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Cardiovascular Research Institute and Departments of Medicine and Physiology, University of California San Francisco, San Francisco, California 94143-0130
Neutrophil products are
implicated in hypersecretory airway diseases. To determine the
mechanisms linking a proteolytic effect of human neutrophil elastase
(HNE) and mucin overproduction, we examined the effects of HNE on
MUC5AC mucin production in human airway epithelial (NCI-H292) cells.
Stimulation with HNE for 5-30 min induced MUC5AC production
24 h later, which was prevented by HNE serine active site
inhibitors, implicating a proteolytic effect of HNE. MUC5AC induction
was preceded by epidermal growth factor receptor (EGFR) tyrosine
phosphorylation and was prevented by selective EGFR tyrosine kinase
inhibitors, implicating EGFR activation. HNE-induced MUC5AC production
was inhibited by a neutralizing transforming growth factor-
(TGF-, an EGFR ligand) antibody and by a neutralizing EGFR antibody
but not by oxygen free radical scavengers, further implicating TGF-
and ligand-dependent EGFR activation in the response. HNE decreased
pro-TGF- in NCI-H292 cells and increased TGF- in cell culture
supernatant. From these results, we conclude that HNE-induced MUC5AC
mucin production occurs via its proteolytic activation of an EGFR
signaling cascade involving TGF-.
human airway epithelium; neutrophils; epithelial differentiation; MUC5AC; transforming growth factor-
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