(Chest. 2005;128:572S-573S.)
© 2005
American College of Chest Physicians
Interleukin-6 Causes Mild Pulmonary Hypertension and Augments Hypoxia-Induced Pulmonary Hypertension in Mice*
Scott M. Golembeski, MS;
James West, PhD;
Yuji Tada, MD and
Karen A. Fagan, MD
* From the University of Colorado Health Sciences Center, Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, Center for Genetic Lung Diseases, Cardiovascular Pulmonary Research Laboratory, Denver, CO. This research was supported by AHA-SDG 0230255N (Dr. West) and NIH RO1 HL66328 and AHA-EIA 0340122N (Dr. Fagan).
Correspondence to: Karen Fagan, MD, University of Colorado Health Sciences Center, Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, Center for Genetic Lung Diseases, Cardiovascular Pulmonary Research Laboratory, 4200 East Ninth Ave, C#272, Denver, CO 80262; e-mail: karen.fagan{at}uchsc.edu
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Introduction
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Inflammation 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.
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Methods/Results
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Male C57BL/6 mice (weight, 25 g) were treated with daily subcutaneous injections of 200 µg/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.
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Conclusions
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IL-6 may play an important role in the pathogenesis of PAH. In mice, IL-6 is sufficient to cause PH, and its effects are augmented by hypoxia. IL-6-augmented hypoxic PH is associated with increases in IL-6 and ET-1 levels. Anti-IL-6 therapy may represent a new therapeutic paradigm in the treatment of PAH.
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Footnotes
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Abbreviations: ET = endothelin; IL = interleukin; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension; RVH = right ventricular hypertrophy
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Introduction
Methods/Results
