Protective role of IL-6 in vascular remodeling in Schistosoma pulmonary hypertension
| Autor: | Graham, Brian B, Chabon, Jacob, Kumar, Rahul, Kolosionek, Ewa, Gebreab, Liya, Debella, Elias, Edwards, Michael, Diener, Katrina, Shade, Ted, Bifeng, Gao, Bandeira, Angela, Butrous, Ghazwan, Jones, Kenneth, Geraci, Mark, Tuder, Rubin M |
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| Rok vydání: | 2013 |
| Předmět: |
STAT3 Transcription Factor
Knockout Messenger Respiratory System Pulmonary Artery Cardiorespiratory Medicine and Haematology Inbred C57BL Cardiovascular Mice Rare Diseases schistosomiasis pulmonary hypertension Genetics gene expression profiling Animals Humans 2.1 Biological and endogenous factors Familial Primary Pulmonary Hypertension Aetiology Lung IL-6 NFATC Transcription Factors Animal Interleukin-6 Gene Expression Profiling Human Genome Schistosoma mansoni Pulmonary Schistosomiasis mansoni Vector-Borne Diseases Good Health and Well Being Hypertension Disease Models RNA Signal Transduction Biotechnology |
| Zdroj: | American journal of respiratory cell and molecular biology, vol 49, iss 6 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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