Defective Innate Immunity and Hyperinflammation in Newborn Cystic Fibrosis Transmembrane Conductance Regulator–Knockout Ferret Lungs

Nicholas W Keiser; Susan E Birket; Idil A Evans; Scott R Tyler; Adrianne K Crooke; Xingshen Sun; Weihong Zhou; Joseph R Nellis; Elizabeth K Stroebele; Kengyeh K Chu; Guillermo J Tearney; Mark J Stevens; J. Kirk Harris; Steven M Rowe; John F Engelhardt

doi:10.1165/rcmb.2014-0250OC

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Defective Innate Immunity and Hyperinflammation in Newborn Cystic Fibrosis Transmembrane Conductance Regulator–Knockout Ferret Lungs

Journal article

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Defective Innate Immunity and Hyperinflammation in Newborn Cystic Fibrosis Transmembrane Conductance Regulator–Knockout Ferret Lungs

Nicholas W Keiser, Susan E Birket, Idil A Evans, Scott R Tyler, Adrianne K Crooke, Xingshen Sun, Weihong Zhou, Joseph R Nellis, Elizabeth K Stroebele, Kengyeh K Chu, …

American journal of respiratory cell and molecular biology, Vol.52(6), pp.683-694

06/2015

DOI: 10.1165/rcmb.2014-0250OC

PMCID: PMC4491130

PMID: 25317669

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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.

Inflammation

Cystic Fibrosis

cystic fibrosis transmembrane conductance regulator

innate immunity

animal model

Original Research

Details

Title: Subtitle: Defective Innate Immunity and Hyperinflammation in Newborn Cystic Fibrosis Transmembrane Conductance Regulator–Knockout Ferret Lungs
Creators: Nicholas W Keiser - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa
Susan E Birket - Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
Idil A Evans - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa
Scott R Tyler - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa
Adrianne K Crooke - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa
Xingshen Sun - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa
Weihong Zhou - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa
Joseph R Nellis - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa
Elizabeth K Stroebele - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa
Kengyeh K Chu - Harvard Medical School, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts; and
Guillermo J Tearney - Harvard Medical School, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts; and
Mark J Stevens - Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado
J. Kirk Harris - Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado
Steven M Rowe - Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
John F Engelhardt - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa
Resource Type: Journal article
Publication Details: American journal of respiratory cell and molecular biology, Vol.52(6), pp.683-694
DOI: 10.1165/rcmb.2014-0250OC
PMID: 25317669
PMCID: PMC4491130
NLM abbreviation: Am J Respir Cell Mol Biol
ISSN: 1044-1549
eISSN: 1535-4989
Publisher: American Thoracic Society
Language: English
Date published: 06/2015
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
Record Identifier: 9984025336702771

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