Role of neutrophil elastase in hypersecretion in asthma.
Goblet cell (GC) hyperplasia and mucous plugging are common in patients with acute asthma. These patients also show neutrophil recruitment into the airways. Neutrophils contain elastase, a potent secretagogue in airways. Therefore, it was reasoned that neutrophil recruitment, by releasing elastase, could result in GC hypersecretion. When neutrophil chemoattractants were instilled in the airways of guinea-pigs, time-dependent neutrophil recruitment and GC degranulation occurred. An inhibitor of leukocyte infiltration (NPC15669) prevented both responses, implicating neutrophils. An inhibitor of neutrophil elastase (ICI 200,355) abolished GC degranulation, implicating elastase. Further studies implicate movement of elastase from cytoplasmic granules to the neutrophil surface, and they suggest a role for adhesion molecules on neutrophils and on GCs in neutrophil-dependent GC degranulation. Similarly, instillation of ovalbumin (OVA) into airways of OVA-sensitized guinea-pigs caused early recruitment of neutrophils and GC degranulation. GC degranulation was prevented by pretreatment with NPC15669 or ICI 200,355. These results implicate neutrophil release of elastase in allergen-induced hypersecretion. The results suggest a mechanism for the mucous plugging that occurs in acute asthma; prevention of neutrophil recruitment, prevention of neutrophil-GC adhesion, or inhibition of elastase activity could provide effective therapy for this serious pathophysiological abnormality.
Nadel
J A
JA
Cardiovascular Research Institute and Dept of Medicine, University of California, San Francisco 94143-0130, USA.
Takeyama
K
K
Agustí
C
C
D000818:Animals; D001249:Asthma / Q000201:enzymology / Q000503:physiopathology*; D015815:Cell Adhesion Molecules / Q000502:physiology; D015550:Cell Degranulation; D020397:Goblet Cells / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000494:pharmacology; D019272:Leukocyte Elastase / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010047:Ovalbumin / Q000494:pharmacology; D013552:Swine
D015815:Cell Adhesion Molecules; D016209:Interleukin-8; D009240:N-Formylmethionine Leucyl-Phenylalanine; D010047:Ovalbumin; D019272:Leukocyte Elastase