title: 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.affiliation: Departments of *General, Visceral, Vascular and Paediatric Surgery (Department of Surgery I) and †Anaesthesia and Critical Care, University of Würzburg, Würzburg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Flemming
authors.forename: Nicolas
authors.initials: N
authors.lastname: Schlegel
authors.forename: Christian
authors.initials: C
authors.lastname: Wunder
authors.forename: Michael
authors.initials: M
authors.lastname: Meir
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baar
authors.forename: Jakob
authors.initials: J
authors.lastname: Wollborn
authors.forename: Norbert
authors.initials: N
authors.lastname: Roewer
authors.forename: Christoph-Thomas
authors.initials: CT
authors.lastname: Germer
authors.forename: Martin Alexander
authors.initials: MA
authors.lastname: Schick
mesh_terms: D000818:Animals; D060085:Coinfection / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004727:Endothelium / Q000187:drug effects*; D006439:Hemodynamics; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000494:pharmacology*; D018805:Sepsis / Q000188:drug therapy / Q000503:physiopathology*
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D020889:Rolipram