• Andreas Link, Simina Selejan, Christoph Maack, Monika Lenz, and Michael Böhm.
• Klinik für Innere Medizin III, Universität des Saarlandes, 66421 Homburg/Saar, Germany. link@med-in.uni-saarland.de
• Crit Care. 2008 Jan 1; 12 (6): R159.

IntroductionStimulation of beta2-adrenergic receptors (beta2-ARs) inhibits tumor necrosis factor-alpha (TNF-alpha) release in monocytes. In septic shock, endogenous catecholamines induce beta2-AR downregulation, leading to an increased TNF-alpha release. The aims of this study were to analyze the molecular mechanisms of beta-adrenergic downregulation and to explore therapeutic interventions with maintained anti-inflammatory efficacy in septic shock using the inhibition of phosphodiesterase 4 (PDE4).MethodsWe conducted in vitro stimulation of peripheral blood mononuclear cells of healthy volunteers (n = 20) and patients with septic shock (n = 20) with lipopolysaccharide (LPS) or Staphylococcus aureus enterotoxin B (SEB) without or with isoprenaline, forskolin (an activator of adenylate cyclase), or ropipram (an inhibitor of PDE4). We also conducted flow cytometric analysis of Toll-like receptor (TLR) 4 and TLR2 surface expression and intracellular TNF-alpha production of untreated and stimulated CD14+ monocytes. Protein expression of beta-ARs, of G proteins, of adenylate cyclase, and of TLRs was measured by Western blotting.ResultsInvestigations were done by LPS (100 ng/mL) or SEB (10 ng/mL) when TLR4 and TLR2 were maximally expressed. LPS- or SEB-treated CD14+ monocytes of healthy volunteers were able to produce TNF-alpha. This effect was attenuated by isoprenaline, forskolin, or rolipram in a concentration-dependent manner. In CD14+ monocytes of patients with septic shock, the anti-inflammatory effect of isoprenaline was completely blunted whereas efficacy of forskolin and rolipram was maintained. CD14+ monocytes of healthy volunteers were compared with patients with septic shock: protein expression of beta2-ARs was reduced and inhibitory G protein was increased, whereas no changes in adenylate cyclase and stimulatory G protein were found.ConclusionsIn septic shock, the anti-inflammatory effects of catecholamines are blunted by downregulation of beta2-ARs and upregulation of the inhibitory G protein in CD14+ monocytes. Beta-adrenergic downregulation is overcome by inhibitors of PDE4. These results provide a mechanistic rationale for the therapeutic use of selective PDE4 inhibitors in the treatment of septic shock.

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