Published Online
on August 9, 2004

A more recent version of this article appeared on August 24, 2004

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Submitted on February 24, 2004
Accepted on April 27, 2004

Soluble CD40 Ligand in Pulmonary Arterial Hypertension. Possible Pathogenic Role of the Interaction Between Platelets and Endothelial Cells

Jan K. Damås MD, PhD, Kari Otterdal MSc, Arne Yndestad MSc, Halfdan Aass MD, PhD, Nils O. Solum PhD, Stig S. Frøland MD, PhD, Svein Simonsen MD, PhD, Pål Aukrust MD, PhD^*, and Arne K. Andreassen MD, PhD

From the Research Institute for Internal Medicine (J.K.D., K.O., A.Y., N.O.S., S.S.F., P.A.), Department of Cardiology (J.K.D., H.A., S.S., A.K.A.), and Section of Clinical Immunology and Infectious Diseases (S.S.F., P.A.), Rikshospitalet, Oslo, Norway.

^* To whom correspondence should be addressed. E-mail: pal.aukrust{at}rikshospitalet.no.

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.

Key words: inflammation • platelets • hypertension, pulmonary • endothelium

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