Phosphodiesterase‐4 inhibition as a therapeutic approach to treat capillary leakage in systemic inflammation

Abstract

Key points• A specific therapy to treat capillary leakage in systemic inflammation and sepsis is not available at present.• Recent studies demonstrated that reduced cAMP levels in endothelial cells contribute to inflammation-induced breakdown of the endothelial barrier.• The present study demonstrates that systemically applied phosphodiesterase-4 inhibitors to increase endothelial cAMP are effective to prevent and to treat capillary leakage followed by improved microcirculation in a rodent model of systemic inflammation.• These data suggest a highly clinically relevant and applicable approach to stabilize capillary leakage in sepsis and 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.

Rolipram Improves Renal Perfusion and Function during Sepsis in the Mouse

“…2006; Wang et al, 2012). Because inhibitors of cyclic 39,59-phospodiesterase-4 have been shown to decrease endothelial permeability in other inflammatory models (Lin et al, 2011;Schick et al, 2012), we evaluated the effects of rolipram on renal vascular permeability at 6 hours following CLP using EBD. At 6 hours post-CLP, there was a significant increase in renal vascular permeability compared with Sham (0.006 mg of EBD/mg of kidney for Sham versus 0.026 mg of EBD/mg of kidney for CLP, n 5 5-7, P , 0.05).…”

“…At least 60 different mammalian isoforms of PDE exist and tissue-specific expression of different isoforms is thought to provide for the compartmentalization of cAMP levels (Lugnier, 2006). PDE4 is highly expressed in endothelial cells (Netherton and Maurice, 2005;Lugnier, 2006), and targeting PDE4 with inhibitors reduces vascular leakage (Miotla et al, 1998;Lin et al, 2011;Schick et al, 2012). In the kidney, several isoforms of PDE are expressed (Cheng and Grande, 2007), and inhibiting PDE4 has been shown to increase RBF by decreasing renal vascular resistance (Tanahashi et al, 1999).…”

“…Levels of cAMP are regulated by cyclic nucleotide phosphodiesterase enzymes (PDE), which convert cAMP into 59-adenosine monophosphate (AMP). In various models of inflammation inhibitors of PDE reduce microvascular leakage (Miotla et al, 1998;Schick et al, 2012). At least 60 different mammalian isoforms of PDE exist and tissue-specific expression of different isoforms is thought to provide for the compartmentalization of cAMP levels (Lugnier, 2006).…”

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

“…Thereafter, relaparotomy was performed; the mesentery was gently taken out and spread over a pillar as has been described before (4). The whole experimental setup was then carefully placed under a modified inverted Zeiss microscope (Axiovert 200; Carl Zeiss, Göttingen, Germany) equipped with different lenses (Achroplan Â10 NA0.25/Â20 NA0.4/Â40 NA 0.6).…”

Quantification of Malignant Breast Cancer Cell MDA-MB-231 Transmigration Across Brain and Lung Microvascular Endothelium

“…LPS can also increase the adhesion of breast cancer cells to endothelium by directly or indirectly activating ECs 9 . In contrast, adenosine 3′, 5′-cyclic monophosphate (cAMP) can prevent capillary leakiness by LPS-induced systemic inflammation 44 . In addition to VEGF, we used LPS and cAMP to simulate pathological (e.g.…”