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.


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.
Damås
Jan K
JK
Research Institute for Internal Medicine, Rikshospitalet, Oslo, Norway.
Otterdal
Kari
K
Yndestad
Arne
A
Aass
Halfdan
H
Solum
Nils O
NO
Frøland
Stig S
SS
Simonsen
Svein
S
Aukrust
Pål
P
Andreassen
Arne K
AK
D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D023201:CD40 Ligand / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D003095:Collagen Diseases / Q000150:complications; D042783:Endothelial Cells / Q000502:physiology*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D011464:Epoprostenol / Q000494:pharmacology; D005260:Female; D005263:Femoral Artery; D005786:Gene Expression Regulation / Q000187:drug effects; D015658:HIV Infections / Q000150:complications; D006330:Heart Defects, Congenital / Q000150:complications; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000503:physiopathology*; D016209:Interleukin-8 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D008103:Liver Cirrhosis / Q000150:complications; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000494:pharmacology; D011651:Pulmonary Artery; D011994:Recombinant Proteins / Q000494:pharmacology; D012995:Solubility; D013923:Thromboembolism / Q000150:complications; D014471:Umbilical Veins; D014859:Warfarin / Q000627:therapeutic use
D000925:Anticoagulants; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016209:Interleukin-8; D010446:Peptide Fragments; D011994:Recombinant Proteins; C082835:thrombin receptor peptide (42-47); D023201:CD40 Ligand; D014859:Warfarin; D011464:Epoprostenol