Debra L. Laskin

Macrophage involvement in the human response to ozone remains poorly defined. In this human crossover exposure study, we characterized ozone-induced changes in airway macrophage populations at 24, 48, and 72 h post-exposure. Ozone exposure caused immediate declines in pulmonary function, which improved 24–72 h later; recovery was associated with increases in airway monocyte-derived macrophage-to-neutrophil and monocyte-derived macrophage-to-monocyte ratios. These findings highlight coordinated, time-related macrophage dynamics that may contribute to recovery from ozone-induced lung injury.

Ozone is an urban air pollutant known to cause lung injury and altered function. Using established models of acute (0.8 ppm, 3 h) and episodic (1.5 ppm, 2 h, 2 times/wk, 6 wk) inhalation exposure, we observed distinct structural changes in the lung; whereas acutely, ozone primarily disrupts the bronchiolar epithelial barrier, episodic exposure causes airway remodeling. Herein we examined how these responses altered pulmonary function. A SCIREQ small animal ventilator was used to assess lung function; impedance was used to conditionally model resistance and elastance. Episodic, but not acute ozone exposure reduced the inherent and frequency-dependent tissue recoil (elastance) of the lung. Episodic ozone also increased central and high-frequency resistance relative to air control after methacholine challenge, indicating airway hyperresponsiveness. Pressure-volume (PV)-loops showed that episodic ozone increased maximum lung volume, whereas acute ozone decreased lung volume. Episodic ozone-induced functional changes were accompanied by increases in alveolar circularization; conversely, minimal histopathology was observed after acute exposure. However, acute ozone exposure caused increases in total phospholipids, total surfactant protein D (SP-D), and low-molecular weight SP-D in bronchoalveolar lavage fluid. Episodic ozone exposure only increased total SP-D. These findings demonstrate that acute and episodic ozone exposure caused distinct alterations in surfactant composition and pulmonary function. Whereas loss in PV-loop area following acute ozone exposure is likely driven by increases in SP-D and inflammation, emphysematous pathology and airway hyperresponsiveness after episodic ozone appear to be the result of alterations in lung structure.

The risk of a terrorist attack in the United States has created challenges on how to effectively treat toxicities that result from exposure to chemical weapons. To address this concern, the United States has organized a trans‐agency initiative across academia, government, and industry to identify drugs to treat tissue injury resulting from exposure to chemical threat agents. We sought to develop and evaluate an interactive educational session that provides hands‐on instruction on how to repurpose FDA‐approved drugs as therapeutics to treat toxicity from exposure to chemical weapons. As part of the Rutgers Summer Undergraduate Research Fellowship program, 23 undergraduate students participated in a 2‐h session that included: (1) an overview of chemical weapon toxicities, (2) a primer on pharmacology principles, and (3) an interactive session where groups of students were provided lists of FDA‐approved drugs to evaluate potential mechanisms of action and suitability as countermeasures for four chemical weapon case scenarios. The interactive session culminated in a competition for the best grant “sales pitch.” From this interactive training, students improved their understanding of (1) the ability of chemical weapons to cause long‐term toxicities, (2) impact of route of administration and exposure scenario on drug efficacy, and (3) re‐purposing FDA‐approved drugs to treat disease from chemical weapon exposure. These findings demonstrated that an interactive training exercise can provide students with new insights into drug development for chemical threat agent toxicities.

The onset of neurodegenerative diseases involves a complex interplay of pathological mechanisms, including protein aggregation, oxidative stress, and impaired autophagy. This review focuses on the intricate connection between oxidative stress and autophagy in neurodegenerative disorders, highlighting autophagy as pivotal in disease pathogenesis. Reactive oxygen species (ROS) play dual roles in cellular homeostasis and autophagy regulation, with disruptions of redox signaling contributing to neurodegeneration. The activation of the Nrf2 pathway represents a critical antioxidant mechanism, while autophagy maintains cellular homeostasis by degrading altered cell components. The interaction among p62/SQSTM1, Nrf2, and Keap1 forms a regulatory pathway essential for cellular stress response, whose dysregulation leads to impaired autophagy and aggregate accumulation. Targeting the Nrf2-p62/SQSTM1 pathway holds promise for therapeutic intervention, mitigating oxidative stress and preserving cellular functions. Additionally, this review explores the potential synergy between the endocannabinoid system and Nrf2 signaling for neuroprotection. Further research is needed to elucidate the involved molecular mechanisms and develop effective therapeutic strategies against neurodegeneration.

Macrophages play a key role in ozone-induced lung injury by regulating both the initiation and resolution of inflammation. These distinct activities are mediated by pro-inflammatory and anti-inflammatory/proresolution macrophages which sequentially accumulate in injured tissues. Macrophage activation is dependent, in part, on intracellular metabolism. Herein, we used RNA-sequencing (seq) to identify signaling pathways regulating macrophage immunometabolic activity following exposure of mice to ozone (0.8 ppm, 3 h) or air control. Analysis of lung macrophages using an Agilent Seahorse showed that inhalation of ozone increased macrophage glycolytic activity and oxidative phosphorylation at 24 and 72 h post-exposure. An increase in the percentage of macrophages in S phase of the cell cycle was observed 24 h post ozone. RNA-seq revealed significant enrichment of pathways involved in innate immune signaling and cytokine production among differentially expressed genes at both 24 and 72 h after ozone, whereas pathways involved in cell cycle regulation were upregulated at 24 h and intracellular metabolism at 72 h. An interaction network analysis identified tumor suppressor 53 (TP53), E2F family of transcription factors (E2Fs), cyclin-dependent kinase inhibitor 1A (CDKN1a/p21), and cyclin D1 (CCND1) as upstream regulators of cell cycle pathways at 24 h and TP53, nuclear receptor subfamily 4 group a member 1 (NR4A1/Nur77), and estrogen receptor alpha (ESR1/ERα) as central upstream regulators of mitochondrial respiration pathways at 72 h. To assess whether ERα regulates metabolic activity, we used ERα−/− mice. In both air and ozone-exposed mice, loss of ERα resulted in increases in glycolytic capacity and glycolytic reserve in lung macrophages with no effect on mitochondrial oxidative phosphorylation. Taken together, these results highlight the complex interaction between cell cycle, intracellular metabolism, and macrophage activation which may be important in the initiation and resolution of inflammation following ozone exposure.

The onset of neurodegenerative diseases involves a complex interplay of pathological mecha-nisms, including protein aggregation, oxidative stress, impaired autophagy. This review focuses on the intricate connection between oxidative stress and autophagy in neurodegenerative disor-ders, highlighting autophagy as pivotal in disease pathogenesis. Reactive oxygen species (ROS) play dual roles in cellular homeostasis and autophagy regulation, with disruptions of redox sig-naling contributing to neurodegeneration. The activation of the Nrf2 pathway represents a criti-cal antioxidant mechanism, while autophagy maintains cellular homeostasis by degrading al-tered cell components. The interaction between p62/SQSTM1, Nrf2 and Keap1 forms a regulatory pathway essential for cellular stress response, whose dysregulation leads to impaired autophagy and aggregate accumulation. Targeting the Nrf2-p62/SQSTM1 pathway holds promise for thera-peutic intervention, mitigating oxidative stress and preserving cellular functions. Additionally, the review explores the potential synergy between the endocannabinoid system and Nrf2 signal-ing for neuroprotection. Further research is needed to elucidate the involved molecular mecha-nisms and develop effective therapeutic strategies against neurodegeneration.

Sulfur mustard (SM) is a threat to both civilian and military populations. Human skin is highly sensitive to SM, causing delayed erythema, edema, and inflammatory cell infiltration, followed by the appearance of large fluid-filled blisters. Skin wound repair is prolonged following blistering, which can result in impaired barrier function. Key to understanding the action of SM in the skin is the development of animal models that have a pathophysiology comparable to humans such that quantitative assessments of therapeutic drugs efficacy can be assessed. Two animal models, hairless guinea pigs and swine, are preferred to evaluate dermal products because their skin is morphologically similar to human skin. In these animal models, SM induces degradation of epidermal and dermal tissues but does not induce overt blistering, only microblistering. Mechanisms of wound healing are distinct in these animal models. Whereas a guinea pig heals by contraction, swine skin, like humans, heals by re-epithelialization. Mice, rats, and rabbits are also used for SM mechanistic studies. However, healing is also mediated by contraction; moreover, only microblistering is observed. Improvements in animal models are essential for the development of therapeutics to mitigate toxicity resulting from dermal exposure to SM.

Pulmonary injury induced by mustard vesicants and radiation is characterized by DNA damage, oxidative stress, and inflammation. This is associated with increases in levels of inflammatory mediators, including tumor necrosis factor (TNF)α in the lung and upregulation of its receptor TNFR1. Dysregulated production of TNFα and TNFα signaling has been implicated in lung injury, oxidative and nitrosative stress, apoptosis, and necrosis, which contribute to tissue damage, chronic inflammation, airway hyperresponsiveness, and tissue remodeling. These findings suggest that targeting production of TNFα or TNFα activity may represent an efficacious approach to mitigating lung toxicity induced by both mustards and radiation. This review summarizes current knowledge on the role of TNFα in pathologies associated with exposure to mustard vesicants and radiation, with a focus on the therapeutic potential of TNFα-targeting agents in reducing acute injury and chronic disease pathogenesis.