The Role of p38 Mitogen-Activated Protein Kinase in Hypoxia-Induced Vascular Cell Proliferation

I nflammation may play a central role in the pathogenesis of pulmonary arterial hypertension (PAH). Levels of interleukin (IL)-6, IL-1, C-reactive protein, regulated on activation normal T cells expressed and secreted (RANTES), and fractalkine are increased in the serum and lungs of PAH patients. Scleroderma, lupus, mixed connective tissue disease, Castleman disease, HIV, and polyneuropathy/organomegaly/endocrinopathy/M protein/skin changes (POEMS syndrome) are associated with increased IL-6 and PAH. IL-6 may play a pathogenic role through inflammation, cellular proliferation, interaction with bone morphogenetic protein pathways, decreasing prostacyclin levels, and induction of the production of other mediators such as serotonin, endothelin (ET)-1 and vascular endothelial growth factor. Experimental models of pulmonary hypertension (PH), including hypoxia and monocrotaline, are associated with increased IL-6 levels. Previous studies have found right ventricular hypertrophy (RVH) in rats treated with recombinant human IL-6. This was associated with evidence of vascular thrombosis and may be a model of chronic thromboembolic PAH. We hypothesized that IL-6 would cause PH in mice and that IL-6 may potentiate the development of PH following chronic hypoxia in mice. Methods/Results Male C57BL/6 mice (weight, 25 g) were treated with daily subcutaneous injections of 200 g/kg recombinant murine IL-6 and saline solution, and exposed to normoxia or hypobaric hypoxia for 14 days. The animals were killed and right ventricular pressure and RVH were measured. IL-6-treated mice had increased right ventricular pressure (p 0.08) and RVH (p 0.05) in normoxia compared to those treated with saline solution. There was no evidence of lung inflammation or vascular thrombosis. During hypoxia, treatment with IL-6 further augmented the increase in RVH compared to treatment with saline solution and this was associated with a greater increase in both IL-6 and ET-1 messages as determined by quantitative polymerase chain reaction.