Phosphodiesterase 4 inhibition dose dependently stabilizes microvascular barrier functions and microcirculation in a rodent model of polymicrobial sepsis.

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.

• Authors: Sven Flemming, Nicolas Schlegel, Christian Wunder, Michael Meir, Wolfgang Baar, Jakob Wollborn, Norbert Roewer, Christoph-Thomas Germer, Martin Alexander Schick
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 41 Issue 6 Pg. 537-45 (Jun 2014) ISSN: 1540-0514 [Electronic] United States
• PMID: 24569506 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphodiesterase 4 Inhibitors
• Rolipram

Topics

• Animals
• Coinfection (drug therapy)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Endothelium (drug effects)
• Hemodynamics
• Male
• Microcirculation (drug effects)
• Phosphodiesterase 4 Inhibitors (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Rolipram (pharmacology)
• Sepsis (drug therapy, physiopathology)