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Protective role of IL-6 in vascular remodeling in Schistosoma pulmonary hypertension.

ABSTRACT: Schistosomiasis is one of the most common causes of pulmonary arterial hypertension worldwide, but the pathogenic mechanism by which the host inflammatory response contributes to vascular remodeling is unknown. We sought to identify signaling pathways that play protective or pathogenic roles in experimental Schistosoma-induced pulmonary vascular disease via whole-lung transcriptome analysis. Wild-type mice were experimentally exposed to Schistosoma mansoni ova by intraperitoneal sensitization followed by tail-vein augmentation, and the phenotype was assessed by right ventricular catheterization and tissue histology, as well as RNA and protein analysis. Whole-lung transcriptome analysis by microarray and RNA sequencing was performed, and RNA sequencing was analyzed according to two bioinformatics methods. Functional testing of the candidate IL-6 pathway was determined using IL-6 knockout mice and the signal transducers and activators of transcription protein-3 (STAT3) inhibitor S3I-201. Wild-type mice exposed to S. mansoni demonstrated increased right ventricular systolic pressure and thickness of the pulmonary vascular media. Whole-lung transcriptome analysis determined that the IL-6-STAT3-nuclear factor of activated T cells c2(NFATc2) pathway was up-regulated, as confirmed by PCR and the immunostaining of lung tissue from S. mansoni-exposed mice and patients who died of the disease. Mice lacking IL-6 or treated with S3I-201 developed pulmonary hypertension, associated with significant intima remodeling after exposure to S. mansoni. Whole-lung transcriptome analysis identified the up-regulation of the IL-6-STAT3-NFATc2 pathway, and IL-6 signaling was found to be protective against Schistosoma-induced intimal remodeling.

SUBMITTER: Graham BB

PROVIDER: S-EPMC3931110 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Protective role of IL-6 in vascular remodeling in Schistosoma pulmonary hypertension.

Graham Brian B BB Chabon Jacob J Kumar Rahul R Kolosionek Ewa E Gebreab Liya L Debella Elias E Edwards Michael M Diener Katrina K Shade Ted T Bifeng Gao G Bandeira Angela A Butrous Ghazwan G Jones Kenneth K Geraci Mark M Tuder Rubin M RM

American journal of respiratory cell and molecular biology 20131201 6

Schistosomiasis is one of the most common causes of pulmonary arterial hypertension worldwide, but the pathogenic mechanism by which the host inflammatory response contributes to vascular remodeling is unknown. We sought to identify signaling pathways that play protective or pathogenic roles in experimental Schistosoma-induced pulmonary vascular disease via whole-lung transcriptome analysis. Wild-type mice were experimentally exposed to Schistosoma mansoni ova by intraperitoneal sensitization fo ...[more]

PMID: 23815102

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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

Protective role of IL-6 in vascular remodeling in Schistosoma pulmonary hypertension.

Publications

Protective role of IL-6 in vascular remodeling in Schistosoma pulmonary hypertension.

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