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Am J Respir Crit Care Med. 2011 Jul 1;184(1):116-23. doi: 10.1164/rccm.201006-0905OC. Epub 2011 Feb 4.

C-kit-positive cells accumulate in remodeled vessels of idiopathic pulmonary arterial hypertension.

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1
University Paris-Sud, Faculté de Médecine, Kremlin-Bicêtre, France.

Abstract

RATIONALE:

C-kit(+) cells, including bone marrow (BM)-derived progenitors and mast cells, may participate in vascular remodelling. Because 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:

To investigate the contribution of c-kit(+) cells in human IPAH.

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 polymerase chain reaction in microdissected pulmonary arteries from patients with IPAH and control subjects. 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 compared with control subjects). Both c-kit(+)/tryptase(+) mast cells and c-kit(+)/tryptase(-) BM-derived cells were increased in pulmonary arteries of patients with IPAH compared with control subjects (106.6 ± 54.5 vs. 28 ± 16.8/mm(2) and 143.8 ± 101.1 vs. 23.3 ± 11.9/mm(2); all P<0.01). Plasma-soluble c-kit was increased in IPAH compared with control subjects (27.4 ± 12.4 vs. 19.5 ± 5.8 ng/ml; P<0.05). Two populations of circulating BM-derived cells (lin-CD34(high)CD133(high) [c-kit(high)CXCR4(low)] and lin-CD34(low)CD133(-) [c-kit(low)CXCR4(high)]) were increased in IPAH compared with control subjects (P=0.01). Pulmonary arterial lesions were associated with vasa vasorum expansion expressing CXL12/SDF-1α that may recruit c-kit(+) cells.

CONCLUSIONS:

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
DOI:
10.1164/rccm.201006-0905OC
[Indexed for MEDLINE]
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