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Cardiovascular Research Institute and Departments of Medicine and Physiology, University of California, San Francisco, California 94143-0130
We hypothesized
that foreign bodies in airways cause inflammation leading to goblet
cell metaplasia. Instilled agarose plugs lodged in the bronchi of
pathogen-free rats caused a time-dependent increase in Alcian
blue-periodic acid-Schiff staining that was detected within 24 h and
markedly increased at 72 h. Control bronchi contained no pregoblet or
goblet cells, but plugged bronchi contained many pregoblet and goblet
cells and a decrease in nongranulated secretory cells. In situ
hybridization showed no expression of MUC5AC in control airways, but
plugged airways showed a marked expression. Control bronchi showed
sparse staining for epidermal growth factor receptor (EGFR) protein,
but plugged bronchi showed intense EGFR staining in the epithelium.
Pretreatment with an EGFR tyrosine kinase inhibitor (BIBX1522)
prevented Alcian blue-periodic acid-Schiff staining and
MUC5AC gene expression in plugged bronchi. Pretreatment with tumor necrosis factor-
neutralizing antibody or
pretreatment with cyclophosphamide abolished plug-induced EGFR protein
expression and goblet cell metaplasia. Thus instillation of agarose
plugs induces profound goblet cell metaplasia by causing EGFR
expression and activation.
epidermal growth factor receptor; tyrosine kinase; MUC5AC
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