title: Pseudomonas aeruginosa sabotages the generation of host proresolving lipid mediators.
abstract: Recurrent Pseudomonas aeruginosa infections coupled with robust, damaging neutrophilic inflammation characterize the chronic lung disease cystic fibrosis (CF). The proresolving lipid mediator, 15-epi lipoxin A4(15-epi LXA4), plays a critical role in limiting neutrophil activation and tissue inflammation, thus promoting the return to tissue homeostasis. Here, we show that a secreted P. aeruginosa epoxide hydrolase, cystic fibrosis transmembrane conductance regulator inhibitory factor (Cif), can disrupt 15-epi LXA4transcellular biosynthesis and function. In the airway, 15-epi LXA4production is stimulated by the epithelial-derived eicosanoid 14,15-epoxyeicosatrienoic acid (14,15-EET). Cif sabotages the production of 15-epi LXA4by rapidly hydrolyzing 14,15-EET into its cognate diol, eliminating a proresolving signal that potently suppresses IL-8-driven neutrophil transepithelial migration in vitro. Retrospective analyses of samples from patients with CF supported the translational relevance of these preclinical findings. Elevated levels of Cif in bronchoalveolar lavage fluid were correlated with lower levels of 15-epi LXA4, increased IL-8 concentrations, and impaired lung function. Together, these findings provide structural, biochemical, and immunological evidence that the bacterial epoxide hydrolase Cif disrupts resolution pathways during bacterial lung infections. The data also suggest that Cif contributes to sustained pulmonary inflammation and associated loss of lung function in patients with CF.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219.
authors.forename: Becca A
authors.initials: BA
authors.lastname: Flitter
authors.affiliation: Department of Biochemistry & Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Hvorecny
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Emiko
authors.initials: E
authors.lastname: Ono
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224.
authors.forename: Taylor
authors.initials: T
authors.lastname: Eddens
authors.affiliation: Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Kwak
authors.affiliation: Department of Biochemistry & Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Bahl
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hampton
authors.affiliation: Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616.
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.affiliation: Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213.
authors.forename: Janet S
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224.
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Levy
authors.affiliation: Department of Biochemistry & Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755; jbomb@pitt.edu drm0001@dartmouth.edu.
authors.forename: Dean R
authors.initials: DR
authors.lastname: Madden
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219; jbomb@pitt.edu drm0001@dartmouth.edu.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Bomberger
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D018360:Crystallography, X-Ray; D003550:Cystic Fibrosis / Q000382:microbiology / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced; D044045:Lipoxins / Q000378:metabolism*; D008171:Lung Diseases / Q000382:microbiology / Q000473:pathology; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D011552:Pseudomonas Infections / Q000382:microbiology / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000378:metabolism* / Q000472:pathogenicity; D012189:Retrospective Studies; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; C547935:Cif protein, Pseudomonas aeruginosa; D044045:Lipoxins; D037521:Virulence Factors; C040527:lipoxin A4; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid
keywords: Pseudomonas aeruginosa; cystic fibrosis; epoxide hydrolase; inflammation; lipoxin