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Transforming growth factor-? signaling promotes pulmonary hypertension caused by Schistosoma mansoni.

ABSTRACT: 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-? (TGF-?) signaling as a consequence of Th2 inflammation is critical for the pathogenesis of this disease.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-? signaling, as pharmacological blockade of the TGF-? ligand and receptor, and mice lacking Smad3 were significantly protected from Schistosoma-induced pulmonary hypertension. Blockade of TGF-? 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-? signaling in their remodeled pulmonary arteries.Experimental S mansoni-induced pulmonary vascular disease relies on canonical TGF-? signaling.

SUBMITTER: Graham BB

PROVIDER: S-EPMC3880024 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Transforming growth factor-β signaling promotes pulmonary hypertension caused by Schistosoma mansoni.

Graham Brian B BB Chabon Jacob J Gebreab Liya L Poole Jennifer J Debella Elias E Davis Laura L Tanaka Takeshi T Sanders Linda L Dropcho Nina N Bandeira Angela A Vandivier R William RW Champion Hunter C HC Butrous Ghazwan G Wang Xiao-Jing XJ Wynn Thomas A TA Tuder Rubin M RM

Circulation 20130819 12

<h4>Background</h4>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.<h4>Methods and results</h4>Mice sensitized and subsequently challenged with Schistosoma mansoni eggs developed pulmonary hypertension associat ...[more]

PMID: 23958565

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Project description:The etiology of schistosomiasis-associated pulmonary arterial hypertension (PAH), a major cause of PAH worldwide, is poorly understood. Schistosoma mansoni exposure results in prototypical type-2 inflammation. Furthermore, transforming growth factor (TGF)-? signaling is required for experimental pulmonary hypertension (PH) caused by Schistosoma exposure.We hypothesized type-2 inflammation driven by IL-4 and IL-13 is necessary for Schistosoma-induced TGF-?-dependent vascular remodeling.Wild-type, IL-4(-/-), IL-13(-/-), and IL-4(-/-)IL-13(-/-) mice (C57BL6/J background) were intraperitoneally sensitized and intravenously challenged with S. mansoni eggs to induce experimental PH. Right ventricular catheterization was then performed, followed by quantitative analysis of the lung tissue. Lung tissue from patients with schistosomiasis-associated and connective tissue disease-associated PAH was also systematically analyzed.Mice with experimental Schistosoma-induced PH had evidence of increased IL-4 and IL-13 signaling. IL-4(-/-)IL-13(-/-) mice, but not single knockout IL-4(-/-) or IL-13(-/-) mice, were protected from Schistosoma-induced PH, with decreased right ventricular pressures, pulmonary vascular remodeling, and right ventricular hypertrophy. IL-4(-/-)IL-13(-/-) mice had less pulmonary vascular phospho-signal transducer and activator of transcription 6 (STAT6) and phospho-Smad2/3 activity, potentially caused by decreased TGF-? activation by macrophages. In vivo treatment with a STAT6 inhibitor and IL-4(-/-)IL-13(-/-) bone marrow transplantation also protected against Schistosoma-PH. Lung tissue from patients with schistosomiasis-associated and connective tissue disease-associated PAH had evidence of type-2 inflammation.Combined IL-4 and IL-13 deficiency is required for protection against TGF-?-induced pulmonary vascular disease after Schistosoma exposure, and targeted inhibition of this pathway is a potential novel therapeutic approach for patients with schistosomiasis-associated PAH.

Dataset Information

Transforming growth factor-? signaling promotes pulmonary hypertension caused by Schistosoma mansoni.

Publications

Transforming growth factor-β signaling promotes pulmonary hypertension caused by Schistosoma mansoni.

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