Neutrophil-dependent goblet cell degranulation: role of membrane-bound elastase and adhesion molecules.
We examined the effect of the neutrophil chemoattractants interleukin (IL)-8 and N-formyl-methionyl-leucyl-phenylalanine on goblet cell (GC) degranulation in guinea pigs. Chemoattractants caused time-dependent neutrophil recruitment and GC degranulation in vivo. NPC 15669 (an inhibitor of leukocyte infiltration) prevented both responses, implicating neutrophils. ICI 200,355 (an inhibitor of neutrophil elastase and proteinase-3) or secretory leukocyte protease inhibitor (an inhibitor of elastase but not of proteinase-3) abolished IL-8-induced GC degranulation, implicating elastase. Incubating tracheal segments with IL-8 plus neutrophils caused GC degranulation in vitro, an effect due to activation of the neutrophils themselves (and not an effect present in the supernatant). Chemoattractant increased surface staining of elastase and the cleavage of elastase-specific fluorogenic substrate by neutrophils. Pretreatment with anti-intercellular adhesion molecule-1, anti-CD18, or anti-CD11b antibody inhibited the chemoattractant-induced GC degranulation in vitro, implicating adhesion molecules. These studies suggest that chemoattractants cause neutrophil-dependent GC degranulation involving adhesive interactions between cells, with elastase activity occurring at the cell interface, causing GC secretion. The findings, reproduced in human airways, suggest novel methods of therapeutic intervention.
Cardiovascular Research Institute and Departments of Medicine and Physiology, University of California, San Francisco, California 94143-0130, USA.
K
K
Takeyama
C
C
Agustí
I
I
Ueki
J
J
Lausier
L O
LO
Cardell
J A
JA
Nadel
D000818:Animals; D001980:Bronchi / Q000473:pathology / Q000503:physiopathology; D015815:Cell Adhesion Molecules / Q000502:physiology*; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000502:physiology*; D006168:Guinea Pigs; D006801:Humans; D016209:Interleukin-8 / Q000494:pharmacology; D019272:Leukocyte Elastase / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000502:physiology* / Q000503:physiopathology; D008297:Male; D009092:Mucous Membrane / Q000166:cytology / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology
D015815:Cell Adhesion Molecules; D016209:Interleukin-8; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; C069366:ICI 200355; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019272:Leukocyte Elastase