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TGF-? activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension.

ABSTRACT: Pulmonary arterial hypertension (PAH) is an obstructive disease of the precapillary pulmonary arteries. Schistosomiasis-associated PAH shares altered vascular TGF-? signalling with idiopathic, heritable and autoimmune-associated etiologies; moreover, TGF-? blockade can prevent experimental pulmonary hypertension (PH) in pre-clinical models. TGF-? is regulated at the level of activation, but how TGF-? is activated in this disease is unknown. Here we show TGF-? activation by thrombospondin-1 (TSP-1) is both required and sufficient for the development of PH in Schistosoma-exposed mice. Following Schistosoma exposure, TSP-1 levels in the lung increase, via recruitment of circulating monocytes, while TSP-1 inhibition or knockout bone marrow prevents TGF-? activation and protects against PH development. TSP-1 blockade also prevents the PH in a second model, chronic hypoxia. Lastly, the plasma concentration of TSP-1 is significantly increased in subjects with scleroderma following PAH development. Targeting TSP-1-dependent activation of TGF-? could thus be a therapeutic approach in TGF-?-dependent vascular diseases.

SUBMITTER: Kumar R

PROVIDER: S-EPMC5459967 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension.

Kumar Rahul R Mickael Claudia C Kassa Biruk B Gebreab Liya L Robinson Jeffrey C JC Koyanagi Daniel E DE Sanders Linda L Barthel Lea L Meadows Christina C Fox Daniel D Irwin David D Li Min M McKeon B Alexandre BA Riddle Suzette S Dale Brown R R Morgan Leslie E LE Evans Christopher M CM Hernandez-Saavedra Daniel D Bandeira Angela A Maloney James P JP Bull Todd M TM Janssen William J WJ Stenmark Kurt R KR Tuder Rubin M RM Graham Brian B BB

Nature communications 20170530

Pulmonary arterial hypertension (PAH) is an obstructive disease of the precapillary pulmonary arteries. Schistosomiasis-associated PAH shares altered vascular TGF-β signalling with idiopathic, heritable and autoimmune-associated etiologies; moreover, TGF-β blockade can prevent experimental pulmonary hypertension (PH) in pre-clinical models. TGF-β is regulated at the level of activation, but how TGF-β is activated in this disease is unknown. Here we show TGF-β activation by thrombospondin-1 (TSP- ...[more]

PMID: 28555642

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Project description:Rationale: 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 by whole-lung transcriptome analysis. Methods: Wildtype mice were experimentally exposed to S. mansoni ova by intraperitoneal sensitization followed by tail vein augmentation, and the phenotype assessed by right ventricular catheterization and tissue histology, RNA and protein analysis. Whole-lung transcriptome analysis by microarray and RNA sequencing was performed, the latter analyzed using 2 bioinformatic methods. Functional testing of the candidate IL-6 pathway was determined using IL6-knockout mice and the STAT3 inhibitor STI-201. Results: Wild-type mice exposed to S. mansoni had increased right ventricular systolic pressure and thickness of the pulmonary vascular media. Whole lung transcriptome analysis identified the IL6-STAT3-NFATc2 pathway as being upregulated, which was confirmed by PCR and immunostaining of lung tissue from S. mansoni-exposed mice and patients who died of the disease. Mice lacking IL6 or treated with STI-201 developed pulmonary hypertension associated with significant intima remodeling after exposure to S. mansoni. Conclusions: Whole lung transcriptome analysis identified upregulation of the IL6-STAT3-NFATc2 pathway, and IL6 signaling was found to be protective against Schistosoma-induced intimal remodeling. Affy Mouse ST1.0 chip used. Data published in: Protective Role of IL6 in Vascular Remodeling in Schistosoma-Pulmonary Hypertension. Graham BB, Chabon J, Kumar R, Kolosionek E, Gebreab L, Debella E, Edwards M, Diener K, Shade T, Bifeng G, Bandeira A, Butrous G, Jones K, Geraci M, Tuder RM. Am J Respir Cell Mol Biol. 2013 Jul 1. [Epub ahead of print] PMID: 23815102

Dataset Information

TGF-? activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension.

Publications

TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension.

Similar Datasets

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