The morphological features of chronic obstructive pulmonary disease (COPD) 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 COPD 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 sacrificed at various time points after fMLP instillation (200μg/50μl). WT mice developed emphysema and goblet cell metaplasia (GCM). 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 of IL-13 expression 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 GCM. The involvement of PAR-1 in airway epithelial cell transdifferentiation was confirmed by demonstrating that intratracheal instillation of a selective PAR-1 agonist (TFLLR) also induced GCM in the airways of WT mice. These data suggest that emphysema and GCM occur independently, and that PAR-1 signaling through IL-13 stimulation may play an important role in inducing GCM.
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|Titolo:||Absence of proteinase-activated receptor-1 signaling in mice confers protection from fMLP-induced goblet cell metaplasia.|
|Citazione:||Atzori, L., Lucattelli, M., Scotton, C.J., Laurent, G.J., Bartalesi, B., DE CUNTO, G., et al. (2009). Absence of proteinase-activated receptor-1 signaling in mice confers protection from fMLP-induced goblet cell metaplasia. AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 41(6), 680-687.|
|Appare nelle tipologie:||1.1 Articolo in rivista|