Phosphodiesterase-4 inhibition reduces ECLS-induced vascular permeability and improves microcirculation in a rodent model of extracorporeal resuscitation.

ABSTRACT

Extracorporeal circulation can be accompanied by increased vascular permeability leading to pathological fluid balance and organ dysfunction. The second messenger cAMP is involved in capillary permeability and maintains endothelial integrity. The aim of the present study was to evaluate the effect of phosphodiesterase-4 (PDE4) inhibition with rolipram on extracorporeal circulation-induced capillary leakage, microcirculatory dysfunction, and organ injury in rodents. Rats were randomly allocated to the following groups sham ( n = 5), venoarterial extracorporeal circulation [extracorporeal life support (ECLS), n = 7], ECLS + rolipram ( n = 7), extracorporeal resuscitation (ECPR; n = 7), and ECPR + rolipram ( n = 7). In the groups that underwent ECPR, ECLS-based cardiopulmonary resuscitation (ECPR) was performed after the induction of hypoxic cardiac arrest. Upon return of spontaneous circulation, rolipram was administered intravenously. The mesenteric microcirculation was studied using intravital microscopy, and organ specimens were harvested upon completion of the study. ECLS and ECPR induced a proinflammatory response (cytokines IL-1ß, IL-6, and TNF-α). Although PDE4 expression was upregulated in vascular tissue, PDE4 inhibition abrogated impaired microcirculation and capillary leak (albumin extravasation of the sham group 1 ± 0.03-fold, ECLS group 1.2 ± 0.05-fold, ECLS + rolipram group 0.99 ± 0.04-fold, ECPR group 1.6 ± 0.04-fold, and ECPR + rolipram group 1.06 ± 0.02-fold from the sham group, P < 0.05). PDE4 inhibition led to stabilization of vascular cAMP levels but did not affect cytokine levels. Capillary leak was reduced, as demonstrated by the decrease of the systemic biomarkers soluble vascular-endothelial cadherin and activated complement 3. Histological analysis revealed reduced injury to the lungs and kidneys after PDE4 inhibition, with a significant decrease in systemic renal damage markers. Our findings demonstrate that extracorporeal circulation causes an inflammatory reaction associated with decreased vascular cAMP levels, increased vascular permeability, and impaired microcirculation. PDE4 inhibition proved to be capable of reducing these side effects in ECLS and ECPR, leading to reduced microcirculatory, renal, and pulmonary injury. NEW & NOTEWORTHY Various complications are common after extracorporeal circulation. Among these, endothelial injury may cause impaired microcirculation and capillary leak. Here, we report that phosphodiesterase-4 inhibition targeting endothelial cAMP is capable of reducing microvascular complications in a rodent model of extracorporeal resuscitation. Microcirculation and vascular permeability are influenced without targeting extracorporeal circulation-induced inflammation. Thus, pulmonary and renal organ protection may be conferred.