Published ahead of print on October 25, 2007, doi:10.1164/rccm.200703-506OC Am. J. Respir. Crit. Care Med., Volume 177, Number 2, January 2008, 202-207 A more recent version of this article appeared on January 15, 2008
Submitted on March 29, 2007 Raised LIGHT Levels in Pulmonary Arterial Hypertension - Potential Role in Thrombus FormationKari Otterdal1*,1 Research Institute for Internal Medicine, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway, 2 Department of Cardiology, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway, 3 Research Institute for Internal Medicine, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway; Department of Cardiology, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway, 4 Research Institute for Internal Medicine, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway; Section of Endocrinology, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway, 5 Research Institute for Internal Medicine, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Medical Department, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway * To whom correspondence should be addressed. E-mail: kari.otterdal{at}medisin.uio.no.
Rationale: Thrombus formation and inflammation are involved in the pathogenesis of pulmonary arterial hypertension (PAH), and LIGHT (Lymphotoxins-like Inducible protein that competes with Glycoprotein D for Herpesvirus entry mediator on T lymphocytes) has been shown to promote vascular inflammation. Objectives: We sought to investigate the role of the tumor necrosis factor superfamily ligand LIGHT in the pathogenesis of PAH. Methods: We studied 73 patients with severe PAH and 10 controls. LIGHT and pro- and anti-thrombotic markers were assessed by enzyme immunoassays. Measurements and main results: (i) Patients with idiopathic PAH (n=21), patients with PAH related to risk factors or associated conditions (n=31) and those with chronic thromboembolic PAH (n=21) all had raised serum levels of LIGHT compared with controls (n=10). (ii) LIGHT levels in femoral artery were significantly related to mortality in the PAH patients. (iii) Immunostaining of LIGHT and its receptors were seen in alveolar macrophages, vascular smooth muscle cells, and endothelial cells in lungs from PAH patients. (iv) Thirteen patients received prostacyclin infusion (3 months), and all showed hemodynamic improvement, accompanied by decreased LIGHT levels. (v) Prostacyclin abolished the release of LIGHT from activated platelets in vitro, suggesting that the decrease in LIGHT during prostacyclin therapy could involve direct effects on platelets. (vi) LIGHT increased tissue factor and plasminogen activator inhibitor type 1 and decreased thrombomodulin levels in endothelial cells, inducing a prothrombotic state in these cells. Conclusions: Our findings suggest prothrombotic effects of LIGHT in PAH involving endothelial-related mechanisms, potentially contributing to the progression of this disorder. Key words: endothelium, inflammation, platelets, prostacyclin
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