ,Alanine Transaminase ,medicine.disease ,Interleukin-10 ,Rats ,Surgery ,Endocrinology ,Complement Factor H ,Creatinine ,Inflammation Mediators ,medicine.symptom ,Peptides ,business - Abstract
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. Design Prospective, controlled, and randomized animal study. Setting A research institute laboratory. Subjects Male adult rats. Interventions 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. Measurements and main 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. Conclusion 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.
- Published
- 2005