Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Konya, V.
PGI2 and the PGE2-EP4 signaling control the transendothelial trafficking of eosinophils
[ Dissertation ] Medical University of Graz; 2010. pp. 114
[OPEN ACCESS]
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- Autor*innen der Med Uni Graz:
- Konya Viktoria
- Betreuer*innen:
- Heinemann Akos
- Sattler Wolfgang
- Schuligoi Rufina
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- Abstract:
- Enhanced eosinophil extravasation into the tissue is a characteristic feature of bronchial asthma and other allergic inflammatory diseases. The process of eosinophil extravasation involves sequential interaction steps with the vessel wall forming endothelial cells. The vascular endothelial cells assure the barrier between the circulating blood cells and the surrounding tissue. During asthma, activated leukocytes cause dramatic remodeling of the microvasculature and the tissue. Major mediators, Prostaglandin I2 and Prostaglandin E2 are products of cyclooxygenase (COX) enzymes. Earlier studies showed that COX-1 or COX-2 deficiency in mice significantly increased lung inflammation and airway hyperresponsiveness in ovalbumin-induced asthma model. Thus, the aim of this thesis was to define the role of PGI2 and PGE2 in the regulation of eosinophil trafficking across endothelial monolayers. PGI2 and PGE2 reduced eosinophil chemotaxis and adhesion to fibronectin, inhibited the activation and the up-regulation of the CD11b/CD18 adhesion molecule, and blocked podosome formation in response to eotaxin. The effects of PGE2 were mainly mediated by the activation of the EP4 receptor subtype. In terms of interaction with lung microvascular endothelial cells, eosinophil adhesion to endothelial cells and transendothelial migration were enhanced upon blocking the endogenous PGI2 release of endothelial cells using a non-selective COX inhibitor, diclofenac. PGE2 and the selective EP4 receptor agonist (ONO-AE1-329) prevented the barrier-disrupting effect of thrombin on the endothelial monolayer, as visualized by VE-Cadherin staining; and accelerated the regeneration of electrically wounded endothelial monolayers. PGE2 and the EP4 receptor agonist attenuated the TNF-induced up-regulation of E-selectin. Eosinophil transmigration across the thrombin-stimulated endothelial cells was also effectively reduced by pre-treatment of the endothelial monolayers with the EP4 agonist. Based on these observations, PGI2 and the PGE2 EP4 signaling axis might be important protective factors in keeping inappropriate eosinophil infiltration under control and might modulate allergic responses by inhibiting eosinophil responsiveness to chemoattractants in terms of adhesion and migration. Furthermore, IP and EP4 receptor activation strengthens the barrier function of the endothelium. Therefore, IP and EP4 agonists might be useful therapeutic options for otherwise inadequately controlled inflammation in eosinophilic diseases.