title: Absence of proteinase-activated receptor-1 signaling in mice confers protection from fMLP-induced goblet cell metaplasia.
abstract: The morphological features of chronic obstructive pulmonary disease in man include emphysema and chronic bronchitis associated with mucus hypersecretion. These alterations can be induced in mice by a single intratracheal instillation of N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), a chemoattractant and degranulating agent for neutrophils. The mechanisms underlying excessive mucus production and, in particular, goblet cell hyperplasia/metaplasia in chronic obstructive pulmonary disease remain poorly understood. The proteinase-activated receptors (PARs) are widely recognized for their modulatory properties during inflammation. In this study, we examined whether PAR-1 contributes to inflammation and lung damage induced by fMLP by comparing the response of PAR-1-deficient (PAR-1(-/-)) mice with that of wild-type (WT) mice. Mice were killed at various time points after fMLP instillation (200 microg/50 microl). WT mice developed emphysema and goblet cell metaplasia. The onset of pulmonary lesions was preceded by an increase in thrombin immunoreactivity in bronchial airways and alveolar tissue. This was followed by a decrease in PAR-1 immunoreactivity, and by an increase in IL-13 immunostaining on the luminal surface of airway epithelial cells. In PAR-1(-/-) mice, fMLP administration induced similar responses in terms of inflammation and emphysema, but these mice were protected from the development of goblet cell metaplasia. The involvement of PAR-1 in airway epithelial cell transdifferentiation was confirmed by demonstrating that intratracheal instillation of the selective PAR-1 agonist (TFLLR) induced goblet cell metaplasia in the airways of WT mice only. These data suggest that emphysema and goblet cell metaplasia occur independently, and that PAR-1 signaling through IL-13 stimulation may play an important role in inducing goblet cell metaplasia.
authors.affiliation: Department of Toxicology, University of Cagliari, Cagliari, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Atzori
authors.forename: Monica
authors.initials: M
authors.lastname: Lucattelli
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Scotton
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Laurent
authors.forename: Barbara
authors.initials: B
authors.lastname: Bartalesi
authors.forename: Giovanna
authors.initials: G
authors.lastname: De Cunto
authors.forename: Benedetta
authors.initials: B
authors.lastname: Lunghi
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Chambers
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lungarella
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D004646:Emphysema / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism; D020397:Goblet Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000633:toxicity*; D009842:Oligopeptides / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology; D044463:Receptor, PAR-1 / Q000819:agonists / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction
chemical_list: D018793:Interleukin-13; D009842:Oligopeptides; C462999:PAR-1-activating peptide; D044463:Receptor, PAR-1; D009240:N-Formylmethionine Leucyl-Phenylalanine; D066246:ErbB Receptors