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UBC Theses and Dissertations
Synthesis and deposition of proteoglycans in fibroproliferative lung disease Burke, Adrian Kevin
Abstract
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.
Item Metadata
Title |
Synthesis and deposition of proteoglycans in fibroproliferative lung disease
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
1999
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Description |
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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Extent |
9877334 bytes
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Genre | |
Type | |
File Format |
application/pdf
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Language |
eng
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Date Available |
2009-06-16
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Provider |
Vancouver : University of British Columbia Library
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Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
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DOI |
10.14288/1.0088954
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
1999-11
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Campus | |
Scholarly Level |
Graduate
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Aggregated Source Repository |
DSpace
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Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.