Abstract
Rationale: Inflammation and endothelial dysfunction are considered two primary instigators of pulmonary arterial hypertension (PAH). CD74 is a receptor for the cytokine macrophage migration-inhibitory factor (MIF). This ligand/receptor complex initiates survival pathways and cell proliferation, triggers the synthesis/secretion of major pro-inflammatory factors and cell adhesion molecules. Objectives: We hypothesized that MIF and endothelial-CD74 are over-expressed and over-activated in PAH and contributes to pulmonary endothelial cells (P-ECs) pro-inflammatory phenotype. Results: Circulating MIF levels is increased in serum of idiopathic PAH (iPAH) patients as compared to controls and T-cells lymphocytes represent a cause of this overabundance. In addition, CD74 is highly expressed in the endothelium of muscularized distal pulmonary arteries as well as in cultured P-ECs from iPAH and contributes to an exaggerated recruitment of PBMC to P-EC in iPAH. Over-activation of CD74 by MIF induces production of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 and causes an increase in intercellular adhesion molecule (ICAM)-1 protein level. These effects are partially abolishes in presence of the selective MIF antagonist ISO-1. Finally, we found that daily treatment of rats with ISO-1 for 2 weeks started 2 weeks after a subcutaneous monocrotaline injection partially reverses development of pulmonary hypertension and this is associated with decreased of IL-6, MCP-1 and inflammatory cell infiltration. Conclusions: We report here that CD74 and MIF are markedly increased and activated from iPAH patients and contribute to the abnormal pro-inflammatory phenotype of P-EC in PAH.
- © 2013 ERS