Caveolin-1 regulates leucocyte behaviour in fibrotic lung disease.
OBJECTIVE
Reduced caveolin-1 levels in lung fibroblasts from patients with scleroderma and the lungs of bleomycin-treated mice promote collagen overexpression and lung fibrosis. This study was undertaken to determine whether caveolin-1 is deficient in leucocytes from bleomycin-treated mice and patients with scleroderma and to examine the consequences of this deficiency and its reversal.


METHODS
Mice or cells received the caveolin-1 scaffolding domain (CSD) peptide to reverse the pathological effects of reduced caveolin-1 expression. In bleomycin-treated mice, the levels of caveolin-1 in leucocytes and the effect of CSD peptide on leucocyte accumulation in lung tissue were examined. To validate the results in human disease and to identify caveolin-1-regulated molecular mechanisms, monocytes and neutrophils were isolated from patients with scleroderma and control subjects and caveolin-1, extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), p38, CXC chemokine receptor 4 (CXCR4) and matrix metalloproteinase 9 (MMP-9) expression/activation were evaluated. These parameters were also studied in monocytes treated with cytokines or CSD peptide.


RESULTS
Leucocyte caveolin-1 is important in lung fibrosis. In bleomycin-treated mice, caveolin-1 expression was diminished in monocytes and CSD peptide inhibited leucocyte recruitment into the lungs. These observations are relevant to human disease. Monocytes and neutrophils from patients with scleroderma contained less caveolin-1 and more activated ERK, JNK and p38 than those from control subjects. Treatment with CSD peptide reversed ERK, JNK and p38 hyperactivation. Scleroderma monocytes also overexpressed CXCR4 and MMP-9, which was inhibited by the CSD peptide. Cytokine treatment of normal monocytes caused adoption of the scleroderma phenotype (low caveolin-1, high CXCR4 and MMP-9 and signalling molecule hyperactivation).


CONCLUSIONS
Caveolin-1 downregulation in leucocytes contributes to fibrotic lung disease, highlighting caveolin-1 as a promising therapeutic target in scleroderma.
Tourkina
Elena
E
Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 912 MSC 637, Charleston, SC 29425, USA. tourkine@musc.edu
Richard
Mathieu
M
Oates
James
J
Hofbauer
Ann
A
Bonner
Michael
M
Gööz
Pal
P
Visconti
Richard
R
Zhang
Jing
J
Znoyko
Sergei
S
Hatfield
Corey M
CM
Silver
Richard M
RM
Hoffman
Stanley
S
D000328:Adult; D000368:Aged; D000818:Animals; D001761:Bleomycin; D051242:Caveolin 1 / Q000097:blood / Q000172:deficiency / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D020556:Neutrophil Infiltration / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D055815:Young Adult
D051242:Caveolin 1; D010446:Peptide Fragments; D001761:Bleomycin
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