title: Hypoxic epithelial necrosis triggers neutrophilic inflammation via IL-1 receptor signaling in cystic fibrosis lung disease.
abstract: BACKGROUND
  In many organs, hypoxic cell death triggers sterile neutrophilic inflammation via IL-1R signaling. Although hypoxia is common in airways from patients with cystic fibrosis (CF), its role in neutrophilic inflammation remains unknown. We recently demonstrated that hypoxic epithelial necrosis caused by airway mucus obstruction precedes neutrophilic inflammation in Scnn1b-transgenic (Scnn1b-Tg) mice with CF-like lung disease.
  
  
  OBJECTIVE
  To determine the role of epithelial necrosis and IL-1R signaling in the development of neutrophilic airway inflammation, mucus obstruction, and structural lung damage in CF lung disease.
  
  
  METHODS
  We used genetic deletion and pharmacologic inhibition of IL-1R in Scnn1b-Tg mice and determined effects on airway epithelial necrosis; levels of IL-1α, keratinocyte chemoattractant, and neutrophils in bronchoalveolar lavage; and mortality, mucus obstruction, and structural lung damage. Furthermore, we analyzed lung tissues from 21 patients with CF and chronic obstructive pulmonary disease and 19 control subjects for the presence of epithelial necrosis.
  
  
  RESULTS
  Lack of IL-1R had no effect on epithelial necrosis and elevated IL-1α, but abrogated airway neutrophilia and reduced mortality, mucus obstruction, and emphysema in Scnn1b-Tg mice. Treatment of adult Scnn1b-Tg mice with the IL-1R antagonist anakinra had protective effects on neutrophilic inflammation and emphysema. Numbers of necrotic airway epithelial cells were elevated and correlated with mucus obstruction in patients with CF and chronic obstructive pulmonary disease.
  
  
  CONCLUSIONS
  Our results support an important role of hypoxic epithelial necrosis in the pathogenesis of neutrophilic inflammation independent of bacterial infection and suggest IL-1R as a novel target for antiinflammatory therapy in CF and potentially other mucoobstructive airway diseases.
authors.affiliation: 1 Department of Translational Pulmonology and.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Fritzsching
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhou-Suckow
authors.forename: Joanna B
authors.initials: JB
authors.lastname: Trojanek
authors.forename: Susanne C
authors.initials: SC
authors.lastname: Schubert
authors.forename: Jolanthe
authors.initials: J
authors.lastname: Schatterny
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hirtz
authors.forename: Raman
authors.initials: R
authors.lastname: Agrawal
authors.forename: Thomas
authors.initials: T
authors.lastname: Muley
authors.forename: Nicolas
authors.initials: N
authors.lastname: Kahn
authors.forename: Carsten
authors.initials: C
authors.lastname: Sticht
authors.forename: Nikolas
authors.initials: N
authors.lastname: Gunkel
authors.forename: Tobias
authors.initials: T
authors.lastname: Welte
authors.forename: Scott H
authors.initials: SH
authors.lastname: Randell
authors.forename: Florian
authors.initials: F
authors.lastname: Länger
authors.forename: Philipp
authors.initials: P
authors.lastname: Schnabel
authors.forename: Felix J F
authors.initials: FJ
authors.lastname: Herth
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Mall
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D003550:Cystic Fibrosis / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004848:Epithelium / Q000473:pathology*; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000473:pathology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis / Q000379:methods; D008875:Middle Aged; D009336:Necrosis; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D017472:Receptors, Interleukin-1
keywords: airway epithelium; airway inflammation; chronic obstructive pulmonary disease; cystic fibrosis; mucus obstruction