Eicosanoids are a group of bioactive
lipids that are shown to be important mediators of neutrophilic
inflammation; selective targeting of their function confers therapeutic benefit in a number of diseases. Neutrophilic airway diseases, including
cystic fibrosis, are characterized by excessive neutrophil infiltration into the airspace. Understanding the role of
eicosanoids in this process may reveal novel therapeutic targets. The
eicosanoid hepoxilin A3 is a pathogen-elicited epithelial-produced neutrophil
chemoattractant that directs transepithelial migration in response to
infection. Following hepoxilin A3-driven transepithelial migration, neutrophil chemotaxis is amplified through neutrophil production of a second
eicosanoid,
leukotriene B4 (
LTB4). The rate-limiting step of
eicosanoid generation is the liberation of
arachidonic acid by
phospholipase A2, and the cytosolic
phospholipase A2 (cPLA2)α
isoform has been specifically shown to direct
LTB4 synthesis in certain contexts. Whether cPLA2α is directly responsible for neutrophil synthesis of
LTB4 in the context of Pseudomonas aeruginosa-induced neutrophil transepithelial migration has not been explored. Human and mouse neutrophil-epithelial cocultures were used to evaluate the role of neutrophil-derived cPLA2α in
infection-induced transepithelial signaling by pharmacological and genetic approaches. Primary human airway basal stem cell-derived epithelial cultures and micro-optical coherence tomography, a new imaging modality that captures two- and three-dimensional real-time dynamics of neutrophil transepithelial migration, were applied. Evidence from these studies suggests that cPLA2α expressed by neutrophils, but not epithelial cells, plays a significant role in
infection-induced neutrophil transepithelial migration by mediating
LTB4 synthesis during migration, which serves to amplify the magnitude of neutrophil recruitment in response to epithelial
infection.