Mechanisms of the beneficial effect of adrenomedullin and adrenomedullin-binding protein-1 in sepsis: down-regulation of proinflammatory cytokines.

ABSTRACT

OBJECTIVE: Our recent study indicates that administration of adrenomedullin (AM) in combination with AM-binding protein-1 (AMBP-1) before sepsis (i.e., pretreatment) maintains cardiovascular stability and reduces the mortality rate. The aim of the present study was to determine whether administration of AM/AMBP-1 after the onset of sepsis (posttreatment) has any salutary effects on the septic host, and if so, whether AM/AMBP-1 down-regulates proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6. DESIGN: Prospective, controlled, randomized animal study. SETTING: A university research laboratory. SUBJECTS: Male adult Sprague-Dawley rats. INTERVENTIONS: Rats were subjected either to polymicrobial sepsis by cecal ligation and puncture or to sham operation followed by the administration of normal saline solution (i.e., fluid resuscitation). MEASUREMENTS AND MAIN RESULTS: At 5 hrs after cecal ligation and puncture, AM (12 microg/kg body weight) and AMBP-1 (40 microg/kg body weight) were administered intravenously over 1 hr. At 20 hrs after cecal ligation and puncture (i.e., the late, hypodynamic stage of sepsis), cardiac output, stroke volume, total peripheral resistance, systemic oxygen delivery, and organ blood flow were determined by radioactive microspheres, and circulating concentrations of proinflammatory cytokines were measured using enzyme-linked immunosorbent assay kits. Moreover, plasma concentrations of transaminases and lactate were measured. The results indicated that administration of AM/AMBP-1 at 5 hrs after cecal ligation and puncture prevented the decrease in measured systemic and regional hemodynamic variables and reduced plasma concentrations of tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 at 20 hrs after the onset of sepsis. Moreover, administration of AM/AMBP-1 attenuated hepatic damage and the increase in plasma lactate and prevented hemoconcentration. CONCLUSION: Administration of AM/AMBP-1 may provide a novel approach to the treatment of sepsis. Moreover, because AM/AMBP-1 significantly reduced circulating concentrations of tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6, down-regulation of those proinflammatory cytokines by AM/AMBP-1 appears to play an important role for the beneficial effects of these agents in polymicrobial sepsis.