IL-6 Overexpression Induces Pulmonary Hypertension
By M. Steiner, O. Syrkina, N. Kolliputi, E. Mark, C. Hales, A. Waxman. Circulation Research, 2008
598 citations recorded by the source corpus.
Inflammatory cytokine interleukin (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 role of IL-6 in the pathogenesis of pulmonary vascular disease. Indices of pulmonary vascular remodeling were measured in lung-specific IL-6–overexpressing 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 proangiogenic factor, vascular endothelial growth factor, the proproliferative kinase extracellular signal-regulated kinase, proproliferative transcription factors c-MYC and MAX, and the antiapoptotic proteins survivin and Bcl-2 and downregulation of the growth inhibitor transforming growth factor-&bgr; and proapoptotic kinases JNK and p38. These findings suggest that IL-6 promotes the development and progression of pulmonary vascular remodeling and PAH through proproliferative antiapoptotic mechanisms.
Subfields: Oncology, Pulmonary and Respiratory Medicine, Surgery
View Paper: https://www.semanticscholar.org/paper/537062417efc2d21960f4f10386f3c381ae573aa
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In Pulmonary and Respiratory Medicine
Citations in the corpus
- Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. (2009, background): “Exposure of mice to chronic hypoxia, although causing an elevation in pulmonary artery pressure, is associated with only minimal vascular remodeling, certainly less than the rat (37, 45, 121, 152).”
- Mechanisms of disease: pulmonary arterial hypertension (2011, background): “147, 148 Furthermore, transgenic overexpression of IL-6 led to severe pulmonary hypertension in mice, 149 and IL-6-deficient mice were protected from hypoxia-driven experimental pulmonary hypertension.”
- Molecular pathogenesis of pulmonary arterial hypertension. (2008, background): “Loss of BMPR2 induces IL-6 (98), a cytokine that can cause severe pulmonary vascular disease in rodents (99) in association with SMC proliferation (100) mediated by the transcription factor Kruppel-like factor 5 (101).”