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A2101 - Paclitaxel Blocks Th2-Mediated TGF-β Activation in Schistosoma Mansoni-Induced Pulmonary Hypertension
Author Block: B. Kassa1, R. Kumar2, C. Mickael3, L. Sanders1, D. Koyanangi1, D. Hernandez-Saavedra1, R. M. Tuder4, B. B. Graham5; 1Medicine, University of Colorado, Denver, Aurora, CO, United States, 2Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, United States, 3Pulmonary Sciences and Critical care, Aurora, CO, United States, 4Pulmonary Dept, Univ of Colorodo Denver Sch of Med, Aurora, CO, United States, 5Medicine, University of Colorado, Aurora, CO, United States.
Title: Paclitaxel Blocks Th2-Mediated TGF-β Activation in Schistosoma mansoni-Induced Pulmonary Hypertension Authors: Biruk Kassa, Rahul Kumar, Claudia Mickael, Linda Sanders, Dan Koyanangi, Daniel Hernandez-Saavedra, Rubin Tuder, Brian Graham Institution: Program in Translational Lung Research, University of Colorado, Denver Rational: Schistosomiasis is a leading cause of pulmonary hypertension (PH), affecting 5-15 million people worldwide. Recent evidence indicates the Th2 inflammatory cytokines IL-4 and IL-13 and subsequent activation of TGF-β is required for Schistosoma-induced PH. Paclitaxel, an FDA approved drug, has been suggested to augment anti-parasite Th2 inflammation and suppress TGF-β activation, and it has been shown to block PH due to monocrotaline and SU5416-hypoxia. Thus, we hypothesized that paclitaxel would be beneficial in Schistosoma-induced PH, without suppressing the anti-parasite Th2 inflammation. Method: Wildtype mice (C57BL6/J background; N=6/group) were intraperitoneally (IP) sensitized to 240 S. mansoni eggs/gram body weight, and then intravenously (IV) challenged with 175 S. mansoni eggs/gram body weight. One day after IV egg challenge, the mice were treated with a single IP dose of 25mg/kg paclitaxel or vehicle alone. 6 days later right ventricular (RV) catheterization was performed and RV hypertrophy (Fulton index), granuloma volumes and vascular remodeling were measured. IL-4 and IL-13 levels in lung homogenates were quantified by ELISA, and the quantity of active TGF-β was determined by assessing luciferase activity using a cell reporter line. Results: Paclitaxel treatment significantly protected mice from Schistosoma-PH, with decreased RV systolic pressure (P=0.005) and RV hypertrophy, although there was no change in vascular intima or media thickness (P=NS for both). Inflammation was significantly suppressed, with decreased IL-4 and IL-13 levels, smaller granuloma volumes, and less active TGF-β following paclitaxel treatment. Conclusion: Paclitaxel protects against Schistosoma-induced PH in mice. However, it blocks the proximate Th2 inflammation as well, which could leave the host susceptible to further infection. Funding sources: This work was supported by NHLBI.