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Absence of Proteinase-Activated Receptor-1 Signaling in Mice Confers Protection from fMLP-Induced Goblet Cell Metaplasia

Luigi Atzori^1,*, Monica Lucattelli^2,*, Chris J. Scotton³, Geoffrey J. Laurent³, Barbara Bartalesi², Giovanna De Cunto², Benedetta Lunghi², Rachel C. Chambers^3, and Giuseppe Lungarella^2,

¹ Department of Toxicology, University of Cagliari, Cagliari, Italy; ² Department of Physiopathology and Experimental Medicine, University of Siena, Siena, Italy; and ³ Centre for Respiratory Research, University College London, London, United Kingdom

Correspondence and requests for reprints should be addressed to Rachel C. Chambers, Ph.D., University College London, Rayne Institute, 5 University Street, London WC1E 6JJ, UK. E-mail: r.chambers{at}ucl.ac.uk

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 µg/50 µl). 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.

Key Words: goblet cell metaplasia • emphysema • proteinase-activated receptor-1 • IL-13 • epidermal growth factor receptor

CLINICAL RELEVANCE The mechanisms underlying excessive mucus production and, in particular, goblet cell hyperplasia/metaplasia in chronic obstructive pulmonary disease remain poorly understood. We show that proteinase-activated receptor (PAR)-1 signaling may play an important role in inducing goblet cell metaplasia in this model. PAR-1 may offer promise as a novel target for interfering with mucus hypersecretion.