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SHR Neuro Cancer Cardio Lipid Metab Microb

Birnhuber, A; Biasin, V; Jain, PP; Kwiatkowski, G; Boiarina, E; Wilhelm, J; Ahrens, K; Nagaraj, C; Olschewski, A; Witzenrath, M; Chlopicki, S; Marsh, LM; Tabeling, C; Kwapiszewska, G.
Pulmonary vascular remodeling in Fra-2 transgenic mice is driven by type 2 inflammation and accompanied by pulmonary vascular hyperresponsiveness.
Am J Physiol Lung Cell Mol Physiol. 2025; Doi: 10.1152/ajplung.00274.2024
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Leading authors Med Uni Graz

Birnhuber Anna

Kwapiszewska-Marsh Grazyna

Co-authors Med Uni Graz

Biasin Valentina

Chandran Nagaraj

Marsh Leigh

Olschewski Andrea

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Abstract:

Lung vessel remodeling leads to increased pulmonary vascular resistance, causing pulmonary arterial hypertension (PAH), and consequently right ventricular hypertrophy and failure. In patients suffering from systemic sclerosis (SSc), PAH can occur and is a life-threatening complication. Dysregulation of immune processes plays a crucial role in pulmonary vascular remodeling, as has previously been shown in Fos-related antigen-2 (Fra-2) transgenic (TG) mice, a model of SSc-PAH. Here, we investigate whether vascular remodeling in the Fra-2 TG model is driven by type 2 inflammation and is associated with vascular hyperresponsiveness, an important feature of PAH pathobiology. Basal pulmonary arterial pressure and pulmonary vascular responsiveness to hypoxic ventilation and serotonin were increased in isolated, perfused and ventilated lungs of Fra-2 TG mice compared to wild-type (WT) littermates. Similarly, contractile responses of isolated intrapulmonary arteries were elevated in Fra-2 TG mice. We also observed increased expression of contractile genes in Fra-2 overexpressing human pulmonary artery smooth muscle cells (PASMCs) with elevated intracellular calcium levels after IL-13 stimulation. These findings were corroborated by transcriptomic data highlighting dysregulation of vascular smooth muscle cell contraction and type 2 inflammation in Fra-2 TG mice. In vivo, type 2-specific anti-inflammatory treatment with IL-13 neutralizing antibodies improved vascular remodeling in Fra-2 TG mice, similar to corticosteroid treatment with budesonide. Our results underscore the importance of type 2 inflammation and its potential therapeutic value in PAH-associated pulmonary vascular remodeling and hyperresponsiveness in SSc-PAH.

Find related publications in this database (Keywords)

hypoxic pulmonary vasoconstriction

pulmonary hypertension

type 2 inflammation

vascular hyperresponsiveness

vascular remodeling

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