Aspirin Triggered Lipoxin A4 regulates NF-κB and induces antimicrobial peptides expression in airway epithelial cells to limit mucosal inflammation to enhance host response in pneumonia

Abstract Bacteria induced pneumonia remains a major global threat to health. Even with effective antibiotic treatment, the host response can be exuberant, resulting in tissue damage and morbidity. Resolution of inflammation is an active process governed in part by specialized pro-resolving mediators (SPMs). We hypothesized that the SPM, aspirin triggered lipoxin A4 (ATL) engaged airway mucosal epithelial cells to enhance resolution. In a murine model of bacterial aspiration pneumonia for E. coli, ATL (100 ng, iv) decreased the lung bacterial burden in an additive manner with ciprofloxacin (0.2 mg/kg, ip). Further, ATL also significantly limited neutrophils recruitment and decreased pro-inflammatory cytokine (IL-1α) and chemokine production (KC). These ATL mediated protective responses were mediated in part via regulation of NF-kB activation. In response to LPS and E. coli in vitro, ATL selectively influenced airway epithelial cells expression of NF-kB regulators A20, SIGIRR and ST2. In an in vitro bacteria killing assay by airway epithelial cells, ATL directly limited bacterial growth by increasing select antimicrobial peptides expression (LL37 and BPI). mCRAMP deficient mice (human homolog of LL37) failed to limit lung bacterial growth in E. coli pneumonia and ATL treatment was significantly less efficient in promoting host defense in these mice. In conclusion, the SPM ATL can limit pathogen mediated mucosal inflammation and enhance host defense in pneumonia via the selective regulation of NF-κB and antimicrobial peptides in airway epithelial cells. These findings with ATL provide evidence for SPM targeted treatment of the host response to pneumonia that has the potential for therapeutic benefit in combination with antibiotics.