Inhalation Toxicology最新文献

Objective: The purpose of these studies was to investigate the uptake of atrazine across the nasal mucosa to determine whether direct transport to the brain through the olfactory epithelium is likely to occur. These studies were undertaken to provide important new information about the potential for the enhanced neurotoxicity of herbicides following nasal inhalation.

Materials and methods: Transport of atrazine from aqueous solution and from commercial atrazine-containing herbicide products was assessed using excised nasal mucosal tissues. The permeation rate and the role of membrane transporters in the uptake of atrazine across the nasal mucosa were also investigated. Histological examination of the nasal tissues was conducted to assess the effects of commercial atrazine-containing products on nasal tissue morphology.

Results: Atrazine showed high flux across both nasal respiratory and olfactory tissues, and efflux transporters were found to play an essential role in limiting its uptake at low exposure concentrations. Commercial atrazine-containing herbicide products showed remarkably high transfer across the nasal tissues, and histological evaluation showed significant changes in the morphology of the nasal epithelium following exposure to the herbicide products.

Discussion: Lipophilic herbicides such as atrazine can freely permeate across the nasal mucosa despite the activity of efflux transporters. The adjuvant compounds in commercial herbicide products disrupt the nasal mucosa's epithelial barrier, resulting in even greater atrazine permeation across the tissues. The properties of the herbicide itself and those of the formulated products play crucial roles in the potential for the enhanced neurotoxicity of herbicides following nasal inhalation.

Multiwalled carbon nanotubes (MWCNTs) have numerous applications in the field of carbon nanomaterials. However, the associated toxicity concerns have increased significantly because of their widespread use. The inhalation of MWCNTs can lead to nanoparticle deposition in the lung tissue, causing inflammation and health risks. In this study, celastrol, a natural plant medicine with potent anti-inflammatory properties, effectively reduced the number of inflammatory cells, including white blood cells, neutrophils, and lymphocytes, and levels of inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, in mice lungs exposed to MWCNTs. Moreover, celastrol inhibited the activation of the NF-κB-signaling pathway. This study confirmed these findings by demonstrating comparable reductions in inflammation upon exposure to MWCNTs in mice with the deletion of NF-κB (P50^-/-). These results indicate the utility of celastrol as a promising pharmacological agent for preventing MWCNT-induced lung tissue inflammation.

Objective: Chronic obstructive pulmonary disease (COPD) is a common disorder that is characterized by systemic and lung inflammation. Notoginsenoside R1 (NGR1) displays anti-inflammatory properties in numerous diseases. We aimed to explore the function and mechanism of NGR1 in COPD.

Materials and methods: COPD rats were established through cigarette smoke exposure, lipopolysaccharide injection, and cold stimulation. Rat airway smooth muscle cells (ASMCs) were separated and identified. Then, ASMCs were treated with NGR1 (25 or 50 μM) and cigarette smoke extract (CSE). Thereafter, the vitality, proliferation, and migration of ASMCs were measured. Additionally, cell cycle, inflammation-related factors, α-SMA, and PI3K/AKT pathway-related marker expressions of the ASMCs were also detected. Molecular docking experiments were conducted to explore the interaction of NGR1 to PI3K, TGF-β, p65, and AKT. Moreover, 740 Y-P (a PI3K/Akt pathway agonist) were used to validate the mechanism of NGR1 on COPD.

Results: NGR1 inhibited the proliferation and migration, but caused cell cycle arrest for CSE-triggered ASMCs. Furthermore, NGR1 not only decreased IL-1β, IL-6, IL-8, and TNF-α contents, but also reduced α-SMA expression in CSE-stimulated ASMCs. Moreover, NGR1restrainedTGF-β1 expression, PI3K, p65, and AKT phosphorylation in CSE-stimulated ASMCs. Molecular docking experiments showed NGR1 exhibited a strong binding ability to PI3K, TGF-β1, p65, and AKT. Notably, the effects of NGR1 on the proliferation and migration of CSE-induced ASMCs were reversed by 740 Y-P.

Conclusions: NGR1 can restrain the proliferation and migration of CSE-induced ASMCs, indicating that NGR1 may be a therapeutic candidate for treating COPD.

Background: Oxygen therapy is an alternative for many patients with hypoxemia. However, this practice can be dangerous as oxygen is closely associated with the development of oxidative stress.

Methods: Male Wistar rats were exposed to hyperoxia with a 40% fraction of inspired oxygen (FIO₂) and hyperoxia (FIO₂ = 60%) for 120 min. Blood and lung tissue samples were collected for gas, oxidative stress, and inflammatory analyses.

Results: Hyperoxia (FIO₂ = 60%) increased PaCO₂ and PaO₂, decreased blood pH and caused thrombocytopenia and lymphocytosis. In lung tissue, neutrophil infiltration, nitric oxide concentration, carbonyl protein formation and the activity of complexes I and II of the mitochondrial respiratory chain increased. FIO₂ = 60% decreased SOD activity and caused several histologic changes.

Conclusion: In conclusion, we have experimentally demonstrated that short-term exposure to high FIO₂ can cause oxidative stress in the lung.

Objective: Inhalation of diesel exhaust (DE) has been shown to be an occupational hazard in the transportation, mining, and gas and oil industries. DE also contributes to air pollution, and therefore, is a health hazard to the general public. Because of its effects on human health, changes have been made to diesel engines to reduce both the amounts of particulate matter and volatile fumes they generate. The goal of the current study was to examine the effects of inhalation of diesel exhaust.

Materials and methods: The study presented here specifically examines the effects of exposure to 0.2 and 1.0 mg/m³ DE or filtered air (6h/d for 4 d) on measures of peripheral and cardio-vascular function, and biomarkers of heart and kidney dysfunction in male rats. A Tier 2 engine used in oil and gas fracking operations was used to generate the diesel exhaust.

Results: Exposure to 0.2 mg/m³ DE resulted in an increase in blood pressure 1d following the last exposure, and increases in dobutamine-induced cardiac output and stroke volume 1 and 27d after exposure. Changes in peripheral vascular responses to norepinephrine and acetylcholine were minimal as were changes in transcript expression in the heart and kidney. Exposure to 1.0 mg/m³ DE did not result in major changes in blood pressure, measures of cardiac function, peripheral vascular function or transcript expression.

Discussion and conclusions: Based on the results of this study, we suggest that exposure to DE generated by a Tier 2 compliant diesel engine generates acute effects on biomarkers indicative of cardiovascular dysfunction. Recovery occurs quickly with most measures of vascular/cardiovascular function returning to baseline levels by 7d following exposure.

Objectives: Mortality from respiratory and cardiovascular health conditions contributes largely to the total mortality that has been associated with exposure to PM_2.5 in epidemiology studies. A mode of action (MoA) for these underlying morbidities has not been established, but it has been proposed that some effects of PM_2.5 occur through activation of neural reflexes.

Materials and methods: We critically reviewed the experimental studies of PM_2.5 (including ambient PM_2.5, diesel exhaust particles, concentrated ambient particles, diesel exhaust, and cigarette smoke) and neural reflex activation, and applied the principles of the International Programme on Chemical Safety (IPCS) MoA/human relevance framework to assess whether they support a biologically plausible and human-relevant MoA by which PM_2.5 could contribute to cardiovascular and respiratory causes of death. We also considered whether the evidence from these studies supports a non-threshold MoA that operates at low, human-relevant PM_2.5 exposure concentrations.

Results and discussion: We found that the proposed MoA of neural reflex activation is biologically plausible for PM_2.5-induced respiratory effects at high exposure levels used in experimental studies, but further studies are needed to fill important data gaps regarding the relevance of this MoA to humans at lower PM_2.5 exposure levels. A role for the proposed MoA in PM_2.5-induced cardiovascular effects is plausible for some effects but not others.

Conclusions: Further studies are needed to determine whether neural reflex activation is the MoA by which PM_2.5 could cause either respiratory or cardiovascular morbidities in humans, particularly at the ambient concentrations associated with total mortality in epidemiology studies.

Introduction: Tissue from a 77-year-old man diagnosed with mesothelioma was referred with a request for identification of the presence of fibrous structures in tissue samples. The individual's work history including working as a "mucker" at a specific "industrial" talc mine.

Methods: Ferruginous bodies in the tissue digests as well as asbestos fibers were found. A bulk sample of a talc containing product from that mine was also analyzed.

Discussions/conclusions: The correlation between the unique asbestos mineral/fibrous content of the talc to which he was exposed and findings of the same type of asbestos found in his lung is discussed. The type of asbestos found (tremolite) is a "non-commercial" type of asbestos that has been identified in some talc deposits. Tremolite, like all forms of asbestos is a causative agent for mesothelioma-the disease from which this individual suffered.

Objective: Occupational exposure to respirable crystalline silica (cSiO₂) has been linked to lupus development. Previous studies in young lupus-prone mice revealed that intranasal cSiO₂ exposure triggered autoimmunity, preventable with docosahexaenoic acid (DHA). This study explores cSiO₂ and DHA effects in mature lupus-prone adult mice, more representative of cSiO₂-exposed worker age.

Methods: Female NZBWF1 mice (14-week old) were fed control (CON) or DHA-supplemented diets. After two weeks, mice were intranasally instilled saline (VEH) or 1 mg cSiO₂ weekly for four weeks. Cohorts were then analyzed 1- and 5-weeks postinstillation for lung inflammation, cell counts, chemokines, histopathology, B- and T-cell infiltration, autoantibodies, and gene signatures, with results correlated to autoimmune glomerulonephritis onset.

Results: VEH/CON mice showed no pathology. cSiO₂/CON mice displayed significant ectopic lymphoid tissue formation in lungs at 1 week, increasing by 5 weeks. cSiO₂/CON lungs exhibited elevated cellularity, chemokines, CD3⁺ T-cells, CD45R ⁺ B-cells, IgG ⁺ plasma cells, gene expression, IgG autoantibodies, and glomerular hypertrophy. DHA supplementation mitigated all these effects.

Discussion: The mature adult NZBWF1 mouse used here represents a life-stage coincident with immunological tolerance breach and one that more appropriately represents the age (20-30 yr) of cSiO2-exposed workers. cSiO₂-induced robust pulmonary inflammation, autoantibody responses, and glomerulonephritis in mature adult mice, surpassing effects observed previously in young adults. DHA at a human-equivalent dosage effectively countered cSiO₂-induced inflammation/autoimmunity in mature mice, mirroring protective effects in young mice.

Conclusion: These results highlight life-stage significance in this preclinical lupus model and underscore omega-3 fatty acids' therapeutic potential against toxicant-triggered autoimmune responses.

Many inhalation exposures induce pulmonary inflammation contributing to disease progression. Inflammatory processes are actively regulated via mediators including bioactive lipids. Bioactive lipids are potent signaling molecules involved in both pro-inflammatory and resolution processes through receptor interactions. The formation and clearance of lipid signaling mediators are controlled by multiple metabolic enzymes. An imbalance of these lipids can result in exacerbated and sustained inflammatory processes which may result in pulmonary damage and disease. Dysregulation of pulmonary bioactive lipids contribute to inflammation and pulmonary toxicity following exposures. For example, inhalation of cigarette smoke induces activation of pro-inflammatory bioactive lipids such as sphingolipids, and ceramides contributing to chronic obstructive pulmonary disease. Additionally, exposure to silver nanoparticles causes dysregulation of inflammatory resolution lipids. As inflammation is a common consequence resulting from inhaled exposures and a component of numerous diseases it represents a broadly applicable target for therapeutic intervention. With new appreciation for bioactive lipids, technological advances to reliably identify and quantify lipids have occurred. In this review, we will summarize, integrate, and discuss findings from recent studies investigating the impact of inhaled exposures on pro-inflammatory and resolution lipids within the lung and their contribution to disease. Throughout the review current knowledge gaps in our understanding of bioactive lipids and their contribution to pulmonary effects of inhaled exposures will be presented. New methods being employed to detect and quantify disruption of pulmonary lipid levels following inhalation exposures will be highlighted. Lastly, we will describe how lipid dysregulation could potentially be addressed by therapeutic strategies to address inflammation.