It was originally assumed that the cells in fibrotic lung tissue that overexpress collagen are resident fibroblasts. Increasing evidence now suggests that cells of hematopoetic origin called fibrocytes migrate into damaged lung tissue where they participate in collagen overexpression and differentiate into fibroblasts. Fibrocytes are derived from monocytes and exhibit both fibroblastic (collagen) and monocyte/hematopoetic surface markers. Previous studies strongly suggest that caveolin-1 is a key signaling molecule in the monocyte-fibrocyte- fibroblast lineage and is responsible for functional differences between these cells isolated from lung fibrosis patients and control subjects. These studies (and our proposed studies) have made good use of the caveolin- 1 scaffolding domain (CSD) peptide which, when synthesized as a fusion peptide with the Antennapedia internalization sequence, enters cells and mimics the function of full-length caveolin-1. Key observations are: Considerably less caveolin-1 is present in monocytes, fibrocytes, and fibroblasts from scleroderma lung disease patients than in the same cell types from control subjects;This decrease in caveolin-1 expression in cells from scleroderma patients increases the activation of signaling molecules and the expression of several proteins involved in lung fibrosis including collagen, 1-smooth muscle actin, and MMP-9;Decreased caveolin-1 expression in scleroderma monocytes promotes their differentiation into fibrocytes;and CSD peptide treatment in vivo promotes the resolution of both pulmonary inflammation and fibrosis in mice receiving intratracheal bleomycin. These observations strongly support the hypothesis that the low levels of caveolin-1 in their monocytes, fibrocytes, and fibroblasts play a critical role in the susceptibility of IPF and scleroderma patients to lung fibrosis. To test this hypothesis, we will: 1) Characterize the functional differences between normal and scleroderma monocytes and fibrocytes and the regulation of these functions by caveolin-1, ERK, and JNK;and 2) Determine whether the beneficial effect of CSD peptide treatment on bleomycin-induced lung injury/fibrosis in vivo involves effects of the CSD peptide on fibrocyte behavior. These experiments will be performed using mice transplanted with EGFP+ monocytes and EGFP+ fibrocytes. The results of these experiments will bring us closer to our goal of using the CSD peptide or a related reagent as a treatment for lung fibrosis in human patients by elucidating the mechanism(s) through which the CSD peptide inhibits the progression of lung fibrosis in an animal model (bleomycin-treated mice).

Public Health Relevance

There are no effective treatments for the several, frequently fatal, diseases in which stiffening of lung tissue due to overproduction of collagen makes breathing difficult. While it used to be believed that the cells that overproduce collagen originated in the lung, there is increasing evidence that the cells that overproduce collagen are cells called fibrocytes that originate in the blood and move into the lungs. Here, we test the idea that a treatment that we have found to relieve lung disease in a mouse model acts primarily on fibrocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
4R03AR056767-03
Application #
8136776
Study Section
Special Emphasis Panel (ZAR1-EHB-H (M1))
Program Officer
Tseng, Hung H
Project Start
2011-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2011
Total Cost
$70,800
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Reese, Charles; Perry, Beth; Heywood, Jonathan et al. (2014) Caveolin-1 deficiency may predispose African Americans to systemic sclerosis-related interstitial lung disease. Arthritis Rheumatol 66:1909-19
Lee, Rebecca; Reese, Charles; Bonner, Michael et al. (2014) Bleomycin delivery by osmotic minipump: similarity to human scleroderma interstitial lung disease. Am J Physiol Lung Cell Mol Physiol 306:L736-48
Reese, Charles; Dyer, Shanice; Perry, Beth et al. (2013) Differential regulation of cell functions by CSD peptide subdomains. Respir Res 14:90
Bains, S N; Tourkina, E; Atkinson, C et al. (2012) Loss of caveolin-1 from bronchial epithelial cells and monocytes in human subjects with asthma. Allergy 67:1601-4
Silver, Richard M; Bogatkevich, Galina; Tourkina, Elena et al. (2012) Racial differences between blacks and whites with systemic sclerosis. Curr Opin Rheumatol 24:642-8
Tourkina, Elena; Richard, Mathieu; Oates, James et al. (2010) Caveolin-1 regulates leucocyte behaviour in fibrotic lung disease. Ann Rheum Dis 69:1220-6