ArticleArthritis & rheumatology (Hoboken, N.J.)2020
Tumor Necrosis Factor Induces Obliterative Pulmonary Vascular Disease in a Novel Model of Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.
Article in Arthritis & rheumatology (Hoboken, N.J.), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 30 citations in OpenAlex.
- Connective Tissue Disease-Associated Pulmonary Arterial Hypertension: Current Therapeutic Strategies and Future Prospects.Biomolecules · 2026Review
- Mixed effects of complement in a chronic murine model of inflammatory erosive arthritis and pulmonary vascular disease.PloS one · 2026Article
- Echocardiographic Pulmonary Hypertension in Patients Positive for Myositis-Specific and Myositis-Associated Antibodies.Journal of clinical medicine · 2025Article
- TNF drives aberrant BMP signaling to induce endothelial and mesenchymal dysregulation in pulmonary hypertension.JCI insight · 2025Article
- Molecular Pathogenesis of Connective Tissue Disease-Associated Pulmonary Arterial Hypertension: A Narrative Review.Biomolecules · 2025Review
- Early detection of cardiac impairment and prediction of right ventricular hypertrophy in patients with connective tissue disease.Biomedical reports · 2025Article
- Progression of pulmonary arterial hypertension: A study in model.Open veterinary journal · 2024Article
- EnFUSiasm for Healing: Ultrasound Neuromodulation in PAH.Circulation research · 2024Article
- Recent Insights into Cellular and Molecular Mechanisms of Defective Angiogenesis in Systemic Sclerosis.Biomedicines · 2024Review
- Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: From Bedside to Bench and Back Again.International journal of molecular sciences · 2024Review
- Article
- Implementation of automated behavior metrics to evaluate voluntary wheel running effects on inflammatory-erosive arthritis and interstitial lung disease in TNF-Tg mice.Arthritis research & therapy · 2023Article
- Potential contribution of early endothelial progenitor cell (eEPC)-to-macrophage switching in the development of pulmonary plexogenic lesion.Respiratory research · 2022Article
- Thy-1 plays a pathogenic role and is a potential biomarker for skin fibrosis in scleroderma.JCI insight · 2022Article
- Euphorbia factor L3 ameliorates rheumatoid arthritis by suppressing the inflammatory response by targeting Rac family small GTPase 1.Bioengineered · 2022Article
- Huangqi Guizhi Wuwu Decoction Improves Arthritis and Pathological Damage of Heart and Lung in TNF-Tg Mice.Frontiers in pharmacology · 2022Article
- Smouldering fire or conflagration? An illustrated update on the concept of inflammation in pulmonary arterial hypertension.European respiratory review : an official journal of the European Respiratory Society · 2021Review
- Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood.Nature communications · 2021Article
- Engineering Advanced In Vitro Models of Systemic Sclerosis for Drug Discovery and Development.Advanced biology · 2021Review
- Article
Corrections and comments
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Authors and funding
16 authors at 1 institution in 1 country.
Funding
Abstract
objectiveConnective tissue disease (CTD)-associated pulmonary arterial hypertension (PAH) is the second most common etiology of PAH and carries a poor prognosis. Recently, it has been shown that female human tumor necrosis factor (TNF)-transgenic (Tg) mice die of cardiopulmonary disease by 6 months of age. This study was undertaken to characterize this pathophysiology and assess its potential as a novel model of CTD-PAH.
methodsHistologic analysis was performed on TNF-Tg and wild-type (WT) mice to characterize pulmonary vascular and right ventricular (RV) pathology (n = 40 [4-5 mice per group per time point]). Mice underwent right-sided heart catheterization (n = 29) and micro-computed tomographic angiography (n = 8) to assess vascular disease. Bone marrow chimeric mice (n = 12), and anti-TNF-treated mice versus placebo-treated mice (n = 12), were assessed. RNA sequencing was performed on mouse lung tissue (n = 6).
resultsTNF-Tg mice displayed a pulmonary vasculopathy marked by collagen deposition (P < 0.001) and vascular occlusion (P < 0.001) with associated RV hypertrophy (P < 0.001) and severely increased RV systolic pressure (mean ± SD 75.1 ± 19.3 mm Hg versus 26.7 ± 1.7 mm Hg in WT animals; P < 0.0001). TNF-Tg mice had increased α-smooth muscle actin (α-SMA) staining, which corresponded to proliferation and loss of von Willebrand factor (vWF)-positive endothelial cells (P < 0.01). There was an increase in α-SMA-positive, vWF-positive cells (P < 0.01), implicating endothelial-mesenchymal transition. Bone marrow chimera experiments revealed that mesenchymal but not bone marrow-derived cells are necessary to drive this process. Treatment with anti-TNF therapy halted the progression of disease. This pathology closely mimics human CTD-PAH, in which patient lungs demonstrate increased TNF signaling and significant similarities in genomic pathway dysregulation.
conclusionThe TNF-Tg mouse represents a novel model of CTD-PAH, recapitulates key disease features, and can serve as a valuable tool for discovery and assessment of therapeutics.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.