This Article Full Text Full Text (PDF) All Versions of this Article: 200712-1827OCv1 200712-1827OCv2 179/5/414    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mercer, P. F. Articles by Chambers, R. C. Search for Related Content PubMed PubMed Citation Articles by Mercer, P. F. Articles by Chambers, R. C.

Pulmonary Epithelium Is a Prominent Source of Proteinase-activated Receptor-1–inducible CCL2 in Pulmonary Fibrosis

¹ Centre for Respiratory Research, University College London, London, United Kingdom; ² Justus Liebig University of Giessen, Giessen, Germany; ³ Centocor, Inc., Radnor, Pennsylvania; and ⁴ National Heart and Lung Institute, Imperial College London, London, United Kingdom

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

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.

Key Words: pulmonary fibrosis • IPF • epithelium • PAR • CCL2

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Studies in patients and experimental animals have provided 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 pulmonary fibrosis. What This Study Adds to the Field This study shows that PAR1 and CCL2 are coexpressed and co–up-regulated on the activated epithelium in idiopathic pulmonary fibrosis and the bleomycin model. PAR1 ligation-induces CCL2 release by cultured lung epithelial cells in vitro. These data implicate the pulmonary epithelium as an important source of PAR1-inducible CCL2 in idiopathic pulmonary fibrosis.