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ABSTRACT: Scleroderma is an autoimmune disease characterized by the progressive and dysregulated accumulation of collagen in the skin and internal organs. Pulmonary complications including interstitial lung disease have emerged as the greatest cause of mortality in this disease. Because treatments are limited, new areas of investigation are sorely needed. An emerging area of interest in this field is a potential role for fibrocytes as biomarkers or mediators of disease. Fibrocytes are monocyte-derived mesenchymal progenitor cells that exhibit features of extracellular matrix production and wound contraction in addition to immunologic functions such as cytokine and chemokine production, antigen presentation, leukocyte trafficking, and modulation of angiogenesis. Fibrocytes could participate in the pathogenesis of scleroderma lung disease through any or all of these functions and may be useful biomarkers of disease activity. This chapter presents protocols that have been developed for the study of fibrocytes obtained from human circulation and tissues. Protocols for the quantification of fibrocytes in murine models also are described, along with discussion of common technical challenges. It is hoped that this information will allow further investigation of the role that fibrocytes might play in Scleroderma-related lung disease and perhaps lead to new areas of study in this difficult-to-treat and deadly disease.
Methods in molecular biology (Clifton, N.J.) 01/2012; 900:327-46.
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ABSTRACT: Fibrocytes are mesenchymal cells that arise from monocyte precursors. They are present in injured organs and have both the inflammatory features of macrophages and the tissue remodelling properties of fibroblasts. Chronic inflammatory stimuli mediate the differentiation, trafficking and accumulation of these cells in fibrosing conditions associated with autoimmunity, cardiovascular disease and asthma. This Opinion article discusses the immunological mediators controlling fibrocyte differentiation and recruitment, describes the association of fibrocytes with chronic inflammatory diseases and compares the potential roles of fibrocytes in these disorders with those of macrophages and fibroblasts. It is hoped that this information prompts new opportunities for the study of these unique cells.
Nature Reviews Immunology 06/2011; 11(6):427-35. · 32.25 Impact Factor
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Ye Gan,
Ronald Reilkoff,
Xueyan Peng,
Thomas Russell,
Qingsheng Chen,
Susan K Mathai,
Robert Homer,
Mridu Gulati,
Jonathan Siner,
Jack Elias, Richard Bucala,
Erica Herzog
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ABSTRACT: Semaphorin 7a regulates transforming growth factor β1 (TGFβ1)-induced fibrosis. This study was undertaken to test the hypothesis that semaphorin 7a exerts its profibrotic effects in part by promoting the tissue accumulation of CD45+ fibrocytes.
A murine model of pulmonary fibrosis in which an inducible, bioactive form of the human TGFβ1 gene is overexpressed in the lung was used. Fibrosis and fibrocytes were evaluated in TGFβ1-transgenic mice in which the semaphorin 7a locus had been disrupted. The effect of replacement or deletion of semaphorin 7a on bone marrow-derived cells was ascertained using bone marrow transplantation. The role of the semaphorin 7a receptor β1 integrin was assessed using neutralizing antibodies. The applicability of these findings to TGFβ1-driven fibrosis in humans was examined in patients with scleroderma-related interstitial lung disease (ILD).
The appearance of fibrocytes in the lungs of TGFβ1-transgenic mice required semaphorin 7a. Replacement of semaphorin 7a on bone marrow-derived cells restored lung fibrosis and fibrocytes. Immunoneutralization of β1 integrin reduced pulmonary fibrocytes and fibrosis. Peripheral blood mononuclear cells (PBMCs) from patients with scleroderma-related ILD showed increased levels of messenger RNA for semaphorin 7a and its receptors, with semaphorin 7a located on collagen-producing fibrocytes and CD19+ lymphocytes. Peripheral blood fibrocyte outgrowth was enhanced in these patients. Stimulation of normal human PBMCs with recombinant semaphorin 7a enhanced fibrocyte differentiation; these effects were attenuated by β1 integrin neutralization.
Our findings indicate that interventions that reduce semaphorin 7a expression or prevent the semaphorin 7a-β1 integrin interaction may ameliorate TGFβ1-driven or fibrocyte-associated autoimmune fibroses.
Arthritis & Rheumatism 04/2011; 63(8):2484-94. · 7.87 Impact Factor
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Xueyan Peng,
Susan K Mathai,
Lynne A Murray,
Thomas Russell,
Ronald Reilkoff,
Qingsheng Chen,
Mridu Gulati,
Jack A Elias, Richard Bucala,
Ye Gan,
Erica L Herzog
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ABSTRACT: Collagen-containing leukocytes (CD45+Col-I+) accumulate in diseased and fibrotic tissues. However, the precise identity of these cells and whether injury is required for their recruitment remain unknown. Using a murine model of pulmonary fibrosis in which an inducible, bioactive form of the human transforming growth factor (TGF)-β1 gene is targeted to the lung, we characterized the cell surface phenotype of collagen-containing CD45+ cells in the lung and tested the hypothesis that apoptotic cell death responses are essential to the accumulation of CD45+Col-I+ cells.
Our studies demonstrate that CD45+Col-I+ cells appearing in the TGF-β1-exposed murine lung express markers of the monocyte lineage. Inhibition of apoptosis via pharmacological caspase blockade led to a significant reduction in CD45+Col-I+ cells, which appear to accumulate independently of alternatively activated macrophages. There are also increased levels of apoptosis and greater numbers of CD45+Col-I+ in the lung tissue of patients with two distinct forms of fibrotic lung disease, idiopathic pulmonary fibrosis and connective tissue disease-related interstitial lung disease, when compared to lung from healthy normal controls. These findings are accompanied by an increase in collagen production in cultured monocytes obtained from subjects with fibrotic lung disease. Treatment of these cultured cells with the caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD/fmk) reduces both apoptosis and collagen production in all subjects.
Interventions that prevent collagen production by monocytes via modulation of caspase activation and of apoptosis may be ameliorative in monocyte-associated, TGF-β1-driven processes such as pulmonary fibrosis.
Fibrogenesis & Tissue Repair 01/2011; 4(1):12.
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ABSTRACT: Fibrocytes are circulating mesenchymal progenitor cells that participate in tissue responses to injury and invasion. Accumulating knowledge from animal models regarding the differentiation, trafficking, and function of these cells implicates them in the development of diseases characterized by chronic inflammation and excessive collagen deposition. Recent data obtained from the clinical setting suggests that the enumeration of circulating fibrocytes may be a biomarker for disease progression in chronic lung diseases including asthma and pulmonary fibrosis. A greater understanding of the immunologic mediators that influence fibrocyte biology suggests new opportunities for therapeutic manipulation of these cells in fibrogenesis. This review integrates new developments in the cellular and molecular biology of fibrocytes with current concepts regarding the etiopathogenesis of fibrosing disorders.
Experimental hematology 03/2010; 38(7):548-56. · 3.11 Impact Factor
