Agarose plug instillation causes goblet cell metaplasia by activating EGF receptors in rat airways.
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-alpha 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.
Lee
H M
HM
Cardiovascular Research Institute and Departments of Medicine and Physiology, University of California, San Francisco, California 94143-0130, USA.
Takeyama
K
K
Dabbagh
K
K
Lausier
J A
JA
Ueki
I F
IF
Nadel
J A
JA
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001991:Bronchitis / Q000473:pathology; D003520:Cyclophosphamide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000378:metabolism; D066246:ErbB Receptors / Q000502:physiology*; D005547:Foreign Bodies; D015870:Gene Expression / Q000187:drug effects; D020397:Goblet Cells / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008679:Metaplasia; D009077:Mucins / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D011916:Rats, Inbred F344; D012685:Sepharose; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D004791:Enzyme Inhibitors; D009077:Mucins; D014409:Tumor Necrosis Factor-alpha; D003520:Cyclophosphamide; D012685:Sepharose; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases