The hallmark of pneumonia caused by Streptococcus pneumoniae (pneumococcus) is massive recruitment of polymorphonuclear cells (PMNs) from the circulation into lung alveolar spaces, causing considerable tissue damage. Moreover, pneumococcal translocation across lung epithelium into blood can lead to potentially lethal septicemia. The PMN influx caused by the bacterial insult, might lead to the disruption of the barrier function of the respiratory epithelium, thus contributing to the transepithelial migration of S. pneumoniae into the bloodstream. Our results show that S. pneumoniae triggered PMN migration from basolateral to apical side of polarized monolayers of lung epithelial cell line H292, and this PMN migration was associated with elevated levels of bacterial migration in the reverse direction. HPLC/MS studies of infected H292 culture supernatants showed increased levels of hepoxilin A3 (HXA3), a 12-LOX-derived eicosanoid that can act as a PMN chemoattractant. Administration of a 12-LOX inhibitor significantly reduced both pneumococcus-induced PMN migration and translocation of bacteria itself. Interestingly, 12-LOX knockout mice, or wild type mice treated with a 12-LOX inhibitor, showed diminished lung inflammation and bacteremia, and showed 100% survival in an otherwise lethal lung challenge. Our results indicate that during S. pneumoniae lung infection, HXA3 plays important roles in both pulmonary inflammation and bacterial invasion of the bloodstream.
- Copyright © 2011 by The American Association of Immunologists, Inc.