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1 INSERM U 492, Dépt de Physiologie, CHU Henri Mondor Créteil, Créteil, 2 UPRES EA2705, Service de Chirurgie Thoracique, Vasculaire et de Transplantation Cardiopulmonaire, Hôpital Marie Lannelongue, Le Plessis-Robinson, 3 INSERM U 551, Hôpital de la Pitié, Paris, and 5 UPRES EA2705, Service de Pneumologie Hôpital A. Béclère, AP-HP, Clamart, France. 4 Laboratoire de Biologie des Tumeurs et du Développement, Université de Liège, Sart Tilman, Liège, Belgium
CORRESPONDENCE: H. Lepetit, INSERM U492, Dépt de Physiologie, Faculté de Médecine, CHU Henri Mondor Créteil, 94010 Créteil, France. Fax: 33 148981777. E-mail: helene.lepetit@creteil.inserm.fr
Keywords: Extracellular matrix, idiopathic pulmonary arterial hypertension, matrix metalloproteinases, smooth muscle cells, tissue inhibitor of matrix metalloproteinase
Received: June 16, 2004
Accepted January 10, 2005
Pulmonary arterial hypertension (PAH) results from persistent vasoconstriction, smooth muscle growth and extracellular matrix (ECM) remodelling of pulmonary arteries (PAs). Matrix metalloproteinases (MMPs) are matrix-degrading enzymes involved in ECM turnover, and in smooth muscle cell (SMC) and endothelial cell migration and proliferation. MMP expression and activity are increased in experimental PAH. Therefore, this study investigated whether similar changes occur in idiopathic PAH (IPAH; formerly known as primary pulmonary hypertension).
Both in situ and in vitro studies were performed on PAs from patients undergoing lung transplantation for IPAH and from patients treated by lobectomy for localised lung cancer, who served as controls.
In IPAH, MMP–tissue inhibitor of metalloproteinase (TIMP) imbalance was found in cultured PA-SMCs, with increased TIMP-1 and decreased MMP-3. MMP-2 activity was markedly elevated as a result of increases in both total MMP-2 and proportion of active MMP-2. In situ zymography and immunolocalisation showed that MMP-2 was associated with SMCs and elastic fibres, and also confirmed the MMP-3–TIMP-1 imbalance.
In conclusion, the findings of this study were consistent with a role for the matrix metalloproteinase–tissue inhibitor of metalloproteinase system in pulmonary vascular remodelling in idiopathic pulmonary arterial hypertension. The matrix metalloproteinase–tissue inhibitor of metalloproteinase imbalance may lead to matrix accumulation, and increased matrix metalloproteinase-2 activity may contribute to smooth muscle cell migration and proliferation. Whether these abnormalities are potential therapeutic targets deserves further investigation.
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