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Title: The role of prostaglandin E2 in airway microvascular leak
Author: Jones, Victoria Clare
ISNI:       0000 0004 5989 5128
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Airway microvascular leak (MVL) is the extravasation of plasma and plasma proteins from post-capillary venules into surrounding tissue. MVL is thought of as a cardinal sign of inflammation and is an important aspect in the pathogenesis of airway inflammatory diseases, including allergic asthma. Prostaglandin E2 (PGE2) is a product of cyclooxygenase mediated metabolism of arachidonic acid and acts via the activation of 4 different receptor subtypes, termed EP1-4. PGE2 has demonstrated a wide variety of effects within the airway, such as on inflammation, sensory nerve activation and airway tone. However, its effects on airway MVL have not been extensively studied. This formed the basis of the thesis hypothesis; PGE2 acts through specific EP receptor(s) to induce microvascular leak within the airways. Using Evans Blue dye as a marker of leak, PGE2 significantly induced airway MVL in mice. I have shown, for the first time that this response is mediated via the activation of the EP2 and the EP4 receptors. This was confirmed using selective EP receptor agonists and antagonists, as well as EP receptor deficient mice. Importantly, this airway MVL was not just exclusive to the mouse; PGE2 significantly increased airway MVL in guinea pigs. To investigate MVL in a disease setting, the ovalbumin model of allergic asthma was employed to study the role of EP receptors in mediating OVA induced MVL. OVA-induced Evans Blue leak was almost completely absent in the airways of EP2 and EP4 receptor knock-out mice. Finally, preliminary work investigating four other prostanoid ligands (PGD2, PGF2α, U46619 and Iloprost) indicates that they too cause airway MVL to some extent and appear to do so via activation of their own receptor subtype (DP1, FP, TP and IP, respectively). Therefore, the findings outlined in this thesis suggest that PGE2 activates the EP2 and EP4 receptors to induce airway microvascular leak and may also be responsible for the MVL observed in the OVA model.
Supervisor: Belvisi, Maria ; Birrell, Mark Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral