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Title: Models of acute lung injury and novel pharmacotherapies
Author: Shyamsundar, Murali
ISNI:       0000 0004 2745 0597
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2012
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There are no proven pharmacological therapies to reduce mortality in acute lung injury (All) and there is a need for clinically relevant human models of All to test novel therapies and provide data to inform the design of subsequent clinical trials in All. Simvastatin which modulates pathways involved in All and keratinocyte growth factor (KGF) which augments epithelial repair may have a potential role in All. I established inhaled lipopolysaccharide (LPS) as a model of All and used this model to study the effects of simvastatin and KGF on inflammation and epithelial repair respectively. I also studied the effects of simvastatin in patients undergoing oesophagectomy and one lung ventilation (OLV) as a model of All. The inhaled LPS model using 50 mcg of LPS was associated with mild self- limiting pulmonary inflammation and epithelial-endothelial barrier dysfunction. In this model pre-treatment with simvastatin for 4 days prior to LPS inhalation was found to decrease pulmonary inflammation. KGF pre-treatment at a dose of 60mcg/kg for 3 days prior to LPS inhalation in the same model of All was shown to increase factors associated with epithelial repair and attenuate LPS induced fall in pulmonary SP-O levels. Using oesophagectomy as a model of All, simvastatin pre-treatment was shown to reduce pulmonary inflammation and epithelial injury, and improve systemic endothelial function. In conclusion, my research work has demonstrated the safety and relevance of inhaled LPS as a model of All. I have also demonstrated the anti-inflammatory effects of simvastatin and epithelial repair actions of KGF. Simvastatin also decreases pulmonary and systemic injury sustained during OLV in patients undergoing oesophagectomy. Simvastatin and KGF appear to act on. two different but interlinked pathomechanisms in All, inflammation and repair. While simvastatin by attenuating inflammation could reduce lung injury, KGF by augmentation of specific mediators of epithelial repair could augment repair. The results of these trials need confirmed in multi-centre studies and if proven to be effective could contribute to reducing the morbidity and mortality associated with ALI.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available