title: Defective innate immunity and hyperinflammation in newborn cystic fibrosis transmembrane conductance regulator-knockout ferret lungs.
abstract: Mucociliary clearance (MCC) and submucosal glands are major components of airway innate immunity that have impaired function in cystic fibrosis (CF). Although both of these defense systems develop postnatally in the ferret, the lungs of newborn ferrets remain sterile in the presence of a functioning cystic fibrosis transmembrane conductance regulator gene. We evaluated several components of airway innate immunity and inflammation in the early CF ferret lung. At birth, the rates of MCC did not differ between CF and non-CF animals, but the height of the airway surface liquid was significantly reduced in CF newborn ferrets. CF ferrets had impaired MCC after 7 days of age, despite normal rates of ciliogenesis. Only non-CF ferrets eradicated Pseudomonas directly introduced into the lung after birth, whereas both genotypes could eradicate Staphylococcus. CF bronchoalveolar lavage fluid (BALF) had significantly lower antimicrobial activity selectively against Pseudomonas than non-CF BALF, which was insensitive to changes in pH and bicarbonate. Liquid chromatography-tandem mass spectrometry and cytokine analysis of BALF from sterile Caesarean-sectioned and nonsterile naturally born animals demonstrated CF-associated disturbances in IL-8, TNF-α, and IL-β, and pathways that control immunity and inflammation, including the complement system, macrophage functions, mammalian target of rapamycin signaling, and eukaryotic initiation factor 2 signaling. Interestingly, during the birth transition, IL-8 was selectively induced in CF BALF, despite no genotypic difference in bacterial load shortly after birth. These results suggest that newborn CF ferrets have defects in both innate immunity and inflammatory signaling that may be important in the early onset and progression of lung disease in these animals.
authors.affiliation: 1 Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Keiser
authors.forename: Susan E
authors.initials: SE
authors.lastname: Birket
authors.forename: Idil A
authors.initials: IA
authors.lastname: Evans
authors.forename: Scott R
authors.initials: SR
authors.lastname: Tyler
authors.forename: Adrianne K
authors.initials: AK
authors.lastname: Crooke
authors.forename: Xingshen
authors.initials: X
authors.lastname: Sun
authors.forename: Weihong
authors.initials: W
authors.lastname: Zhou
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Nellis
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Stroebele
authors.forename: Kengyeh K
authors.initials: KK
authors.lastname: Chu
authors.forename: Guillermo J
authors.initials: GJ
authors.lastname: Tearney
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Stevens
authors.forename: J Kirk
authors.initials: JK
authors.lastname: Harris
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rowe
authors.forename: John F
authors.initials: JF
authors.lastname: Engelhardt
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003550:Cystic Fibrosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005289:Ferrets; D055786:Gene Knockout Techniques; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D009079:Mucociliary Clearance; D020543:Proteome / Q000378:metabolism; D011552:Pseudomonas Infections / Q000276:immunology / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000276:immunology; D014132:Trachea / Q000473:pathology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D020543:Proteome; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: animal model; cystic fibrosis; cystic fibrosis transmembrane conductance regulator; inflammation; innate immunity