Pulmonary epithelium is a prominent source of proteinase-activated receptor-1-inducible CCL2 in pulmonary fibrosis.
BACKGROUND
Studies in patients and experimental animals provide compelling evidence of the involvement of the major thrombin receptor, proteinase-activated receptor-1 (PAR(1)), and the potent chemokine, chemokine (CC motif) ligand-2 (CCL2)/monocyte chemotactic protein-1, in the pathogenesis of idiopathic pulmonary fibrosis (IPF). PAR(1) knockout mice are protected from bleomycin-induced lung inflammation and fibrosis and this protection is associated with marked attenuation in CCL2 induction.


OBJECTIVE
The aim of this study was to determine which cell types represent the major source of PAR(1)-inducible CCL2 in the fibrotic lung.


METHODS
Using immunohistochemistry and dual immunofluorescence, we examined PAR(1) and CCL2 expression in the bleomycin model and human IPF lung. PAR(1) and CCL2 gene expression was also assessed in laser-captured alveolar septae from patients with IPF. The ability of PAR(1) to induce CCL2 production by lung epithelial cells was also examined in vitro.


RESULTS
We report for the first time that PAR(1) 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 PAR(1)-dependent mechanism.


CONCLUSIONS
These data support the notion that PAR(1) activation on lung epithelial cells may represent an important mechanism leading to increased local CCL2 release in pulmonary fibrosis. Targeting PAR(1) 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.
Mercer
Paul F
PF
Centre for Respiratory Research, University College London, London, United Kingdom.
Johns
Robin H
RH
Scotton
Chris J
CJ
Krupiczojc
Malvina A
MA
Königshoff
Melanie
M
Howell
David C J
DC
McAnulty
Robin J
RJ
Das
Anuk
A
Thorley
Andrew J
AJ
Tetley
Terry D
TD
Eickelberg
Oliver
O
Chambers
Rachel C
RC
D000595:Amino Acid Sequence; D000818:Animals; D001761:Bleomycin; D016022:Case-Control Studies; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D044463:Receptor, PAR-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology
D018932:Chemokine CCL2; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D054390:Receptors, CCR2; D001761:Bleomycin; D013917:Thrombin