Tumor Necrosis Factor Induces Obliterative Pulmonary Vascular Disease in a Novel Model of Connective Tissue Disease–Associated Pulmonary Arterial Hypertension

Abstract

Objective. Connective 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. Methods. Histologic 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). Results. TNF-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, vWFpositive 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. Conclusion. The 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.

Huangqi Guizhi Wuwu Decoction Improves Arthritis and Pathological Damage of Heart and Lung in TNF-Tg Mice

“…RA complicated with heart disease, including myocardial hypertrophy, myocardial fibrosis, and RA-ILD including pulmonary fibrosis and inflammatory infiltration, have been reported in other animal models of RA ( Bell et al, 2020 ; Keith et al, 2012 ; Pironti et al, 2018 ; Redente et al, 2018 ). For the TNF-Tg model used in this study, It has been previously reported that TNF-Tg mice have lung lesions, including pulmonary inflammatory cell accumulation, pulmonary arteriole thickening, pulmonary fibrosis, and emphysema ( Lundblad et al, 2005 ; Bell et al, 2018 ).…”

Engineering Advanced In Vitro Models of Systemic Sclerosis for Drug Discovery and Development

“…[ 32 ] A TNF‐transgenic model was recently shown to develop spontaneous and severe pulmonary hypertension and have genomic overlap with SSc‐PAH but to lack systemic fibrosis. [ 33 ] Another model is represented by urokinase‐type plasminogen activator receptor (uPAR)‐deficient mice. Urokinase‐type plasminogen activator receptor is a glycosylphosphatidylinositol‐anchored cell surface receptor which concentrates its ligand, urokinase‐type plasminogen activator (uPA), at the cell–matrix interface.…”

High-throughput analysis of lung immune cells in a combined murine model of agriculture dust-triggered airway inflammation with rheumatoid arthritis

“…Likewise, the ODE group lacked clusters 1a and 2a. A subset of cluster 12 (12b) and cluster 10 (10b) were [22] unique to the CIA group, while clusters 10a and 12a were unique to the ODE group (Fig 3). The combination group with CIA+ODE showed a mixed population representing CIA and ODE, while leaning more towards the CIA group (Fig 3).…”

“…In general, animal modeling of arthritis-lung disease interactions are overall limited. The over-expressing TNF-alpha transgenic mice that develop an array of connective tissue diseases has been associated with interstitial lung disease and pulmonary hypertension, particularly in female mice [22]. The arthritic SKG mice develop a cellular and fibrotic interstitial pneumonia [140], but SKG mice do not develop compelling evidence of autoimmunity or arthritis following inhalation injury (i.e tobacco smoke or bleomycin) [140].…”