Neutrophils as therapeutic targets in abdominal sepsis

Sepsis is among the top 10 killers in the western world and rapid emergence of resistant bacteria endangers efficacy of antibiotics making new ways to treat infectious diseases urgent. Neutrophils are first responders in the host response to infection. Accumulation of neutrophils are mediated by specific adhesion molecules expressed on activated endothelial cells (EC).

Activated neutrophils can expel nuclear DNA containing specific proteins, which are referred to as neutrophil extracellular traps (NETs).

The main aim of this program is to define translational regulation of NET formation, mechanisms of NET-induced activation of EC and fibrin deposition in septic lungs. Moreover, intracellular regulation of adhesion molecule expression will by studied in isolated lung microvascular EC.

NET formation will be studied by electron microscopy and enzymatic assays will be used for quantification of thrombin generation.

Neutrophil-endothelial cell interactions in the septic lung microcirculation will be examined by use of intravital fluorescence microscopy.

Transcriptome analysis will be performed in sorted neutrophils undergoing NET formation and isolated lung EC from septic animals.

From this will specific microRNAs targets be identified and examined in septic animals by use of siRNA and gene-deficient mice.

This project will provide important and novel data about host responses to microbes and serve as a basis for the development of next generation therapeutics for septic patients.