Human neutrophil peptides and phagocytic deficiency in bronchiectatic lungs.
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.
Voglis
Stefanos
S
The Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
Quinn
Kieran
K
Tullis
Elizabeth
E
Liu
Mingyao
M
Henriques
Melanie
M
Zubrinich
Celia
C
Peñuelas
Oscar
O
Chan
Holman
H
Silverman
Frances
F
Cherepanov
Vera
V
Orzech
Neil
N
Khine
Aye Aye
AA
Cantin
André
A
Slutsky
Arthur S
AS
Downey
Gregory P
GP
Zhang
Haibo
H
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*
D017452:Receptors, IgG; D023084:alpha-Defensins; D019272:Leukocyte Elastase