Inflammatory cytokine IL-6 is elevated in the serum and lungs of patients with pulmonary artery hypertension (PAH). Several animal models of PAH cite the potential role of inflammatory mediators. We investigated IL-6’s role in the pathogenesis of pulmonary vascular disease. Indices of pulmonary vascular remodeling were measured in lung specific IL-6 over expression transgenic mice (Tg(+)) and compared to wild type (Tg(-)) controls in both normoxic and chronic hypoxic conditions. The Tg(+) mice exhibited elevated right ventricular systolic pressures and right ventricular hypertrophy with corresponding pulmonary vasculopathic changes, all of which were exacerbated by chronic hypoxia. IL-6 overexpression increased muscularization of the proximal arterial tree, and hypoxia enhanced this effect. It also reproduced the muscularization and proliferative arteriopathy seen in the distal arteriolar vessels of PAH patients. The latter was characterized by the formation of occlusive neointimal angioproliferative lesions that worsened with hypoxia and were composed of endothelial cells and T-lymphocytes. IL-6-induced arteriopathic changes were accompanied by activation of pro-angiogenic factor, vascular endothelial growth factor, the pro-proliferative kinase, ERK, pro-proliferative transcription factors c-MYC and MAX, the anti-apoptotic proteins survivin and Bcl-2, and down-regulation of the growth inhibitor transforming growth factor-β, and pro-apoptotic kinases JNK and p38. These findings suggest that IL-6 promotes the development and progression of pulmonary vascular remodeling and PAH through pro-proliferative anti-apoptotic mechanisms.

Introduction Mechanical ventilation with even moderate-sized tidal volumes synergistically increases lung injury in sepsis and has been associated with proinflammatory low-molecular-weight hyaluronan production. High-molecular-weight hyaluronan (HMW HA), in contrast, has been found to be anti-inflammatory. We hypothesized that HMW HA would inhibit lung injury associated with sepsis and mechanical ventilation.