Abstract
PurposeAdrenomedullin (ADM) has been referred to as a double-edged sword during septic shock: On one hand, ADM supplementation improved organ perfusion and function, attenuated systemic inflammation, and ultimately reduced tissue apoptosis and mortality. On the other hand, ADM overproduction can cause circulatory collapse and organ failure due to impaired vasoconstrictor response and reduced myocardial contractility. Since most of these data originate from un-resuscitated shock models, we tested the hypothesis whether the newly developed anti-ADM antibody HAM1101 may improve catecholamine responsiveness and thus attenuate organ dysfunction during resuscitated murine, cecal ligation and puncture (CLP)-induced septic shock.MethodsImmediately after CLP, mice randomly received vehicle (phosphate-buffered saline, n = 11) or HAM1101 (n = 9; 2 μg·g−1). Fifteen hours after CLP, animals were anesthetized, mechanically ventilated, instrumented, and resuscitated with hydroxyethylstarch and continuous i.v. norepinephrine to achieve normotensive hemodynamics (mean arterial pressure > 50 to 60 mmHg).ResultsHAM1101 pretreatment reduced the norepinephrine infusion rates required to achieve hemodynamic targets, increased urine flow, improved creatinine clearance, and lowered neutrophil gelatinase-associated lipocalin blood levels, which coincided with reduced expression of the inducible nitric oxide synthase and formation of peroxynitrite (nitrotyrosine immunostaining) in the kidney and aorta, ultimately resulting in attenuated systemic inflammation and tissue apoptosis.ConclusionsDuring resuscitated murine septic shock, early ADM binding with HAM1101 improved catecholamine responsiveness, blunted the shock-related impairment of energy metabolism, reduced nitrosative stress, and attenuated systemic inflammatory response, which was ultimately associated with reduced kidney dysfunction and organ injury.Electronic supplementary materialThe online version of this article (doi:10.1186/2197-425X-1-2) contains supplementary material, which is available to authorized users.
Highlights
Adrenomedullin (ADM) has been referred to as a double-edged sword in sepsis [1]: during cecal ligation and puncture (CLP)- [2,3,4], endotoxin- [5], or Staphylococcus aureus α-toxin-induced sepsis [6], ADM administration restored organ perfusion during the hypodynamic shock phase. This effect coincided with attenuated systemic inflammation [7], decreased activation of the inducible nitric oxide synthase and peroxynitrite formation [8], and reduced organ dysfunction [9], apoptosis [10], and mortality [6]
All animals needed continuous i.v. noradrenaline to achieve hemodynamic targets, and HAM1101 was associated with significantly lower mean infusion rates during the 5-h observation period (0.010 (0.09, 0.012) vs. 0.019 (0.016, 0.24) μg·g−1·h−1, p < 0.001)
HAM1101 was associated with three- and twofold higher diuresis and creatinine clearance, (Table 3), respectively, resulting in lower creatinine, urea, and neutrophil gelatinase-associated lipocalin (NGAL) concentrations
Summary
Adrenomedullin (ADM) has been referred to as a double-edged sword in sepsis [1]: during cecal ligation and puncture (CLP)- [2,3,4], endotoxin- [5], or Staphylococcus aureus α-toxin-induced sepsis [6], ADM administration restored organ perfusion during the hypodynamic shock phase. This effect coincided with attenuated systemic inflammation [7], decreased activation of the inducible nitric oxide synthase (iNOS) and peroxynitrite formation [8], and reduced organ dysfunction [9], apoptosis [10], and mortality [6]. We tested the hypothesis whether a newly developed ADM antibody may improve catecholamine responsiveness and attenuate kidney dysfunction in resuscitated, CLP-induced septic shock [27]
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