Whitehead, Bruce Foster; (2001) Injury in the transplanted lung: Mechanisms, clinical correlates, and the development of novel therapeutic approaches. Doctoral thesis (Ph.D), UCL (University College London).

Text Injury_in_the_transplanted_lun.pdf Download (14MB)

Abstract

This thesis reviews injurious events in the transplanted lung, describes the clinical correlates of these, and presents two novel therapeutic approaches. The mechanisms of injury in the transplanted lung have been detailed with special reference to allograft ischaemia, rejection, and infection. Clinical correlation of these injurious factors incorporated an extensive review of pulmonary function in a cohort of paediatric lung transplant recipients with cystic fibrosis. This study demonstrated an improvement in all dynamic lung function parameters at 12 months post transplant compared with pre transplant values (p0.001). Subsequently, there was a persistent decline in these values denoting the development of obliterative bronchiolitis. Measuring area under the curve of FEV1% graphs (FEV1% AUC) represented a unique method for assessing pulmonary function. This correlated negatively with graft ischaemic times (cold: p0.05, and total: p0.01) to 36 months post transplant, although not with the number of rejection or infection episodes in the first 12 months post transplant. Novel therapeutic approaches included the evaluation of a non-viral, synthetic peptide gene vector system. This incorporated the administration, into the airway, of a ligand-polylysine (polylysine-molossin) vector in an in vivo rat lung model. The vector showed widespread distribution throughout the lung parenchyma, although limited attachment to the airway epithelium. However, gene transfer was not demonstrated despite the use of two reporter genes and additional methods to improve endocytic release. Antisense oligodeoxynucleotide (ODN) therapy for adenovirus infection constituted the other novel therapeutic approach. This study comprised the use of an in vitro biological assay to assess the efficacy of ODNs in modulating adenovirus infection. There was a small, but consistent reduction (p0.005) in adenovirus cytopathic effect associated with an antisense ODN directed to the El A gene of adenovirus 5, compared with the nonsense control ODN. This result suggests a potential therapeutic role for ODNs in adenoviral infection.

Download activity - last month

Export as XMLCSVJSON

Download activity - last 12 months

Export as XMLCSVJSON

Downloads by country - last 12 months

Export as CSVXMLJSON

Archive Staff Only

View Item