PT  - JOURNAL ARTICLE
AU  - Le Hiress, Morane
AU  - Tu, Ly
AU  - Phan, Carole
AU  - Thuillet, Raphaël
AU  - Ricard, Nicolas
AU  - Seferian, Andrei
AU  - Fadel, Elie
AU  - Simonneau, Gerald
AU  - Huertas, Alice
AU  - Tamura, Yuichi
AU  - Humbert, Marc
AU  - Guignabert, Christophe
TI  - Endothelial-derived MIF contributes to pulmonary endothelial cell proliferation in human pulmonary arterial hypertension
AID  - 10.1183/13993003.congress-2015.PA4900
DP  - 2015 Sep 01
TA  - European Respiratory Journal
PG  - PA4900
VI  - 46
IP  - suppl 59
4099  - http://erj.ersjournals.com/content/46/suppl_59/PA4900.short
4100  - http://erj.ersjournals.com/content/46/suppl_59/PA4900.full
SO  - Eur Respir J2015 Sep 01; 46
AB  - Rationale: In idiopathic pulmonary arterial hypertension (iPAH), pulmonary-endothelial cells (P-ECs) display phenotypic abnormalities including a greater proliferative response to growth factors and apoptosis resistance; however, the precise underlying mechanisms remain obscure. Excessive MIF (macrophage migration-inhibitory factor) expression during the initial stages of tumor contributes to endothelial proliferation, tumor growth and progression.Objectives: We therefore hypothesized that MIF could function as a growth/survival factor promoting the altered P-EC phenotype in iPAH and disease progression.Results: In distal pulmonary arteries (PAs) of patients with iPAH, we found a strong immunoreactivity for MIF in the endothelium compared with PAs from control patients. This aberrant endothelial MIF expression is also found in the SU5416 plus hypoxia/normoxia- exposed rats and the monocrotaline-injected rats as models of human PAH. These in situ observations were replicated in vitro, with cultured P-ECs from patients with iPAH exhibiting increased MIF expression and release compared with control P-ECs. Decreasing MIF expression and signaling by RNA interference or a specific MIF inhibitor called ISO-1 decreased proliferation and induced apoptosis of iPAH P-ECs. Finally, we found that daily treatment of rats with ISO-1 for 2 weeks started 1 week after a subcutaneous monocrotaline injection partially reverses development of pulmonary hypertension. Conclusions: We report here that the pulmonary endothelium of iPAH patients represents a local abnormal source of MIF that could contribute to the hyperproliferative phenotype of iPAH endothelial cells.