title: Lipoxin A(4) analogues inhibit leukocyte recruitment to Porphyromonas gingivalis: a role for cyclooxygenase-2 and lipoxins in periodontal disease.
abstract: The potential involvement of the inducible cyclooxygenase isoform (COX-2) and the role of novel lipid mediators were investigated in the pathogenesis of periodontal disease. Crevicular fluids from localized juvenile periodontitis (LJP) patients contained prostaglandin (PG)E(2) and 5-lipoxygenase-derived products, leukotriene B(4), and the biosynthesis interaction product, lipoxin (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 responses of interest to periodontal pathogens, Porphyromonas gingivalis was introduced within murine dorsal air pouches. In the air pouch cavity, P. gingivalis elicited leukocyte infiltration, concomitant with elevated PGE(2) levels in the cellular exudates, and upregulated COX-2 expression in infiltrated leukocytes. In addition, human neutrophils exposed to P. gingivalis also upregulated COX-2 expression. Blood borne P. gingivalis gave significant increases in the murine tissue levels of COX-2 mRNA associated with both heart and lungs, supporting a potential role for this oral pathogen in the evolution of systemic events. The administration of metabolically stable analogues of LX and of aspirin-triggered LX potently blocked neutrophil traffic into the dorsal pouch cavity and lowered PGE(2) levels within exudates. Together, these results identify PMN as an additional and potentially important source of PGE(2) in periodontal tissues. Moreover, they provide evidence for a novel protective role for LX in periodontitis, limiting further PMN recruitment and PMN-mediated tissue injury that can lead to loss of inflammatory barriers that prevent systemic tissue invasion of oral microbial pathogens.
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: M
authors.initials: M
authors.lastname: Pouliot
authors.forename: C B
authors.initials: CB
authors.lastname: Clish
authors.forename: N A
authors.initials: NA
authors.lastname: Petasis
authors.forename: T E
authors.initials: TE
authors.lastname: Van Dyke
authors.forename: C N
authors.initials: CN
authors.lastname: Serhan
mesh_terms: D010520:Aggressive Periodontitis / Q000097:blood / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D016866:Bacteroidaceae Infections / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D004790:Enzyme Induction; D005883:Gingival Crevicular Fluid / Q000737:chemistry / Q000276:immunology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D007975:Leukotriene B4 / Q000378:metabolism; D044045:Lipoxins; D008168:Lung / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology; D016966:Porphyromonas gingivalis / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D007527:Isoenzymes; D044045:Lipoxins; D008565:Membrane Proteins; D012333:RNA, Messenger; C040527:lipoxin A4; D007975:Leukotriene B4; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D001241:Aspirin