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Synthesis and deposition of proteoglycans in fibroproliferative lung disease Burke, Adrian Kevin
Idiopathic pulmonary fibrosis (IPF) is characterized by chronic inflammation leading to progressive deposition of collagenous extracellular matrix. Proteoglycan metabolism may be altered in inflammation and fibrosis. The aim of this study is to characterize changes in proteoglycan synthesis and deposition in the remodeling lung. Lung biopsy tissue from 6 IPF and 6 control patients was studied using histochemistry and immunohistochemistry. Histochemistry revealed dense deposits of glycosaminoglycan in fibroblast foci unique to remodeling lung, which enzyme digestion showed to contain predominantly chondroitin sulfate/dermatan sulfate. Immunohistochemistry showed that glycosaminoglycan deposition was concordant with versican, but not decorin, biglycan or hyaluronan. The distribution of versican, decorin, biglycan and hyaluronan were described in the normal and IPF lung for the first time. Versican in IPF was associated with a-smooth muscle actin (α-SMA)-positive myofibroblasts migrating into airspace and myofibroblasts in fibroblast foci. In control and diseased lung, versican was associated with smooth muscle in blood vessel walls, in airway walls and with α -SMA-positive cells in alveolar entrance rings. 22.6%±4.1% of tissue area in IPF biopsies was versican-positive, compared to 2.6±2.0% of tissue area in control lung (p<0.00001). Decorin was localized intracellularly in the fibroblast foci. Hyaluronan was found throughout the remodeling lung including the fibroblast foci. Morphometry showed higher mononuclear phagocyte densities in versican-rich fibroblast foci in the IPF lung. Mononuclear phagocyte densities were 3.74±1.14 cells/ 10⁴μm² in versican- rich matrix and 1.97±0.54 cells/10⁴μm² in versican-poor matrix (p<0.01). Total nonmononuclear phagocytes leukocyte densities were 5.97±1.05 cells/10⁴μm² in versican-rich matrix and 9.34±1.21 cells/10⁴μm² in versican-poor matrix (p<0.003) in IPF. In a second series of tissue samples, versican was localized to thickened alveolar walls in fibroproliferative adult respiratory distress syndrome and intraluminal buds in bronchiolitis obliterans organizing pneumonia, and versican deposition preceded accumulation of collagen. Versican mRNA expression was analyzed in 10IPF biopsies and 5 control lung samples collected prospectively. Reverse transcriptase-polymerase chain reaction showed a relative increase in the synthesis of the two mRNA splice variants coding for the versican isoforms V₀ and V₁ , in fibrosis. V₀ and V₁ are the largest isoforms, with the highest number of potential glycosaminoglycan-attachment sites. Versican is associated with proliferating, collagen-synthesizing myofibroblasts in early lesions in fibrosis. The function of versican in these processes is still unknown, but our work suggests it may be important in the cell biology of tissue remodeling in the lung.
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