Abstract 18456: Epsins Deficiency Protects Against LPS Induced Septic Shock

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Abstract

Introduction: Sepsis is caused by a deleterious host response to infection, which is primarily responsible for further injury of host tissue and cause of organ dysfunction. Despite significant progress, the pathophysiology of sepsis and the underlying regulatory mechanisms are still not fully understood. We have established that endothelial epsins play a pivotal role in mediating internalization and degradation of Thrombomodulin.

Hypothesis: Given that LPS triggers “cytokine storm” that causes hyper-permeability in the endothelium of lungs and excessive inflammation in the vital organs, we assessed the hypothesis that epsins play a prominent role in promoting endothelial permeability and augmenting endothelial activation and inflammation.

Methods and Results: Using innovative tissue-specific inducible epsins double knock out mice, we investigated the role for epsins during sepsis. We administered by intraperitoneal injection lethal dose of LPS into endothelial-specific inducible epsins double knock out mice, myeloid cell-specific epsins double knock out mice, and platelet-specific epsins double knock out mice. In each animal model, the sample size was larger than ten mice. We uncover a potent protective role for endothelial epsins deficiency against the development of LPS-induced sepsis, whereas deletion of epsins in myeloid cells offers 40% ~ 50% of protection, and loss of epsins in platelets exhibits little protection. We further show that endothelial epsin-deficiency upregulates Thrombomodulin surface protein level by preventing its internalization and degradation induced by LPS exposure. Given LPS challenge mimics chronic inflammatory conditions, we show endothelial epsin-deficiency downregulates LPS-induced proinflammatory cytokine production and suppresses endothelial hyper-permeability in the lungs assessed by tissue ELSA and Evans Blue perfusion, respectively.

Conclusions: Epsins depletion promotes septic shock resolution after LPS challenge by protecting Thrombomodulin against degradation, blocking proinflammatory cytokine production and inhibiting endothelial leakage in the lungs, highlighting the therapeutic potential for targeted inhibition of epsins in the endothelium as a treatment during sepsis.

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