title: Phosphodiesterase-4 inhibition as a therapeutic approach to treat capillary leakage in systemic inflammation.
abstract: In sepsis and systemic inflammation, increased microvascular permeability and consecutive breakdown of microcirculatory flow significantly contribute to organ failure and death. Evidence points to a critical role of cAMP levels in endothelial cells to maintain capillary endothelial barrier properties in acute inflammation. However, approaches to verify this observation in systemic models are rare. Therefore we tested here whether systemic application of the phosphodiesterase-4-inhibitors (PD-4-Is) rolipram or roflumilast to increase endothelial cAMP was effective to attenuate capillary leakage and breakdown of microcirculatory flow in severe lipopolysaccharide (LPS)-induced systemic inflammation in rats. Measurements of cAMP in mesenteric microvessels demonstrated significant LPS-induced loss of cAMP levels which was blocked by application of rolipram. Increased endothelial cAMP by application of either PD-4-I rolipram or roflumilast led to stabilization of endothelial barrier properties as revealed by measurements of extravasated FITC-albumin in postcapillary mesenteric venules. Accordingly, microcirculatory flow in mesenteric venules was significantly increased following PD-4-I treatment and blood gas analyses indicated improved metabolism. Furthermore application of PD-4-I after manifestation of LPS-induced systemic inflammation and capillary leakage therapeutically stabilized endothelial barrier properties as revealed by significantly reduced volume resuscitation for haemodynamic stabilization. Accordingly microcirculation was significantly improved following treatment with PD-4-Is. Our results demonstrate that inflammation-derived loss of endothelial cAMP contributes to capillary leakage which was blocked by systemic PD-4-I treatment. Therefore these data suggest a highly clinically relevant and applicable approach to stabilize capillary leakage in sepsis and systemic inflammation.
authors.affiliation: University of Würzburg, Department of General, Visceral, Vascular and Paediatric Surgery (Department of Surgery I), Oberdürrbacherstraße 6, D-97080 Würzburg, Germany.
authors.forename: Martin Alexander
authors.initials: MA
authors.lastname: Schick
authors.forename: Christian
authors.initials: C
authors.lastname: Wunder
authors.forename: Jakob
authors.initials: J
authors.lastname: Wollborn
authors.forename: Norbert
authors.initials: N
authors.lastname: Roewer
authors.forename: Jens
authors.initials: J
authors.lastname: Waschke
authors.forename: Christoph-Thomas
authors.initials: CT
authors.lastname: Germer
authors.forename: Nicolas
authors.initials: N
authors.lastname: Schlegel
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D002196:Capillaries / Q000187:drug effects / Q000502:physiology; D002199:Capillary Permeability / Q000187:drug effects; D000242:Cyclic AMP / Q000502:physiology; D003521:Cyclopropanes / Q000494:pharmacology / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D008070:Lipopolysaccharides; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000494:pharmacology / Q000627:therapeutic use*; D014652:Vascular Diseases / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D008070:Lipopolysaccharides; D058988:Phosphodiesterase 4 Inhibitors; C424423:Roflumilast; D000242:Cyclic AMP; D020889:Rolipram