A study of platelets and the endothelium in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease associated with significant morbidity and early mortality. Despite this, the pathogenesis remains poorly understood and there is no effective disease modifying treatment. Epidemiological studies demonstrate an association between IPF and vascular disease. Platelets and the endothelium play an important role in maintaining vascular integrity, patency and function. In addition to their role in haemostasis, platelets have significant inflammatory and pro-fibrotic potential. Platelets and the lung have a close relationship in physiology and in disease however the role of platelets in IPF has not previously been investigated.In this thesis we investigate the link between IPF and vascular disease and consider a potential pathogenic role of platelets in IPF. We do this through the following series of experiments: (1) investigation of the platelet endothelial cell adhesion molecule-1 single nucleotide polymorphisms in IPF and controls; (2) assessment of markers of platelet activation in IPF and controls; (3) investigation of the effect of IPF plasma on control platelets; (4) assessment of platelet function by measurement of platelet-endothelial cell adhesion; and (5) evaluation of plasma markers of endothelial activation and fibrinolysis in IPF.We demonstrate that IPF patients exhibit increased platelet reactivity and that this can be reproduced in control platelets following incubation in IPF plasma suggesting that a plasma factor is responsible for this phenomenon. In addition, we show that the increased platelet reactivity in IPF is associated with an increased propensity to adhere to vascular endothelium confirming abnormal platelet function in IPF patients and suggesting a potential pathogenic mechanism. We do not demonstrate any difference in plasma levels of endothelial activation markers or fibrinolysis between IPF patients and controls. Similarly, we find no clinically significant difference in the prevalence of the PECAM-1 polymorphisms in IPF and controls.

Name dc:type.qualificationname

MD

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

Hull York Medical School, the University of Hull and the University of York

Year dc:date.issued

2012

Author dc:creator

• Crooks, Michael George

Advisor dc:contributor.advisor

• Hart, Simon P.

• Medicine

Language dc:language

en

Identifier

oai:hull-repository.worktribe.com:4214095

OAI identifier oai:identifier

oai:hull-repository.worktribe.com:4214095