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Examination of endothelial integrity in a rat cardiac transplant model : implications for the pathogenesis of transplant vascular disease Lai, John Chi Keung
Abstract
Background: One of the major complications associated with solid organ transplantation is a progressive form of allo-atherosclerosis known as transplant vascular disease (TVD), an expression of chronic allograft rejection. Events occurring early post-transplantation, particularly immune recognition of alloendothelium, initiate TVD. Previous work has suggested an important compromise of endothelial integrity as the allo-immune milieu evolves, although mechanisms by which integrity is altered remain to be resolved. Increased vascular permeability due to endothelial damage may allow entrance of inflammatory cells, lipoproteins, other proteins and plasma fluid into the subendothelial space, thereby contributing to the initiation of atherosclerosis in thoroughfare arteries. In this study, endothelial integrity in coronary arteries and proximal aorta was examined following cardiac transplantation in rats. Hypothesis: Altered endothelial integrity, as reflected in structural changes, is present in the rat allograft cardiac transplant model. Methods: Lewis-to-Lewis and Lewis-to-F-344 rat heterotopic cardiac transplants were examined at 1, 4, 21 and 42 days post-transplantation. The effects of cyclosporine treatment (5mg/kg/day) on maintaining endothelial integrity were studied and compared with control saline treated animals. At the light microscopy level, en face silver nitrate staining was performed to demonstrate endothelial cell borders and gaps. Scanning electron microscopy was used to extend silver nitrate findings and to further define the presence and nature of endothelial disruptions. Transmission electron microscopy was performed to further characterize endothelial integrity, immune cell identity and interaction with endothelium, and disease progression. Results: Syngrafts and cyclosporine treated allografts showed normal looking endothelium similar to that observed in arteries from native and control hearts. However, saline treated allografts displayed progressive endothelial destruction including large intercellular gaps, missing cells, and areas of bare extracellular matrix. Exfoliated surfaces were covered by platelets at various stages of adhesion, activation and spreading. Similarly, numerous leukocytes were observed a s either adherent to the endothelial lining or transmigrating into the sub-endothelial space. Cessation of cyclosporine therapy was associated with development of similar abnormalities. Conclusion: These findings suggest that early endothelial damage may promote vascular permeability and thereby initiate TVD, especially when immunosuppression is insufficient.
Item Metadata
Title |
Examination of endothelial integrity in a rat cardiac transplant model : implications for the pathogenesis of transplant vascular disease
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2006
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Description |
Background: One of the major complications associated with solid organ
transplantation is a progressive form of allo-atherosclerosis known as transplant
vascular disease (TVD), an expression of chronic allograft rejection. Events
occurring early post-transplantation, particularly immune recognition of alloendothelium,
initiate TVD. Previous work has suggested an important
compromise of endothelial integrity as the allo-immune milieu evolves, although
mechanisms by which integrity is altered remain to be resolved. Increased
vascular permeability due to endothelial damage may allow entrance of
inflammatory cells, lipoproteins, other proteins and plasma fluid into the subendothelial
space, thereby contributing to the initiation of atherosclerosis in
thoroughfare arteries. In this study, endothelial integrity in coronary arteries and
proximal aorta was examined following cardiac transplantation in rats.
Hypothesis: Altered endothelial integrity, as reflected in structural changes, is
present in the rat allograft cardiac transplant model.
Methods: Lewis-to-Lewis and Lewis-to-F-344 rat heterotopic cardiac transplants
were examined at 1, 4, 21 and 42 days post-transplantation. The effects of
cyclosporine treatment (5mg/kg/day) on maintaining endothelial integrity were
studied and compared with control saline treated animals. At the light
microscopy level, en face silver nitrate staining was performed to demonstrate
endothelial cell borders and gaps. Scanning electron microscopy was used to
extend silver nitrate findings and to further define the presence and nature of
endothelial disruptions. Transmission electron microscopy was performed to
further characterize endothelial integrity, immune cell identity and interaction with
endothelium, and disease progression.
Results: Syngrafts and cyclosporine treated allografts showed normal looking
endothelium similar to that observed in arteries from native and control hearts.
However, saline treated allografts displayed progressive endothelial destruction
including large intercellular gaps, missing cells, and areas of bare extracellular
matrix. Exfoliated surfaces were covered by platelets at various stages of
adhesion, activation and spreading. Similarly, numerous leukocytes were
observed a s either adherent to the endothelial lining or transmigrating into the
sub-endothelial space. Cessation of cyclosporine therapy was associated with
development of similar abnormalities.
Conclusion: These findings suggest that early endothelial damage may
promote vascular permeability and thereby initiate TVD, especially when
immunosuppression is insufficient.
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Genre | |
Type | |
Language |
eng
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Date Available |
2010-01-07
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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 |
10.14288/1.0092535
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2006-05
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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.