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dc.contributor.authorMedford, Andrew R.L
dc.date.accessioned2013-04-17T13:17:42Z
dc.date.available2013-04-17T13:17:42Z
dc.date.issued2007
dc.identifier.urihttp://hdl.handle.net/1842/6661
dc.description.abstractAcute 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.language.isoenen_US
dc.publisherThe University of Edinburghen_US
dc.subjectAcute Respiratory Distress Syndromeen_US
dc.subjectVascular Endothelial Growth Factoren_US
dc.titleThe role of vascular endothelial growth factor (VEGF) in repair and recovery from acute respiratory distress syndrome (ARDS)en_US
dc.typeThesis or Dissertationen_US
dc.type.qualificationlevelDoctoralen_US
dc.type.qualificationnameMD Doctor of Medicineen_US


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