Abstract 4368327: Targeting PDE4B (Phosphodiesterase-4 Subtype B) alleviates sepsis-induced multiple organ dysfunction via inhibiting endothelial cells pyroptosis

Abstract

Introduction: Sepsis, a leading cause of mortality and critical illness globally, is a life-threatening condition due to dysregulated host immune response to infection, which may lead to multiple organ dysfunction. We previously reported that depletion of PDE4B, ameliorated myocardial ischemia-reperfusion injury, revealing a pivotal role of PDE4B in sterile inflammation. This study aimed to elucidate the role of PDE4B in sepsis. Approaches: PDE4B global knock-out (PDE4B -/- ), endothelial cell-specific (PDE4B EC-/- ) and myeloid cell-specific (PDE4B LYZ-/- ) PDE4B knock-out male mice and their littermate controls were induced to develop sepsis following cecal ligation and puncture (CLP) surgery. Animal survival was recorded for 7 days after CLP. Early pathological changes were assessed at 12h-post CLP by determining vascular permeability, echocardiography, plasma level of markers for liver and kidney injury (ALT, AST, CREA and BUN). Microcirculation was detected by laser Doppler flowmetry. Histology staining was performed on lung sections and lipopolysaccharide transfected isolated lung endothelial cells were used to delineate the mechanism of pyroptosis. Results: Deletion of PDE4B significantly improved the survival rate of septic mice (73% versus 31%). Meanwhile, PDE4B deletion markedly reduced organ injury, including reduced lung vascular permeability and myeloid cell infiltration, improved function of heart (LVEF: 40.2±6.0% versus 75.2±5.0%), liver and kidney, and increased hindlimb blood perfusion (48.46±9.08 versus 90.41±5.86). Strikingly, deficiency of endothelial cell (but not myeloid cell)-PDE4B protected against sepsis to an extent similar to global PDE4B knock-out (survival rate: PDE4B EC-/- 70% versus PDE4B LYZ-/- 30%). Mechanismly, sepsis induced extensive pyroptosis in lung tissue and PDE4B deletion essentially abolished the activation of gasdermin-D, the key executor of pyroptosis. Further in vitro study showed that PDE4B played a critical role in endothelial cells pyroptosis, in both transcription dependent and in-dependent manner. Conclusions: Endothelial cell PDE4B promotes pyroptosis, critically involving in sepsis induced multiple organ dysfunction. Selective inhibition of PDE4B represent a promising approch to sepsis treatment.