Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Normal Monocyte and Fibrocyte Behavior in Scleroderma Is Restored by Caveolin-1 Scaffolding Domain (CSD) Peptide: Implications for Treating Scleroderma Lung Disease.
Tourkina, Elena, Oates, James, Hofbauer, Ann, Bonner, Michael, Visconti, Richard P., Zhang, Jing, Silver, Richard M.
Scleroderma (systemic sclerosis, SSc) is a complex autoimmune disease characterized by inflammation and fibrosis of the skin, lungs and other organs. Despite the accepted importance of the contribution of monocyte-derived fibrocytes in the development of lung fibrosis, their role in scleroderma is not clear. The aim of this study was to investigate the role of caveolin-1 on monocyte and fibrocyte migration into injured lung tissue in scleroderma and in the animal model of bleomycin-induced lung fibrosis.
Normal lung tissue was obtained from the Brain and Tissue Bank of Developmental Disorders; Scleroderma lung tissue was obtained from autopsy of patients at the Medical University of South Carolina (MUSC). The study was approved by MUSC's IRB for Human Subject Research. Monocytes (PBM) were isolated from blood of scleroderma and healthy donors using negative selection. Scleroderma patients fulfilled the preliminary ACR criteria for the classification of systemic sclerosis. Monocyte migration was assayed in Multiwell Chemotaxis Chambers, with or without priming with TGFb and with or without treatment with caveolin-1 scaffolding domain (CSD) peptide and control peptides. Fibrocytes in human peripheral blood and mouse lungs were detected by flow cytometry. Protocols for bleomycin-induced lung injury and CSD peptide treatment were approved by MUSC's Institutional Animal Care & Use Committee. Ten-week old, male CD1 mice received daily i.p. injections of CSD or control peptide throughout the entire experiment from the day prior to bleomycin treatment until the day of sacrifice. Mice were treated intra-orally with bleomycin or PBS vehicle. Seven days after bleomycin treatment, lungs were removed and analyzed.
Fibrocytes were observed in lung tissue of scleroderma patients (n=7), but not healthy control subjects (n=4). Upregulation of fibrocytes (CD45+/Col+, CD45+/CXCR4+, and CD45+/CXCR4+/Col+) was observed in the peripheral blood of scleroderma patients (n=7) compared to healthy control subjects (n=9): 2.5 ± 0.3 % vs 1.0 ± 0.07 %; 3.0 ± 0.5 % vs 1.0 ± 0.08 %; and 0.74 ± 0.09 vs 0.4 ± 0.08 %, respectively. Scleroderma PBM also differed from control PBM in signaling and in function. On average, SSc PBM contained less than half as much caveolin-1 and three-fold more CXCR4 compared to normal PBM. The percentage of scleroderma PBM that migrated in response to the CXCR-4 ligand, CXCL12, was more than four-fold enhanced compared to normal PBM. When scleroderma PBM were treated with the CSD peptide to overcome their diminished expression of caveolin-1, CXCR4 expression and migration in response to CXCL12 were inhibited by at least 80%. Similar results were obtained in vivo in a mouse model. CSD peptide inhibited bleomycin-induced recruitment of CD45/CXCR4/Col-positive cells into injured mouse lung tissue by > 50 %.
Our results support the notion that using the CSD peptide to compensate for low caveolin-1 levels may be a useful treatment strategy for scleroderma and other inflammatory/fibrotic lung diseases.
To cite this abstract, please use the following information:
Tourkina, Elena, Oates, James, Hofbauer, Ann, Bonner, Michael, Visconti, Richard P., Zhang, Jing, et al; Normal Monocyte and Fibrocyte Behavior in Scleroderma Is Restored by Caveolin-1 Scaffolding Domain (CSD) Peptide: Implications for Treating Scleroderma Lung Disease. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :622