title: Human neutrophil peptides and phagocytic deficiency in bronchiectatic lungs.
abstract: BACKGROUND
  A well-known clinical paradox is that severe bacterial infections persist in the lungs of patients with cystic fibrosis (CF) despite the abundance of polymorphonuclear neutrophils (PMN) and the presence of a high concentration of human neutrophil peptides (HNP), both of which are expected to kill the bacteria but fail to do so. The mechanisms remain unknown.
  
  
  OBJECTIVE
  This study examined several possible mechanisms to understand this paradox.
  
  
  METHODS
  PMN were isolated from sputum and blood of subjects with and without CF or non-CF bronchiectasis for phagocytic assays. HNP isolated from patients with CF were used to stimulate healthy PMN followed by phagocytic tests.
  
  
  RESULTS
  PMN isolated from the sputum of the bronchiectatic patients display defective phagocytosis that correlated with high concentrations of HNP in the lung. When healthy PMN were incubated with HNP, decreased phagocytic capacity was observed in association with depressed surface Fc gamma RIII, actin-filament remodeling, enhanced intracellular Ca(2+), and degranulation. Treatment of PMN with an intracellular Ca(2+) blocker or alpha1-proteinase inhibitor to attenuate the activity of HNP largely prevented the HNP-induced phagocytic deficiency. Intratracheal instillation of HNP in Pallid mice (genetically deficient in alpha1-proteinase inhibitor) resulted in a greater PMN lung infiltration and phagocytic deficiency compared with wild-type mice.
  
  
  CONCLUSIONS
  HNP or PMN alone exert antimicrobial ability, which was lost as a result of their interaction. These effects of HNP may help explain the clinical paradox seen in patients with inflammatory lung diseases, suggesting HNP as a novel target for clinical therapy.
authors.affiliation: The Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Stefanos
authors.initials: S
authors.lastname: Voglis
authors.forename: Kieran
authors.initials: K
authors.lastname: Quinn
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tullis
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Melanie
authors.initials: M
authors.lastname: Henriques
authors.forename: Celia
authors.initials: C
authors.lastname: Zubrinich
authors.forename: Oscar
authors.initials: O
authors.lastname: Peñuelas
authors.forename: Holman
authors.initials: H
authors.lastname: Chan
authors.forename: Frances
authors.initials: F
authors.lastname: Silverman
authors.forename: Vera
authors.initials: V
authors.lastname: Cherepanov
authors.forename: Neil
authors.initials: N
authors.lastname: Orzech
authors.forename: Aye Aye
authors.initials: AA
authors.lastname: Khine
authors.forename: André
authors.initials: A
authors.lastname: Cantin
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Slutsky
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Downey
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001987:Bronchiectasis / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D016022:Case-Control Studies; D018929:Cell Culture Techniques; D003550:Cystic Fibrosis / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D020556:Neutrophil Infiltration / Q000502:physiology; D009504:Neutrophils / Q000502:physiology*; D010587:Phagocytosis / Q000502:physiology*; D017452:Receptors, IgG / Q000378:metabolism; D055815:Young Adult; D023084:alpha-Defensins / Q000378:metabolism*
chemical_list: D017452:Receptors, IgG; D023084:alpha-Defensins; D019272:Leukocyte Elastase