Cytosolic Phospholipase Aα Promotes Pulmonary Inflammation and Systemic Disease during Streptococcus pneumoniae Infection.

Pulmonary infection by is characterized by a robust alveolar infiltration of neutrophils (polymorphonuclear cells [PMNs]) that can promote systemic spread of the infection if not resolved. We previously showed that 12-lipoxygenase (12-LOX), which is required to generate the PMN chemoattractant hepoxilin A (HXA) from arachidonic acid (AA), promotes acute pulmonary inflammation and systemic infection after lung challenge with As phospholipase A (PLA) promotes the release of AA, we investigated the role of PLA in local and systemic disease during infection. The group IVA cytosolic isoform of PLA (cPLAα) was activated upon infection of cultured lung epithelial cells and was critical for AA release from membrane phospholipids. Pharmacological inhibition of this enzyme blocked -induced PMN transepithelial migration Genetic ablation of the cPLA isoform cPLAα dramatically reduced lung inflammation in mice upon high-dose pulmonary challenge with The cPLAα-deficient mice also suffered no bacteremia and survived a pulmonary challenge that was lethal to wild-type mice. Our data suggest that cPLAα plays a crucial role in eliciting pulmonary inflammation during pneumococcal infection and is required for lethal systemic infection following lung challenge.