Am J Respir Crit Care Med. 2011 Jul 1;184(1):116-23. Epub 2011 Feb 4.
C-Kit Positive Cells AccumulaAte in Remodeled Vessels of Idiopathic Pulmonary Arterial Hypertension.
Montani D, Perros F, Gambaryan N, Girerd B, Dorfmuller P, Price LC, Huertas A, Hammad H, Lambrecht B, Simonneau G, Launay JM, Cohen-Kaminsky S, Humbert M.
Faculté de Médecine, Univ. Paris-Sud, Kremlin-Bicêtre, France; Service de Pneumologie et Réanimation Respiratoire, Hôpital Antoine Béclère, Centre National de Référence de l'Hypertension Pulmonaire Sévère, Clamart, France; Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
Abstract
RATIONALE: c-kit positive cells, including bone marrow (BM)-derived progenitors and mast cells, may participate in vascular remodelling. As recent studies suggest that c-kit may be a target for innovative therapies in experimental pulmonary hypertension, we investigated the contribution of c-kit+ cells in human idiopathic pulmonary arterial hypertension (IPAH).
OBJECTIVES AND METHODS: Single c-kit, CXCL12/SDF-1α, CXCR4, CD34, and multiple c-kit, α-smooth muscle actin (α-SMA) and tryptase immunostainings were performed in IPAH lungs. C-kit mRNA expression was quantified by real-time PCR in microdissected pulmonary arteries from IPAH patients and controls. Phenotype and function of circulating progenitors were analyzed by flow cytometry. Plasma levels of soluble c-kit and CXCL12/SDF-1α were measured by ELISA.
MEASUREMENTS AND MAIN RESULTS: Infiltration of c-kit+ cells in pulmonary arterial lesions was associated with an increase in c-kit mRNA expression (P<0.01 as compared to controls). Both c-kit+/tryptase+ mast cells and c-kit+/tryptase- BM-derived cells were increased in pulmonary arteries of IPAH patients, as compared to controls (106.6±54.5 versus 28±16.8/mm² and 143.8±101.1 versus 23.3±11.9/mm², all P<0.01). Plasma soluble c-kit was increased in IPAH compared to controls (27.4±12.4 vs 19.5±5.8ng/ml, P<0.05). Two populations of circulating BM-derived cells (lin-CD34highCD133high(c-kithighCXCR4low) and lin-CD34lowCD133-(c-kitlowCXCR4high)) were increased in IPAH as compared to controls (P=0.01). Pulmonary arterial lesions were associated with vasa vasorum expansion expressing CXL12/SDF-1α that may recruit c-kit+ cells.
CONCLUSION: In IPAH, c-kit+ cells infiltrate pulmonary arterial lesions and may participate to vascular remodeling. Therefore, c-kit may represent a potential target for innovative PAH therapy.
PMID:21471108