|dc.contributor.author||Medford, Andrew R.L||
|dc.description.abstract||Acute Respiratory Distress Syndrome (ARDS) is the most extreme form of acute
lung injury and continues to have a significant morbidity and mortality.
Unfortunately, the mechanisms involved in the recovery and repair of the lung
following ARDS remain poorly understood. An understanding of these is pivotal to
improving outcome from acute lung injury. Several observational studies have
suggested a potential relationship between Vascular Endothelial Growth Factor
(VEGF) in the lung and the development/outcome of ARDS. In this thesis, three potential mechanisms underlying these observations have been explored:
1. What is the anatomical distribution of VEGF receptor and isoform expression in
normal and ARDS lung? How does this change at early and later time points
following acute lung injury?
2. Are human type 2 alveolar epithelial (ATII) cells a source of and target for
VEGF? How does exposure to a pro-inflammatory milieu modify their
expression of VEGF isoforms and receptors?
3. Is there a relationship between a functional VEGF polymorphism and
susceptibility to developing and severity of ARDS?
I have demonstrated VEGF receptor expression on both sides of the alveolarcapillary
membrane with upregulation in later ARDS. All three principal isoforms
(VEGF121, VEGF165 and VEGF189) are expressed in normal human lung with uniform
downregulation of all three in early ARDS, which normalises with increasing time
following injury. I have not found any evidence of VEGF isoform switching.
I have also demonstrated human ATII cells are both a significant cellular source of
and a target for VEGF (via VEGF receptor expression) confirming autocrine VEGF
activity in the lung. VEGF is an ATII cell survival factor. ATII cells differentially
respond to pro-inflammatory stimuli by increasing VEGF isoform but not receptor
expression, which may serve as a regulatory control mechanism.
Finally, I have demonstrated the VEGF 936 T allele increases susceptibility to and
the severity of lung injury. The T allele is associated with an increase in plasma
VEGF level in ARDS patients but intra-alveolar levels are unaffected.||en_US
|dc.publisher||The University of Edinburgh||en_US
|dc.subject||Acute Respiratory Distress Syndrome||en_US
|dc.subject||Vascular Endothelial Growth Factor||en_US
|dc.title||The role of vascular endothelial growth factor (VEGF) in repair and recovery from acute respiratory distress syndrome (ARDS)||en_US
|dc.type||Thesis or Dissertation||en_US
|dc.type.qualificationname||MD Doctor of Medicine||en_US