Pulmonary fibrosis is a major cause of disability and death in patients with autoimmune rheumatic diseases such as scleroderma, rheumatoid arthritis, dermatomyositis and polymyositis. The mechanisms of lung fibrosis are complex and poorly understood, and modern therapies are utterly inadequate. The severity of fibrosis and subsequent decline in lung function are frequently associated with pulmonary accumulation of T lymphocytes, although the mechanisms by which T cells promote fibrosis remain controversial. Our observations point to a possible central role of a CC chemokine CCL18 in pulmonary accumulation of profibrotic T lymphocytes and fibrosis. The Specific Objective of this study is to investigate the phenotypes and the mechanisms of the profibrotic action of pulmonary T lymphocytes, and to investigate whether CCL18 can directly skew the phenotype of normal human pulmonary T cells toward profibrotic. The Overall Hypothesis is that pulmonary fibrosis is part of an exaggerated Treg-mediated immunosuppressive and anti-inflammatory response. The Specific Hypothesis of this study is that pulmonary T cells promote fibrosis because of their regulatory phenotype (Treg). Specifically, we hypothesize that these pulmonary T cells are TGF-?+, similar to Th3 and Tregs acting through membrane-bound TGF-?. We further hypothesize that these cells facilitate pulmonary fibrosis by persisting in the lung in an integrin-dependent fashion, secreting and activating TGF-? through integrin-dependent mechanisms, retaining TGF-? on the cell surface, and ultimately stimulating fibroblasts through soluble and membrane-bound TGF-?. To evaluate the validity of this hypothesis, the following Specific Aims will be addressed: 1. Define the profibrotic phenotype of pulmonary T lymphocytes leading to their prolonged persistence in the lungs and increased production, activation, and cell surface binding of TGF-? in the CCL18 pulmonary overexpression model, with a specific focus on the expression profile and role of integrins. 2. Determine whether aV-containing and ?2-containing integrins facilitate cell-cell interactions between pulmonary T cell and fibroblasts, the increase in TGF-? production and/or activation, cell surface binding of TGF-? by T cells, and stimulation of collagen production by fibroblasts. 3. Investigate the ability of CCL18 to directly modulate the phenotype of pulmonary T cells toward profibrotic, by stimulating the expression, activation, and cell surface binding of TGF-?, and expression of aV- containing and ?2-containing integrins. The results of this study may identify T lymphocytes and CCL18 as targets for future antifibrotic therapies in patients with autoimmune rheumatic diseases.
|Luzina, Irina G; Kopach, Pavel; Lockatell, Virginia et al. (2013) Interleukin-33 potentiates bleomycin-induced lung injury. Am J Respir Cell Mol Biol 49:999-1008|
|Luzina, Irina G; Pickering, Edward M; Kopach, Pavel et al. (2012) Full-length IL-33 promotes inflammation but not Th2 response in vivo in an ST2-independent fashion. J Immunol 189:403-10|
|Luzina, Irina G; Keegan, Achsah D; Heller, Nicola M et al. (2012) Regulation of inflammation by interleukin-4: a review of ""alternatives"". J Leukoc Biol 92:753-64|
|Luzina, Irina G; Todd, Nevins W; Nacu, Natalia et al. (2009) Regulation of pulmonary inflammation and fibrosis through expression of integrins alphaVbeta3 and alphaVbeta5 on pulmonary T lymphocytes. Arthritis Rheum 60:1530-9|
|Nacu, Natalia; Luzina, Irina G; Highsmith, Kendrick et al. (2008) Macrophages produce TGF-beta-induced (beta-ig-h3) following ingestion of apoptotic cells and regulate MMP14 levels and collagen turnover in fibroblasts. J Immunol 180:5036-44|