Endothelial cell responses in sepsis are attenuated by targeting truncated procalcitonin

TL;DR

Blocking truncated procalcitonin helps protect blood vessels and organs in sepsis by reducing inflammation and improving vascular function in mice.

Contribution

This study demonstrates that targeting truncated procalcitonin preserves endothelial function and reduces sepsis severity in mice.

Findings

Anti-procalcitonin antibodies reduced endothelial gene changes by over 50% in septic mice.

Neutralizing procalcitonin preserved vascular integrity and reduced organ injury in sepsis.

Procalcitonin neutralization decreased interleukin-17 signaling in septic mice.

Abstract

Sepsis is associated with hypotension, vascular leakage, vasoplegia and microvascular dysfunction. Therefore, the endothelium is a target for sepsis therapies. Since truncated procalcitonin exerts vascular activity, we here evaluated the efficacy of targeting procalcitonin for vascular integrity and sepsis outcomes. Sepsis up-regulated >2000 genes involved in pro-inflammatory responses while similar numbers of genes involving cell growth and maintenance were down-regulated. Transcriptomic changes in endothelial cells diminished by >50% by anti-procalcitonin antibodies and this was functionally associated with preserved vascular barrier integrity in lungs and intestines, reduced sepsis-induced vasoplegia, preserved endothelial nitric oxide bioavailability, improved organ integrity and reduced sepsis severity in mice. Mechanistically, procalcitonin neutralization was associated with reduced signaling of the interleukin-17 pathway. We here show sepsis induces substantial changes to the endothelial transcriptome and vascular integrity and neutralizing procalcitonin is a suitable means to preserve endothelial homeostasis at a transcriptomic and functional level that could translate into organ protection during sepsis.

Sepsis causes endothelial dysfunction that drives vascular failure and organ injury. Here the authors show that neutralizing truncated procalcitonin reduced pro-inflammatory activation and leakage in the endothelium, resulting in preserved organ integrity, improved clinical outcomes and predicted survival in septic mice.

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