title: Pseudomonas aeruginosa exotoxin pyocyanin causes cystic fibrosis airway pathogenesis.
abstract: The cystic fibrosis (CF) airway bacterial pathogen Pseudomonas aeruginosa secretes multiple virulence factors. Among these, the redox active exotoxin pyocyanin (PCN) is produced in concentrations up to 100 mumol/L during infection of CF and other bronchiectatic airways. However, the contributions of PCN during infection of bronchiectatic airways are not appreciated. In this study, we demonstrate that PCN is critical for chronic infection in mouse airways and orchestrates adaptive immune responses that mediate lung damage. Wild-type FVBN mice chronically exposed to PCN developed goblet cell hyperplasia and metaplasia, airway fibrosis, and alveolar airspace destruction. Furthermore, after 12 weeks of exposure to PCN, mouse lungs down-regulated the expression of T helper (Th) type 1 cytokines and polarized toward a Th2 response. Cellular analyses indicated that chronic exposure to PCN profoundly increased the lung population of recruited macrophages, CD4(+) T cells, and neutrophils responsible for the secretion of these cytokines. PCN-mediated goblet cell hyperplasia and metaplasia required Th2 cytokine signaling through the Stat6 pathway. In summary, this study establishes that PCN is an important P. aeruginosa virulence factor capable of directly inducing pulmonary pathophysiology in mice, consistent with changes observed in CF and other bronchiectasis lungs.
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Caldwell
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Holly S
authors.initials: HS
authors.lastname: Goetzmann
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Hao
authors.forename: Michael T
authors.initials: MT
authors.lastname: Borchers
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hassett
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Young
authors.forename: Dmitri
authors.initials: D
authors.lastname: Mavrodi
authors.forename: Linda
authors.initials: L
authors.lastname: Thomashow
authors.forename: Gee W
authors.initials: GW
authors.lastname: Lau
mesh_terms: D000818:Animals; D003550:Cystic Fibrosis / Q000276:immunology / Q000382:microbiology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D020397:Goblet Cells / Q000473:pathology; D006965:Hyperplasia; D007150:Immunohistochemistry; D051379:Mice; D011552:Pseudomonas Infections / Q000150:complications* / Q000276:immunology / Q000473:pathology; D011550:Pseudomonas aeruginosa; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D011710:Pyocyanine / Q000633:toxicity*; D012141:Respiratory Tract Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D037521:Virulence Factors / Q000633:toxicity
chemical_list: D016207:Cytokines; D037521:Virulence Factors; D011710:Pyocyanine