Brian B Graham1, Jacob Chabon, Liya Gebreab, Jennifer Poole, Elias Debella, Laura Davis, Takeshi Tanaka, Linda Sanders, Nina Dropcho, Angela Bandeira, R William Vandivier, Hunter C Champion, Ghazwan Butrous, Xiao-Jing Wang, Thomas A Wynn, Rubin M Tuder. 1. Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine (B.B.G., J.C., L.G., J.P., E.D., L.D., T.T., L.S., N.D., R.W.V.) and Department of Pathology (X.-J.W.), Anschutz Medical Campus, Aurora, CO; Pulmonary Vascular Research Institute (B.B.G., A.B., H.C.C., G.B., R.M.T.); Memorial S. Jose Hospital, Universidade de Pernambuco in Recife, Recife, Brazil (A.B.); Division of Cardiology, University of Pittsburgh, Pittsburgh, PA (H.C.C.); School of Pharmacy, University of Kent, Kent, UK (G.B.); and Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (T.A.W.).
Abstract
BACKGROUND: The pathogenic mechanisms underlying pulmonary arterial hypertension resulting from schistosomiasis, one of the most common causes of pulmonary hypertension worldwide, remain unknown. We hypothesized that transforming growth factor-β (TGF-β) signaling as a consequence of Th2 inflammation is critical for the pathogenesis of this disease. METHODS AND RESULTS: Mice sensitized and subsequently challenged with Schistosoma mansoni eggs developed pulmonary hypertension associated with an increase in right ventricular systolic pressure, thickening of the pulmonary artery media, and right ventricular hypertrophy. Rho-kinase-dependent vasoconstriction accounted for ≈60% of the increase in right ventricular systolic pressure. The pulmonary vascular remodeling and pulmonary hypertension were dependent on increased TGF-β signaling, as pharmacological blockade of the TGF-β ligand and receptor, and mice lacking Smad3 were significantly protected from Schistosoma-induced pulmonary hypertension. Blockade of TGF-β signaling also led to a decrease in interleukin-4 and interleukin-13 concentrations, which drive the Th2 responses characteristic of schistosomiasis lung pathology. Lungs of patients with schistosomiasis-associated pulmonary arterial hypertension have evidence of TGF-β signaling in their remodeled pulmonary arteries. CONCLUSION: Experimental S mansoni-induced pulmonary vascular disease relies on canonical TGF-β signaling.
BACKGROUND: The pathogenic mechanisms underlying pulmonary arterial hypertension resulting from schistosomiasis, one of the most common causes of pulmonary hypertension worldwide, remain unknown. We hypothesized that transforming growth factor-β (TGF-β) signaling as a consequence of Th2inflammation is critical for the pathogenesis of this disease. METHODS AND RESULTS:Mice sensitized and subsequently challenged with Schistosoma mansoni eggs developed pulmonary hypertension associated with an increase in right ventricular systolic pressure, thickening of the pulmonary artery media, and right ventricular hypertrophy. Rho-kinase-dependent vasoconstriction accounted for ≈60% of the increase in right ventricular systolic pressure. The pulmonary vascular remodeling and pulmonary hypertension were dependent on increased TGF-β signaling, as pharmacological blockade of the TGF-β ligand and receptor, and mice lacking Smad3 were significantly protected from Schistosoma-induced pulmonary hypertension. Blockade of TGF-β signaling also led to a decrease in interleukin-4 and interleukin-13 concentrations, which drive the Th2 responses characteristic of schistosomiasis lung pathology. Lungs of patients with schistosomiasis-associated pulmonary arterial hypertension have evidence of TGF-β signaling in their remodeled pulmonary arteries. CONCLUSION: Experimental S mansoni-induced pulmonary vascular disease relies on canonical TGF-β signaling.
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