Soluble CD40 ligand in pulmonary arterial hypertension -: Possible pathogenic role of the interaction between platelets and endothelial cells

Background - Inflammatory processes seem to be involved in pulmonary arterial hypertension (PAH). CD40 ligand ( L) may promote inflammation and thrombus formation, and we hypothesized that CD40L could be involved in the pathogenesis of PAH. Methods and Results - Several significant findings were revealed when examining the possible role of CD40L in PAH. ( 1) Patients with primary (n = 13) and secondary ( n = 11) PAH but not those with chronic thromboembolic pulmonary hypertension ( n = 8) had increased plasma levels of soluble (s) CD40L compared with control subjects ( n = 8). ( 2) PAH patients using warfarin had markedly lower sCD40L levels than those without such therapy. ( 3) sCD40L levels were higher in arterial ( femoral artery) compared with mixed venous blood ( pulmonary artery), suggesting enhanced release or reduced clearance in the pulmonary vasculature. ( 4) Platelets from PAH patients showed enhanced spontaneous and SFLLRN-stimulated release of sCD40L compared with control subjects. ( 5) In vitro, recombinant sCD40L induced monocyte chemoattractant protein (MCP)-1 and interleukin-8 gene expression in endothelial cells, and plasma levels of these chemokines were raised in all PAH groups, significantly correlated to sCD40L and hemodynamic parameters. ( 6) Although prostacyclin therapy ( 3 months) showed clinical benefit, this therapy had no effect on sCD40L and increased MCP-1 levels in PAH patients, and prostacyclin enhanced MCP-1 in CD40L-stimulated endothelial cells. Conclusions - Our findings suggest a role for CD40L in the pathogenesis of PAH, possibly operating through an interaction between platelets and endothelial cells involving chemokine-related mechanisms.