Lipoxin A(4) analogues inhibit leukocyte recruitment to Porphyromonas gingivalis: A role for cyclooxygenase-2 and lipoxins in periodontal disease

The potential involvement of the inducible cyclooxygenase isoform (COX-2) a nd the role of novel lipid mediators were investigated in the pathogenesis of periodontal disease. Crevicular fluids from localized juvenile periodont itis (LJP) patients contained prostaglandin (PG)E-2 and 5-lipoxygenase-deri ved products, leukotriene B-4, and the biosynthesis interaction product, li poxin (LX)A(4). Neutrophils from peripheral blood of LJP patients, but not from asymptomatic donors, also generated LXA(4), suggesting a role for this immunomodulatory molecule in periodontal disease. To characterize host res ponses of interest to periodontal pathogens, Porphyromonas gingivalis was i ntroduced within murine dorsal air pouches. In the air pouch cavity, P. gin givalis elicited leukocyte infiltration, concomitant with elevated PGE(2) l evels in the cellular exudates, and upregulated COX-2 expression in infiltr ated leukocytes. In addition, human neutrophils exposed to P, gingivalis al so upregulated COX-2 expression. Blood borne P. gingivalis gave significant increases in the murine tissue levels of COX-2 mRNA associated with both h eart and lungs, supporting a potential role for this oral pathogen in the e volution of systemic events. The administration of metabolically stable ana logues of LX and of aspirin-triggered LX potently blocked neutrophil traffi c into the dorsal pouch cavity and lowered PGE(2) levels within exudates. T ogether, these results identify PMN as an additional and potentially import ant source of PGE(2) in periodontal tissues. Moreover, they provide evidenc e for a novel protective role for LX in periodontitis, limiting further PMN recruitment and PMN-mediated tissue injury that can lead to loss of inflam matory barriers that prevent systemic tissue invasion of oral microbial pat hogens.