%0 Journal Article %A Morane Le Hiress %A Ly Tu %A Carole Phan %A Raphaƫl Thuillet %A Nicolas Ricard %A Andrei Seferian %A Elie Fadel %A Gerald Simonneau %A Alice Huertas %A Yuichi Tamura %A Marc Humbert %A Christophe Guignabert %T Endothelial-derived MIF contributes to pulmonary endothelial cell proliferation in human pulmonary arterial hypertension %D 2015 %R 10.1183/13993003.congress-2015.PA4900 %J European Respiratory Journal %P PA4900 %V 46 %N suppl 59 %X 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. %U