Assessment of mustard vesicant lung injury and anti‐TNF‐α efficacy in rodents using live‐animal imaging

Abstract

Nitrogen mustard (NM) causes acute lung injury, which progresses to fibrosis. This is associated with a macrophagedominant inflammatory response and the production of proinflammatory/profibrotic mediators, including tumor necrosis factor alpha (TNF-α). Herein, we refined magnetic resonance imaging (MRI) and computed tomography (CT) imaging methodologies to track the progression of NM-induced lung injury in rodents and assess the efficacy of anti-TNF-α antibody in mitigating toxicity. Anti-TNF-α antibody was administered to rats (15 mg/kg, every 8 days, intravenously) beginning 30 min after treatment with phosphate-buffered saline control or NM (0.125 mg/kg, intratracheally). Animals were imaged by MRI and CT prior to exposure and 1-28 days postexposure. Using MRI, we characterized acute lung injury and fibrosis by quantifying high-signal lung volume, which represents edema, inflammation, and tissue consolidation; these pathologies were found to persist for 28 days following NM exposure. CT scans were used to assess structural components of the lung and to register changes in tissue radiodensities. CT scans showed that in control animals, total lung volume increased with time. Treatment of rats with NM caused loss of lung volume; anti-TNF-α antibody mitigated this decrease. These studies demonstrate that MRI and CT can be used to monitor lung disease and the impact of therapeutic intervention.

Overlapping Science in Radiation and Sulfur Mustard Exposures of Skin and Lung: Consideration of Models, Mechanisms, Organ Systems, and Medical Countermeasures: Overlapping science in radiation and sulfur mustard injuries to lung and skin

“…BARDA continues to fund work on the anti-TNFα antibody, to advance the approach through the FDA approval process to treat mustard toxicity. 66,[69][70][71][72][73][74][75][76][77] As mentioned above, M2 macrophages accumulate early within the lung. As lung macrophages differentiate to M2 macrophages, following mustard exposure, their morphology changes.…”

“…71,72 These animals are exposed to a range of mustard doses and followed from 1 to 28 days post-exposure, with an assessment of lung tissue and lining, bronchoalveolar lavage (BAL) fluid, and immune cells, as well as pulmonary function analyses and live animal MRI/ CT scanning. 73 Histopathological effects of SM on the lung include early thickening of the epithelium and airways that become more prominent over time. These effects are pronounced at 16 days, with increased thickening of the alveolar areas, marked presence of immune-inflammatory cells, and increased sloughing of the upper epithelial lining.…”

“…The levels of each subset of macrophages and their mediators directly correlated with the time course of acute and chronic injury seen in lung tissue. [69][70][71][72][73][74][75][76][77] Involvement of these macrophages' subsets in pathogenesis of SM-induced lung fibrosis provides potential targets for mitigating damage. One approach is by targeting M1 macrophages and proinflammatory/ cytotoxic mediators specifically, rather than general anti-inflammatory agents.…”

Effects and early diagnostic value of lncRNA H19 on sepsis‑induced acute lung injury

“…3A and D ). As a systemic inflammatory response syndrome, sepsis inevitably causes changes in inflammatory factors (TNF-α, IL-6 and IL-17) ( 28-30 ), thus the levels of these factors were determined as well to evaluate the inflammatory response. TNF-α, IL-6, and IL-17 were increased in the pulmonary tissue and serum of septic rats compared to the control group, while upregulation of lncRNA H19 reduced their levels compared with the model group ( Fig.…”

Effects of Overexpression of Fibroblast Growth Factor 15/19 on Hepatic Drug Metabolizing Enzymes

“…Body Composition CT Imaging. Male 5-month old WT and Fgf15 Tg mice (n=5/group) were imaged using an Albira PET/CT (Bruker, Billerica, MA) as previously described (Metzinger et al, 2014;Murray et al, 2020). In brief, anesthetized mice were scanned using the following settings: Good Low High scan setting (400 slices), field of view (120mm 2 ) with tube current (200 μA) and voltage (45kV).…”