Pulmonary epithelium is a prominent source of proteinase-activated receptor-1–inducible CCL2 in pulmonary fibrosis
PF Mercer, RH Johns, CJ Scotton… - American journal of …, 2009 - atsjournals.org
American journal of respiratory and critical care medicine, 2009•atsjournals.org
Rationale: Studies in patients and experimental animals provide compelling evidence of the
involvement of the major thrombin receptor, proteinase-activated receptor-1 (PAR1), and the
potent chemokine, chemokine (CC motif) ligand-2 (CCL2)/monocyte chemotactic protein-1,
in the pathogenesis of idiopathic pulmonary fibrosis (IPF). PAR1 knockout mice are
protected from bleomycin-induced lung inflammation and fibrosis and this protection is
associated with marked attenuation in CCL2 induction. Objectives: The aim of this study was …
involvement of the major thrombin receptor, proteinase-activated receptor-1 (PAR1), and the
potent chemokine, chemokine (CC motif) ligand-2 (CCL2)/monocyte chemotactic protein-1,
in the pathogenesis of idiopathic pulmonary fibrosis (IPF). PAR1 knockout mice are
protected from bleomycin-induced lung inflammation and fibrosis and this protection is
associated with marked attenuation in CCL2 induction. Objectives: The aim of this study was …
Rationale: Studies in patients and experimental animals provide compelling evidence of the involvement of the major thrombin receptor, proteinase-activated receptor-1 (PAR1), and the potent chemokine, chemokine (CC motif) ligand-2 (CCL2)/monocyte chemotactic protein-1, in the pathogenesis of idiopathic pulmonary fibrosis (IPF). PAR1 knockout mice are protected from bleomycin-induced lung inflammation and fibrosis and this protection is associated with marked attenuation in CCL2 induction.
Objectives: The aim of this study was to determine which cell types represent the major source of PAR1-inducible CCL2 in the fibrotic lung.
Methods: Using immunohistochemistry and dual immunofluorescence, we examined PAR1 and CCL2 expression in the bleomycin model and human IPF lung. PAR1 and CCL2 gene expression was also assessed in laser-captured alveolar septae from patients with IPF. The ability of PAR1 to induce CCL2 production by lung epithelial cells was also examined in vitro.
Measurements and Main Results: We report for the first time that PAR1 and CCL2 are coexpressed and co–up-regulated on the activated epithelium in fibrotic areas in IPF. Similar observations were found in bleomycin-induced lung injury. Furthermore, we show that thrombin is a potent inducer of CCL2 gene expression and protein release by cultured lung epithelial cells via a PAR1-dependent mechanism.
Conclusions: These data support the notion that PAR1 activation on lung epithelial cells may represent an important mechanism leading to increased local CCL2 release in pulmonary fibrosis. Targeting PAR1 on the pulmonary epithelium may offer a unique opportunity for therapeutic intervention in pulmonary fibrosis and other inflammatory and fibroproliferative conditions associated with excessive local generation of thrombin and CCL2 release.
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