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Raised LIGHT Levels in Pulmonary Arterial Hypertension

Potential Role in Thrombus Formation

¹ Research Institute for Internal Medicine, ² Department of Cardiology, ³ Section of Endocrinology, and ⁴ Section of Clinical Immunology and Infectious Diseases, Medical Department, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway

Correspondence and requests for reprints should be addressed to Kari Otterdal, M.Sc., Research Institute for Internal Medicine, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, N-0027 Oslo, Norway. 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 (Lymphotoxin-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 control subjects. LIGHT and pro- and antithrombotic markers were assessed by enzyme immunoassays.

Measurements and Main Results: (1) 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 control subjects (n = 10). (2) LIGHT levels in femoral artery were significantly related to mortality in the patients with PAH. (3) Immunostaining of LIGHT and its receptors was seen in alveolar macrophages, vascular smooth muscle cells, and endothelial cells in lungs from patients with PAH. (4) Thirteen patients received prostacyclin infusion (3 mo), and all showed hemodynamic improvement, accompanied by decreased LIGHT levels. (5) 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. (6) 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 endothelium-related mechanisms, potentially contributing to the progression of this disorder.

Key Words: endothelium • inflammation • platelets • prostacyclin

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Thrombus formation and inflammation are involved in the pathogenesis of pulmonary arterial hypertension, but there are no data on the role of LIGHT, a platelet-derived ligand of the tumor necrosis factor superfamily, in this disorder. What This Study Adds to the Field LIGHT could, through prothrombotic effects on endothelial cells, contribute to the progression of pulmonary arterial hypertension.