Restrictive lung disease in TNF-transgenic mice: correlation of pulmonary function testing and micro-CT imaging

Wu, Emily; Eliseeva, Sophia; Rahimi, Homaira; Schwarz, Edward M.; Georas, Steve N.

doi:10.1080/01902148.2019.1636899

Cited by 13 publications

(11 citation statements)

References 39 publications

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“…The TNF‐Tg 3467 mouse line, which harbors an insertion of a single copy of the human TNF transgene, has been described as a model of erosive inflammatory arthritis for over 20 years . A “pulmonary vasculitis” was described in these mice in 2016 , and our group recently identified a sexually dimorphic lung pathology with functional and histologic features consistent with restrictive lung disease and RV involvement . Building on this work, the present study comprehensively assessed the cardiopulmonary phenotype in these mice and has now established this TNF‐Tg line as a bona fide mouse model of CTD‐PAH.…”

Section: Discussionmentioning

confidence: 79%

“…Our group has recently shown that transgenic mice expressing chronic low levels of human tumor necrosis factor (TNF‐Tg mice; line 3647) display interstitial lung disease (ILD) , which is more severe in female mice . These mice die prematurely, and we were intrigued to find that in addition to ILD, these animals also had perivascular lung inflammation and right‐sided heart disease .…”

Section: Introductionmentioning

confidence: 99%

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

Bell

White

García-Hernández

et al. 2020

Arthritis & Rheumatology

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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.

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Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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

Bell

White

García-Hernández

et al. 2020

Arthritis & Rheumatology

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“…Activation and nuclear localization of Caspase-3 by TNF-α has been suggested in relation to adipocytes [33], and TNF-α-dependent apoptosis by SDF-1 has been reported in cardiac myocytes [34]. Interestingly, the role of proinflammatory cytokine TNF-α in lung fibrosis has been investigated with contradictory reports, two studies showing permanent expression of TNF-α by alveolar epithelial cells leading to fibrotic lesions in the mice lung [35,36]. However, a recent study suggests that TNF-α can resolve lung fibrosis by targeting the profibrotic macrophages in the rodent model of lung fibrosis [37].…”

Section: Discussionmentioning

confidence: 99%

Anti-Fibrotic Effect of SDF-1β Overexpression in Bleomycin-Injured Rat Lung

Fytianos

Schliep²,

Mykoniati³

et al. 2022

Pharmaceutics

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Rational: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease and is associated with high mortality due to a lack of effective treatment. Excessive deposition of the extracellular matrix by activated myofibroblasts in the alveolar space leads to scar formation that hinders gas exchange. Therefore, selectively removing activated myofibroblasts with the aim to repair and remodel fibrotic lungs is a promising approach. Stromal-derived growth factor (SDF-1) is known to stimulate cellular signals which attract stem cells to the site of injury for tissue repair and remodeling. Here, we investigate the effect of overexpression of SDF-1β on lung structure using the bleomycin-injured rat lung model. Methods: Intratracheal administration of bleomycin was performed in adult male rats (F344). Seven days later, in vivo electroporation-mediated gene transfer of either SDF-1β or the empty vector was performed. Animals were sacrificed seven days after gene transfer and histology, design-based stereology, flow cytometry, and collagen measurement were performed on the tissue collected. For in vitro experiments, lung fibroblasts obtained from IPF patients were used. Results: Seven days after SDF-1β gene transfer to bleomycin-injured rat lungs, reduced total collagen, reduced collagen fibrils, improved histology and induced apoptosis of myofibroblasts were observed. Furthermore, it was revealed that TNF-α mediates SDF-1β-induced apoptosis of myofibroblasts; moreover, SDF-1β overexpression increased alveolar epithelial cell numbers and proliferation in vivo and also induced their migration in vitro. Conclusions: Our study demonstrates a new antifibrotic mechanism of SDF-1β overexpression and suggests SDF-1β as a potential new approach for the treatment of lung fibrosis.

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“…Исследования действия провоспалительных цитокинов (ФНО-a, ИЛ-1β, ИФН-γ) на нормальные эпителиальные клетки бронхов человека выявили, что ФНО-a, ИФН-γ и, в меньшей степени, ИЛ-1β могут вызывать повреждения митохондрий и десмосом, снижать уровень окисления глюкозы, увеличивать содержание внутриклеточного Na + /К + , аккумуляцию NO, индуцировать некроз и апоптоз эндотелиальных клеток, что может приводить к шеддингу эпителия при повреждении лёгких [14,15]. Есть исследования, показывающие, что LPS-индуцированный апоптоз макрофагов во многом связан с ИФН-γ, при этом его интенсивность снижается под действием ИЛ-4, ИЛ-10 [16,17].…”

Section: Abstract: Influenza; Treatment; Riamilovir; Umifenovir; Cytokines Tnf-a; Il-10unclassified

Comparative Effectiveness of Riamilovir and Umifenovir for Treating Influenza

Popov

Маркелова

Комарова

et al. 2021

A&Ch

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The present study focuses on the comparative assessment of the therapeutic efficacy of the antiviral drugs riamilovir and umifenovir in the treatment of patients diagnosed with influenza. The aim of the study was to compare the clinical efficacy and safety, as well as the incidence of complications, of the use of antiviral drugs riamilovir and umifenovir and the use of only symptomatic therapy in patients with a confirmed diagnosis of influenza. All patients were hospitalized at the Regional Clinical Hospital No. 2 in Vladivostok. The study included 150 patients, who were divided into 3 groups (50 patients in each group), comparable in gender, age, and admission to the hospital. Patients of the first group received riamilovir, the second group received uminofenovir, patients of the third group received only symptomatic therapy (control group). The duration of clinical manifestations of the disease, hematological disorders, as well as the content of cytokines TNF-α and IL-10 in blood serum were assessed. The incidence of complications in each group was taken into account. As a result of the study, it was found that the inclusion of the antiviral drugs riamilovir and umifenovir in the therapy of influenza decreases the amount of the pro-inflammatory cytokine TNF-α after 5 days of treatment; and in case of symptomatic therapy its level significantly exceeded the reference values. The level of anti-inflammatory cytokine IL-10 on the 5th day of treatment in the main group was three times lower than in the control group. Thus, riamilovir and umifenovir effectively relieve the main symptoms of the disease, reduce the incidence of complications, and reduce the severity of the inflammatory response by the 5th day of treatment.

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Restrictive lung disease in TNF-transgenic mice: correlation of pulmonary function testing and micro-CT imaging

Cited by 13 publications

References 39 publications

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

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

Anti-Fibrotic Effect of SDF-1β Overexpression in Bleomycin-Injured Rat Lung

Comparative Effectiveness of Riamilovir and Umifenovir for Treating Influenza

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