Inhalation Toxicology最新文献

Purpose: Airborne pathogen scan penetrate in human respiratory tract and can cause illness. The use of animal models to predict aerosol deposition and study respiratory disease pathophysiology is therefore important for research and a prerequisite to test and study the mechanism of action of treatment. NHPs are relevant animal species for inhalation studies because of their similarities with humans in terms of anatomical structure, respiratory parameters and immune system.

Materials and methods: The aim of this review is to provide an overview of the state of the art of pathogen aerosol studies performed in non-human primates (NHPs). Herein, we present and discuss the deposition of aerosolized bacteria and viruses. In this review, we present important advantages of using NHPs as model for inhalation studies.

Results: We demonstrate that deposition in the respiratory tract is not only a function of aerosol size but also the technique of administration influences the biological activity and site of aerosol deposition. Finally, we observe an influence of a region of pathogen deposition in the respiratory tract on the development of the pathophysiological effect in NHPs.

Conclusion: The wide range of methods used for the delivery of pathogento NHP respiratory airways is associated with varying doses and deposition profiles in the airways.

Objective: Acute intranasal (IN) instillation of lupus-prone NZBWF1 mice with crystalline silica (cSiO₂) triggers robust lung inflammation that drives autoimmunity. Prior studies in other preclinical models show that soluble epoxide hydrolase (sEH) inhibition upregulates pro-resolving lipid metabolites that are protective against pulmonary inflammation. Herein, we assessed in NZBWF1 mice how acute IN cSiO₂ exposure with or without the selective sEH inhibitor TPPU influences lipidomic, transcriptomic, proteomic, and histopathological biomarkers of inflammation, fibrosis, and autoimmunity.

Methods: Female 6-week-old NZBWF1 mice were fed control or TPPU-supplemented diets for 2 weeks then IN instilled with 2.5 mg cSiO₂ or saline vehicle. Cohorts were terminated at 7 or 28 days post-cSiO₂ instillation (PI) and lungs analyzed for prostaglandins, cytokines/chemokines, gene expression, differential cell counts, histopathology, and autoantibodies.

Results: cSiO₂-treatment induced prostaglandins, cytokines/chemokine, proinflammatory gene expression, CD206⁺ monocytes, Ly6B.2⁺ neutrophils, CD3⁺ T cells, CD45R⁺ B cells, centriacinar inflammation, collagen deposition, ectopic lymphoid structure neogenesis, and autoantibodies. While TPPU effectively inhibited sEH as reflected by skewed lipidomic profile in lung and decreased cSiO₂-induced monocytes, neutrophils, and lymphocytes in lung lavage fluid, it did not significantly impact other biomarkers.

Discussion: cSiO₂ evoked robust pulmonary inflammation and fibrosis in NZBWF1 mice that was evident at 7 days PI and progressed to ELS development and autoimmunity by 28 days PI. sEH inhibition by TPPU modestly suppressed cSiO₂-induced cellularity changes and pulmonary fibrosis. However, TPPU did not affect ELS formation or autoantibody responses, suggesting sEH minimally impacts cSiO₂-triggered lung inflammation, fibrosis, and early autoimmunity in our model.

Background: The abnormality of the immune system caused by infection is a contributor to the organ dysfunctions associated with sepsis. The balance between Th17/Treg cells is essential for maintaining immune homeostasis. Bergapten is a natural furocoumarin and has been reported to alleviate the Th17/Treg imbalance. Here, we explored the effects of bergapten on the inflammation and immune state in mouse models of sepsis.

Methods: The model was established using the cecal ligation and puncture method. Mice were administered 30 mg/kg bergapten. Histological examination, RT-qPCR, enzyme-linked immunosorbent assay, immunoblotting, immunofluorescence, immunohistochemistry, and flow cytometry were used to evaluate the effects of bergapten in vivo.

Results: Bergapten ameliorated lung damage, reduced lung wet/dry weight ratio, inhibited myeloperoxidase activity, and reduced inflammatory cell infiltration. Bergapten also restrained sepsis-induced inflammation via inhibition of inflammatory cytokines and NF-κB signaling. These effects were accompanied by the restored Th17/Treg balance induced by bergapten. Bergapten decreased the number of Th17 cells and elevated the number of Tregs, and this effect was mediated by the signal transducer and activator of transcription 5 (STAT5)/Forkhead box P3 (Foxp3) and STAT3/retinoid-related orphan receptor-γt (RORγt) pathways.

Conclusions: Bergapten exerted anti-inflammatory effects in acute lung injury by improving the Th17/Treg balance, which suggested a potential of bergapten as an immunomodulatory drug treating sepsis-associated diseases.

Respiratory co-exposure to ambient PM_2.5 and electronic cigarettes (e-cigarettes) frequently occurs in public. However, the combined effects on human respiratory health have not been well documented. To discuss potential co-effects and possible biological mechanisms, A549/THP-1 co-cultures and BEAS-2B cells were exposed to unvapedtobacco or mint-flavored e-liquids (0-7.2% v/v), e-cigarette aerosol extract (ECE, 0-50% v/v), PM_2.5 (60 μg/mL), or PM_2.5 + ECE for 24 h. Cell viability assessments on e-liquids, ECE, PM_2.5 + ECE showed that the mint flavor exhibited higher cytotoxicity compared to the tobacco flavor in both A549/THP-1 and BEAS-2B. However, the influence of flavors on ROS levels and mRNA expression of inflammatory markers (IL-6, TNF-α, IL-8, IL-1β) after ECE exposure demonstrated inconsistency in the two cell models. PM_2.5 + ECE treatment notably elevated ROS production and inflammation responses compared to ECE alone exposure. Only co-exposure induced a significant increase in nuclear transcription factor-κB p65 (NF-κB p65) and NOD-like receptor 3 (NLRP3) protein expression regardless of flavors. Our results indicate that PM_2.5-treated cells exacerbate the adverse effects induced by ECE in both A549/THP-1 and BEAS-2B cells. Flavors in unvaped e-liquids affect cytotoxicity, oxidative stress and inflammation response, but these effects vary depending on the vaping process and the specific cell line.

Introduction: Particulate matter (PM) air pollution is associated with an increased incidence of lung diseases, but the underlying mechanisms have not been fully elucidated. In this study, a mouse model of subacute lung inflammation was employed to investigate the cellular responses and gene expression changes induced by exposure to natural ambient air pollution.

Methods: C57BL/6J mice were exposed to road dust (primarily PM10) at 150 µg/m³ for 21 days (8 h/day) through a nose-only inhalation exposure system. Lung tissues were analyzed for the expression of proinflammatory signaling, oxidative stress, and fibrosis markers. RNA-sequencing analysis was conducted to identify differentially expressed genes (DEGs). A gene ontology over-representation analysis was performed to identify the altered genetic pathways.

Results: Elevated levels of proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, and an increase in phosphorylated MAPK were determined in the road dust exposure group compared to the control group. Histopathological examinations revealed more severe lung inflammation and damage in the exposed mice, including fibrosis and bronchiolar hyperplasia. Gene expression profiling identified 108 DEGs, with decreases in most except genes such as Krt15 and Reg3g. The protein-protein interaction network analysis together with text-mining identified 18 key hub genes, associated with fatty acid oxidation, lipid metabolism, and peroxisomes.

Conclusion: This study identified key genes, signaling pathways, and cellular responses in mouse lung affected by road dust exposure. These findings contribute to a deeper understanding of the transcriptional and cellular responses induced by subacute exposure to the PM in road dust.

Objective: Cigarette smoking can lead to a host of adverse health effects such as lung and heart disease. Increased lung cancer risk is associated with inhalation of carcinogens present in a puff of smoke. These carcinogenic compounds deposit in the lung at different sites and trigger a cascade of events leading to adverse outcomes. Understanding the site-specific deposition of various smoke constituents will inform the study of respiratory diseases from cigarette smoking. We previously developed a deposition model for inhalation of aerosol from electronic nicotine delivery systems. In this study, the model was modified to simulate inhalation of cigarette smoke consisting of soluble and insoluble tar, nicotine, and cigarette-specific constituents that are known or possible human carcinogens.

Materials and methods: The deposition model was further modified to account for nicotine protonation and other cigarette-specific physics-based mechanisms that affect smoke deposition. Model predictions showed a total respiratory tract uptake in the lung for formaldehyde (99%), nicotine (80%), and benzo[a]pyrene (60%).

Results: The site of deposition and uptake depended primarily on the constituent's saturation vapor pressure. High vapor pressure constituents such as formaldehyde were preferentially absorbed in the oral cavity and proximal lung regions, while low vapor pressure constituents such as benzo[a]pyrene were deposited in the deep lung regions. Model predictions of exhaled droplet size, droplet retention, nicotine retention, and uptake of aldehydes compared favorably with experimental data.

Conclusion: The deposition model can be integrated into exposure assessments and other studies that evaluate potential adverse health effects from cigarette smoking.

Objectives: Living conditions play a major role in health and well-being, particularly for the cardiovascular and pulmonary systems. Depleted housing contributes to impairment and development of disease, but how it impacts body resiliency during exposure to environmental stressors is unknown. This study examined the effect of depleted (DH) versus enriched housing (EH) on cardiopulmonary function and subsequent responses to wildfire smoke. Materials and Methods: Two cohorts of healthy female mice, one of them surgically implanted with radiotelemeters for the measurement of electrocardiogram, body temperature (Tco) and activity, were housed in either DH or EH for 7 weeks. Telemetered mice were exposed for 1 h to filtered air (FA) and then flaming eucalyptus wildfire smoke (WS) while untelemetered mice, which were used for ventilatory assessment and tissue collection, were exposed to either FA or WS. Animals were continuously monitored for 5-7 days after exposure. Results: EH prevented a decrease in Tco after radiotelemetry surgery. EH mice also had significantly higher activity levels and lower heart rate during and after FA and WS. Moreover, EH caused a decreased number of cardiac arrhythmias during WS. WS caused ventilatory depression in DH mice but not EH mice. Housing enrichment also upregulated the expression of cardioprotective genes in the heart. Conclusions: The results of this study indicate that housing conditions impact overall health and cardiopulmonary function. More importantly, depleted housing appears to worsen the response to air pollution. Thus, non-chemical factors should be considered when assessing the susceptibility of populations, especially when it comes to extreme environmental events.

Objectives: Delayed neuropsychiatric sequelae (DNS) are critical complications following acute carbon monoxide (CO) poisoning that can substantially affect the patient's life. Identifying high-risk patients for developing DNS may improve the quality of follow-up care. To date, the predictive DNS determinants are still controversial. Consequently, this study aimed to construct a practical nomogram for predicting DNS in acute CO-poisoned patients.

Methods: This retrospective study was conducted on patients with acute CO poisoning admitted to the Tanta University Poison Control Center (TUPCC) from December 2018 to December 2022. Demographic, toxicological, and initial clinical characteristics data, as well as laboratory investigation results, were recorded for the included patients. After acute recovery, patients were followed up for six months and categorized into patients with and without DNS.

Results: Out of 174 enrolled patients, 38 (21.8%) developed DNS. The initial Glasgow Coma Scale (GCS), carboxyhemoglobin (COHb) level, CO exposure duration, oxygen saturation, PaCO₂, and pulse rate were significantly associated with DNS development by univariate analysis. However, the constructed nomogram based on the multivariable regression analysis included three parameters: duration of CO exposure, COHb level, and GCS with adjusted odd ratios of 1.453 (95% CI: 1.116-1.892), 1.262 (95% CI: 1.126-1.415), and 0.619 (95% CI: 0.486-0.787), respectively. The internal validation of the nomogram exhibited excellent discrimination (area under the curve [AUC] = 0.962), good calibration, and satisfactory decision curve analysis for predicting the DNS probability.

Conclusions: The proposed nomogram could be considered a simple, precise, and applicable tool to predict DNS development in acute CO-poisoned patients.

Objectives: To evaluate potential airborne asbestos exposures during brake maintenance and repair activities on a P&H overhead crane, and during subsequent handling of the mechanic's clothing.

Methods: Personal (n = 27) and area (n = 61) airborne fiber concentrations were measured during brake tests, removal, hand sanding, compressed air use, removal and reattachment of chrysotile-containing brake linings, and reinstallation of the brake linings. The mechanic's clothing was used to measure potential exposure during clothes handling.

Results: All brake linings contained between 19.9% to 52.4% chrysotile asbestos. No amphibole fibers were detected in any bulk or airborne samples. The average full-shift airborne chrysotile concentration was 0.035 f/cc (PCM-equivalent asbestos-specific fibers, or PCME). Average task-based personal air samples collected during brake maintenance, sanding, compressed air use, and brake lining removal tasks ranged from 0 to 0.48 f/cc (PCME). The calculated 30-minute time-weighted average (TWA) airborne chrysotile concentration associated with 5-15 minutes of clothes handling was 0-0.035 f/cc PCME.

Conclusion: The results indicated that personal and area TWA fiber concentrations measured during all crane brake maintenance and clothes handling tasks were below the current OSHA 8-h TWA Permissible Exposure Limit for asbestos of 0.1 f/cc. Further, no airborne asbestos fibers were measured during routine brake maintenance tasks following the manufacturer's maintenance manual procedures. All short-term airborne chrysotile concentrations measured during non-routine tasks were below the current 30-minute OSHA excursion limit for asbestos of 1 f/cc. This study adds to the available data regarding chrysotile exposure potential during maintenance on overhead cranes.

Due to climate change, wildfires have increased in intensity and duration. While wildfires threaten lives directly, the smoke has more far-reaching adverse health impacts. During an extreme 2017 wildfire event, residents of Seeley Lake, Montana were exposed to unusually high levels of wood smoke (WS) causing sustained effects on lung function (decreased FEV₁/FVC). Objective: The present study utilized an animal model of WS exposure to research cellular and molecular mechanisms of the resulting health effects. Methods: Mice were exposed to inhaled WS utilizing locally harvested wood to recapitulate community exposures. WS was generated at a rate resulting in a 5 mg/m³ PM_2.5 exposure for five days. Results: This exposure resulted in a similar 0.28 mg/m² particle deposition (lung surface area) in mice that was calculated for human exposure. As with the community observations, there was a significant effect on lung function, increased resistance, and decreased compliance, that was more pronounced in males at an extended (2 months) timepoint and males were more affected than females: ex vivo assays illustrated changes to alveolar macrophage functions (increased TNFα secretion and decreased efferocytosis). Female mice had significantly elevated IL-33 levels in lungs, however, pretreatment of male mice with IL-33 resulted in an abrogation of the observed WS effects, suggesting a dose-dependent role of IL-33. Additionally, there were greater immunotoxic effects in male mice. Discussion: These findings replicated the outcomes in humans and suggest that IL-33 is involved in a mechanism of the adverse effects of WS exposures that inform on potential sex differences.