Abstract
Sepsis is a life-threatening condition caused by dysregulated host responses to infection. Widespread vascular hyperpermeability and a “cytokine storm” are two pathophysiological hallmarks of sepsis. Here, we show that intermedin (IMD), a member of the calcitonin family, alleviates organ injury and decreases mortality in septic mice by concurrently alleviating vascular leakage and inflammatory responses. IMD promotes the relocation of vascular endothelial cadherin through a Rab11-dependent pathway to dynamically repair the disrupted endothelial junction. Additionally, IMD decreases inflammatory responses by reducing macrophage infiltration via downregulating CCR2 expression. IMD peptide administration ameliorates organ injuries and significantly improves the survival of septic mice, and the experimental results correlate with the clinical data. Patients with high IMD levels exhibit a lower risk of shock, lower severity scores, and greatly improved survival outcomes than those with low IMD levels. Based on our data, IMD may be an important self-protective factor in response to sepsis.
Highlights
Sepsis is a life-threatening condition caused by dysregulated host responses to infection
Sepsis is a clinical syndrome occurring in patients following infection or injury, which is linked to multi-organ dysfunction and inadequate tissue perfusion in many cases, and is the major cause of death in intensive care units, with an associated mortality rate ranging from 30 to 70%1–3
Strategies designed to repair the VEC complex at endothelial cell–cell contacts may resolve the vascular leakage and provide patients with sepsis the opportunity to recover from organ dysfunction caused by oedema and inadequate tissue perfusion
Summary
Sepsis is a life-threatening condition caused by dysregulated host responses to infection. We show that intermedin (IMD), a member of the calcitonin family, alleviates organ injury and decreases mortality in septic mice by concurrently alleviating vascular leakage and inflammatory responses. Strategies designed to repair the VEC complex at endothelial cell–cell contacts may resolve the vascular leakage and provide patients with sepsis the opportunity to recover from organ dysfunction caused by oedema and inadequate tissue perfusion. We aim to explore whether IMD expression is altered during sepsis, whether IMD alleviates the widespread vascular leakage and protects against the cytokine storm and the inflammatory mediators-induced endothelial barrier dysfunction, and whether the administration of IMD peptide is beneficial for the survival of septic mice. Our study may provide novel insights that improve our understanding of the mechanism of endothelial barrier stabilization and inflammatory response regulation during sepsis
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