Abstract
IntroductionAdrenomedullin (ADM), a circulating vasodilatory peptide, plays an important role in the development of sepsis-associated hemodynamic and microcirculatory disorders. While administration of exogenous ADM had beneficial effects in several septic animal models, elevated ADM concentrations are associated with a bad outcome. This prompted us to test the effect of various anti-ADM antibodies in a cecal ligation and puncture (CLP) mouse model.MethodsTo gain new potential compounds for the treatment or prevention of septic shock we followed an alternative strategy to influence the ADM system: High-affinity anti-ADM antibodies with different epitope specificities were developed and their antagonist activity in vitro and their ability to reduce mortality in a CLP mouse model were assessed.ResultsAn anti-ADM antibody directed against the N-terminus substantially increased the survival of mice in a CLP model (HR = 0.077 (CI = 0.0189 to 0.315), p = 0.0004), whereas other antibodies with similar affinities but different epitope specificities were much less potent. The efficacious antibody, in contrast to an anti-C-terminal antibody, only partially inhibited ADM agonist activity in vitro. Healthy mice were not negatively affected by the N-terminal antibody.ConclusionsAn anti-N-terminal ADM antibody, as opposed to antibodies with other epitope specificities, strongly reduces mortality in CLP mice.Electronic supplementary materialThe online version of this article (doi:10.1186/2197-425X-1-3) contains supplementary material, which is available to authorized users.
Highlights
Adrenomedullin (ADM), a circulating vasodilatory peptide, plays an important role in the development of sepsis-associated hemodynamic and microcirculatory disorders
ADM has multiple functions, the most prominent being its vasodilatory activity. It acts on vascular smooth muscle cells and vascular endothelial cells by binding to a G protein-coupled receptor system composed of the calcitonin receptor-like receptor (CRLR) and an accessory protein (receptor activity-modifying protein (RAMP) 2 or 3) via downstream cyclic adenosine monophosphate and NO signaling
The agonist and antagonist activities of the antibodies were tested in an established ADM bioassay system employing a CHO cell line overexpressing the human recombinant ADM receptor (CRLR + RAMP3) with a cyclic adenosine monophosphate (cAMP) readout
Summary
Adrenomedullin (ADM), a circulating vasodilatory peptide, plays an important role in the development of sepsis-associated hemodynamic and microcirculatory disorders. While administration of exogenous ADM had beneficial effects in several septic animal models, elevated ADM concentrations are associated with a bad outcome. The peptide adrenomedullin (ADM) has been implicated in the development of septic shock: It is important in initiating the hyperdynamic response during the early stage of sepsis, and the reduced vascular responsiveness to ADM is associated with the transition from the hyperdynamic phase to the hypodynamic phase during the progression of sepsis [11,12,13,14]. In several preclinical studies exogenous ADM reduced mortality from septic shock and multiple organ failure (MOF) by reducing vascular hyperpermeability, preventing endothelial cell dysfunction and down-regulating the inflammatory response [12,18,19,20,21]
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