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Published ahead of print on September 6, 2007, doi:10.1164/rccm.200610-1559OC
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American Journal of Respiratory and Critical Care Medicine Vol 176. pp. 1041-1047, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200610-1559OC

Original Article

Role of Endothelium-derived CC Chemokine Ligand 2 in Idiopathic Pulmonary Arterial Hypertension

Olivier Sanchez1, Elisabeth Marcos1, Frédéric Perros2, Elie Fadel3, Ly Tu1, Marc Humbert2, Philippe Dartevelle3, Gérald Simonneau2, Serge Adnot1 and Saadia Eddahibi1

1 INSERM U841 and Département de Physiologie Explorations Fonctionnelles, Hôpital H. Mondor, AP-HP, Créteil, France; 2 INSERM U764, UPRES EA2705, Service de Pneumologie, Centre National de Référence de l'Hypertension Artérielle Pulmonaire, Hôpital Antoine-Béclère, Assistance-Publique Hôpitaux de Paris, Université Paris-Sud 11, Clamart, France; and 3 UPRES EA2705, Service de Chirurgie Thoracique, Vasculaire et de Transplantation Cardiopulmonaire, Hôpital Marie Lannelongue, Le Plessis Robinson, France

Correspondence and requests for reprints should be addressed to Saadia Eddahibi, Ph.D., INSERM U841, Faculté de Médecine 8, avenue Général Sarrail, 94010 Créteil, France. E-mail: eddahibi{at}im3.inserm.fr

Rationale: Inflammatory cytokines may affect pulmonary vascular remodeling in idiopathic pulmonary arterial hypertension (IPAH). CC chemokine ligand 2 (CCL2) is synthesized by vascular cells and can stimulate monocyte/macrophage migration and smooth muscle cell (SMC) proliferation.

Objectives: To investigate the role of CCL2 in IPAH.

Methods: CCL2 levels in plasma, monocytes, lungs, and medium from pulmonary endothelial cell (P-EC) or pulmonary artery SMC (PA-SMC) cultures were measured by ELISA and Western blot analysis. CCL2 receptor CCR2 mRNA levels in monocytes, P-ECs, and PA-SMCs were measured by real-time polymerase chain reaction. Effect of CCL2 on PA-SMC proliferation and migration was assessed using [3H]thymidine incorporation and a modified Boyden's chamber. The effect of endothelial cell–derived CCL2 on monocyte migration was measured using a modified Boyden's chamber.

Measurements and Main Results: Compared with control subjects, we found the following in patients with IPAH: elevated CCL2 protein levels in plasma and lung tissue, whereas monocyte CCL2 levels were similar between patients and control subjects, and elevated CCL2 release by P-ECs or PA-SMCs. P-ECs released twice as much CCL2 than did PA-SMCs. Monocyte migration was markedly increased in the presence of P-ECs, and the increase was larger with P-ECs from patients with IPAH. CCL2-blocking antibodies reduced P-ECs' chemotactic activity by 60%. Compared with controls, PA-SMCs from patients exhibited stronger migratory and proliferative responses to CCL2, in keeping with the finding that CCR2 was markedly increased in PA-SMCs from patients.

Conclusions: These results suggest that CCL2 overproduction may be a feature of the abnormal P-EC phenotype in IPAH, contributing to the inflammatory process and to pulmonary vascular remodeling.

Key Words: pulmonary hypertension • endothelial cells • smooth muscle cells • chemokines • CCL2


AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject
Accumulating evidence suggests a role for inflammation in the pathogenesis of pulmonary arterial hypertension. One major cytokine synthesized by vascular cells and able to stimulate monocyte/macrophage migration is CC chemokine ligand 2 (CCL2).

What This Study Adds to the Field
Idiopathic pulmonary arterial hypertension is associated with an overproduction of CCL2. Pulmonary endothelial cells are a major source of CCL2, which behaves as chemoattractant for circulating inflammatory cells and as growth factor for pulmonary artery smooth muscle cells.

 



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