Conference: 2012 International PHA Conference and Scientific Sessions
Release Date: 06.22.2012
Presentation Type: Abstracts
BACKGROUND: Endothelial cell injury resulting from oxidative stress and the subsequent cellular responses can increase endovascular thrombosis, promote elaboration of cytokines by macrophages and endothelial cells in PAH. A set of molecules CD40 and its ligand (CD40L) present in endothelial cells and platelets are important in oxidative stress and vascular inflammation and through a chemokine-related mechanism involving platelets and endothelial cells, these molecules may contribute to the pathogenesis of PAH in a manner similar to their role in atherosclerotic inflammation; however, the precise associative role of CD40L, oxidative stress and platelet/endothelial activation contributing to PAH progression is unknown.
METHODS AND RESULTS: Plasma from a cohort of PAH patients and healthy controls were measured for platelet and endothelial activation-associated proteins soluble CD40 ligand (sCD40L) and von Willebrand Factor (vWF) by ELISA. It can be observed from Figure 1(a) that both sCD40L and vWF are enhanced in PAH compared to control plasma. In addition, a 9-plex cytokine measurement assay with a range of pro-inflammatory / anti-oxidant markers were also performed (Figure 1(b)). There was an induction of pro-inflammatory markers, IL-1, IL-6, IL-8 and TNF but reduction of anti-oxidant marker IL-10 in PAH plasma compared to control plasma. These initial studies indicate that platelet and endothelial cell activation and abnormalities in oxidative stress may exist in PAH patients.
Figure 1: (a) Platelet activation-induced release of soluble CD40 ligand (sCD40L) and endothelial activation-induced release of von Willebrand factor (vWF) is upregulated in PAH compared to healthy individuals (ELISA, n=9, *P<0.04vs control). (b) Plasma inflammatory cytokines (IL-8, TNF, IL-1, IL-12) are enhanced while antioxidant cytokine IL-10 decreased in a PAH patient compared to healthy individual (measured by MSD human pro-inflammatory 9-plex kit).
CONCLUSIONS: Enhanced sCD40L and vWF level in PAH patients implicate the involvement of both platelet and endothelial activation in this disease state. Moreover, enhanced pro-inflammatory and decreased anti-oxidant cytokine indicates that changes in oxidative stress may also contribute to the pathophysiology of PAH. Functional studies with platelet and endothelial cells in PAH will shed further light in the PAH progression mechanisms.