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Phosphodiesterase 4 Inhibition Dose Dependently Stabilizes Microvascular Barrier Functions and Microcirculation in a Rodent Model of Polymicrobial Sepsis

Flemming, Sven*; Schlegel, Nicolas*; Wunder, Christian; Meir, Michael*; Baar, Wolfgang; Wollborn, Jakob; Roewer, Norbert; Germer, Christoph-Thomas*; Schick, Martin Alexander

doi: 10.1097/SHK.0000000000000152
Basic Science Aspects

ABSTRACT Background: Breakdown of microvascular endothelial barrier functions contributes to disturbed microcirculation, organ failure, and death in sepsis. Increased endothelial cAMP levels by systemic application of phosphodiesterase 4 inhibitors (PD-4-I) have previously been demonstrated to protect microvascular barrier properties in a model of systemic inflammation (systemic inflammatory response syndrome) suggesting a novel therapeutic option to overcome this problem. However, in a clinically relevant model of polymicrobial sepsis long-term effects, immunomodulatory effects and effectivity of PD-4-I to stabilize microvascular barrier functions and microcirculation remained unexplored. Methods: We induced polymicrobial sepsis using the colon ascendens stent peritonitis (CASP) model in which we performed macrohemodynamic and microhemodynamic monitoring with and without systemic intravenous application of different doses of PD-4-I rolipram in Sprague-Dawley rats over 26 h. Results: All animals with CASP showed clinical and laboratory signs of sepsis and peritonitis. Whereas macrohemodynamic adverse effects were not evident, application of PD-4-I led to stabilization of endothelial barrier properties as revealed by reduced extravasation of fluorescein isothiocyanate–albumin. However, only low-dose application of 1 mg/kg body weight per hour of PD-4-I improved microcirculatory flow in the CASP model, whereas high-dose therapy of 3 mg/kg BW per hour PDI-4-I had adverse effects. Accordingly, sepsis-induced acute kidney injury and lung edema were prevented by PD-4-I treatment. Furthermore, PD-4-I showed immunomodulatory effects as revealed by decreased interleukin 1α (IL-1α), IL-1β, IL-12, and tumor necrosis factor α levels following PD-4-I treatment, which appeared not to correlate with barrier-stabilizing effects of rolipram. Conclusions: These data provide further evidence that systemic application of PD-4-I could be suitable for therapeutic microvascular barrier stabilization and improvement of microcirculatory flow in sepsis.

Departments of *General, Visceral, Vascular and Paediatric Surgery (Department of Surgery I) and Anaesthesia and Critical Care, University of Würzburg, Würzburg, Germany

Received 23 Jan 2014; first review completed 31 Jan 2014; accepted in final form 05 Feb 2014

Address reprint requests to Nicolas Schlegel, MD, Department of General, Visceral, Vascular and Paediatric Surgery (Department of Surgery I), Oberdürrbacherstraße 6, D-97080 Würzburg, Germany. E-mail:

S.F. and N.S. contributed equally to this work.

These studies were supported by a grant from the Deutsche Forschungsgemeinschaft SCHL 1962/2-1.

None of the authors has a conflict of interest to declare.

© 2014 by the Shock Society