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Is CF airway inflammation still relevant in the era of highly effective modulators?

  • Charles D. Bengtson
    Affiliations
    Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
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  • Michael D. Kim
    Affiliations
    Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
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  • Matthias Salathe
    Correspondence
    Corresponding author at: Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd., 4032 Delp, MS 1022, Kansas City, KS 66160, USA.
    Affiliations
    Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Published:August 24, 2022DOI:https://doi.org/10.1016/j.jcf.2022.08.013
      Historically, airway inflammation has been recognized to play a key role in the pathogenesis of pulmonary disease progression in cystic fibrosis (CF). Inflammatory markers are elevated in the airways of children with CF as well as CF ferret models even before chronic airway infections take hold [
      • Sly PD
      • Brennan S
      • Gangell C
      • de Klerk N
      • Murray C
      • Mott L
      • et al.
      Lung disease at diagnosis in infants with cystic fibrosis detected by newborn screening.
      ,
      • Sly PD
      • Gangell CL
      • Chen L
      • Ware RS
      • Ranganathan S
      • Mott LS
      • et al.
      Risk factors for bronchiectasis in children with cystic fibrosis.
      ,
      • Khan TZ
      • Wagener JS
      • Bost T
      • Martinez J
      • Accurso FJ
      • Riches DW
      Early pulmonary inflammation in infants with cystic fibrosis.
      ,
      • Balough K
      • McCubbin M
      • Weinberger M
      • Smits W
      • Ahrens R
      • Fick R.
      The relationship between infection and inflammation in the early stages of lung disease from cystic fibrosis.
      ,
      • Keiser NW
      • Birket SE
      • Evans IA
      • Tyler SR
      • Crooke AK
      • Sun X
      • et al.
      Defective innate immunity and hyperinflammation in newborn cystic fibrosis transmembrane conductance regulator-knockout ferret lungs.
      ,
      • Rosen BH
      • Evans TIA
      • Moll SR
      • Gray JS
      • Liang B
      • Sun X
      • et al.
      Infection Is Not Required for Mucoinflammatory Lung Disease in CFTR-Knockout Ferrets.
      ], though the lungs of newborn CF pigs show no signs of inflammation [
      • Stoltz DA
      • Meyerholz DK
      • Pezzulo AA
      • Ramachandran S
      • Rogan MP
      • Davis GJ
      • et al.
      Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth.
      ]. Importantly, levels of inflammatory markers are predictive of future pulmonary exacerbations and even structural lung damage [
      • Sly PD
      • Brennan S
      • Gangell C
      • de Klerk N
      • Murray C
      • Mott L
      • et al.
      Lung disease at diagnosis in infants with cystic fibrosis detected by newborn screening.
      ,
      • Sly PD
      • Gangell CL
      • Chen L
      • Ware RS
      • Ranganathan S
      • Mott LS
      • et al.
      Risk factors for bronchiectasis in children with cystic fibrosis.
      ]. In addition, there is an abnormal immune response, possibly mediated directly by dysfunctional CF transmembrane conductance regulator (CFTR) on inflammatory cells, that hinders bacterial clearance and further propagates the cycle of inflammation [
      • Lara-Reyna S
      • Holbrook J
      • Jarosz-Griffiths HH
      • Peckham D
      • McDermott MF.
      Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations.
      ].
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