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.