Abstract
Neutrophilic infiltration is a leading contributor to pathology in a number of pulmonary disease states including acute bacterial pneumonia, cystic fibrosis, ARDS, as well as several others. Hepoxilin A3 (HXA3) is a chemotactic eicosanoid shown in vitro to mediate the transepithelial passage of neutrophils. Using a murine model of acute infection with Pseudomonas aeruginosa, we demonstrate HXA3 plays a significant role in transepithelial migration of neutrophils in vivo. Here we present data that modulation of HXA3 signaling during bacterial lung infection of mice significantly reduces neutrophil accumulation in the airspace. Using bronchoalveolar lavage, we measure the numbers of neutrophils and quantify lipid‐associated chemotactic bioactivity within the airspace. We target HXA3 through inhibition of the HXA3 biosynthetic pathway, enzymatic degradation of HXA3 chemotactic potential, and competitive inhibition. We conclude that modulation of HXA3 signaling represents a viable therapeutic target for the prevention of neutrophil infiltration and subsequent immunopathology.
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