Inhalation Toxicology最新文献

Objective: Endosulfan, an organochlorine pesticide, consists of two isomers (α-Endosulfan and β-Endosulfan) and a primary metabolite, Endosulfan sulfate (END-SO₄). Due to its pervasive environmental contamination and harmful effects-such as neurotoxicity, endocrine disruption, and reproductive toxicity in humans-END was included in the Stockholm Convention on Persistent Organic Pollutants (Annex A) in 2011, leading to its prohibition in many regions. The toxic effects of END have been extensively studied, but the specific mechanism of its lung injury remains unknown. This study explores how α/β-Endosulfan and END-SO₄ may induce lung injury using in silico approaches.

Methods: Toxicity prediction was performed using STopTox, ADMETlab 3.0, and Deep-PK. Network toxicology analyses were conducted via the Comparative Toxicogenomic Database, DAVID, Metascape, GeneMANIA, STRING, and Cytoscape. AUTODOCK was used for molecular docking of α/β-END and END-SO₄ with key targets.

Results: The study identified 4658 targets for α/β-END and 21 for END-SO4, with 126 linked to lung injury. Of these, 53 targets were common to both the compounds and lung injury, primarily associated with inflammation and fibrosis. Centrality analysis highlighted IL1B, TNF, and IL6 as key targets. Docking results showed binding affinities ranging from -4.53 to -8.32 kcal/mol between α/β-END, END-SO₄, and IL1B/TNF.

Conclusion: These findings suggest that exposure to α/β-END and END-SO₄ may trigger inflammation and fibrosis, contributing to lung injury. These findings provide a basis for further experimental studies aimed at validating the role of IL1B and TNF in α/β-END-induced lung injury.

Objective: Cyclin-dependent kinase inhibitor 2 A, CDKN2A/p16INK4a (p16), is a gene involved in regulating the cell cycle, cellular senescence, and inflammatory responses. The role of p16 in pulmonary immune-inflammatory and cellular senescence responses to low-dose, sub-chronic environmental tobacco smoke (ETS) is not known. We hypothesized that p16-deficient (knockout, KO) mice would exhibit adverse lung responses compared to wild-type (WT) mice, characterized by a decline in lung function, impaired immune responses, lung remodeling, and dysregulated inflammatory responses at low-level ETS exposure.

Materials and methods: C57BL/6J (WT) and p16 knockout, p16^-/-, were exposed to low dose ETS [10 mg/m³ total particulate matter (TPM)] for 3 months. Bronchoalveolar fluid (BALF) and lung tissue were used in subsequent analyses.

Results: Histological analysis revealed mild alveolar simplification in p16 KO mice compared to WT mice. CDKN2A/p16 KO BALF did not have the same immune cell infiltration or cytokine response as the WT counterparts, where IL-17A, TNF-α, and GM-CSF were significantly elevated, indicating impaired immune response with p16 deficiency. Proteomic analysis revealed significantly elevated proteins related to inflammation, extracellular matrix remodeling, cellular metabolism, pro-senescence, and oxidative stress in p16 KO mice (Kynu, Col5a3, Lamtor3). NLRP3 and PTGS2 (COX-2) activation z-scores were lower in p16 KO mice, while IL33 and CCR5 activation z-scores were higher compared to WT mice.

Discussion: Thus, p16 deficiency amplifies ETS-induced alveolar architecture, impaired immune responses, and altered inflammatory pathways, contributing to heightened susceptibility to emphysema-like changes compared to WT mice even at low ETS levels. This study revealed that p16 deletion alters response to low-level ETS, not necessarily by amplifying the classic 'damage response' but by modifying immune and senescence signaling in the lungs.

Conclusion: Overall, p16 has a complex and nuanced protective role in lung health, and careful targeting p16-related pathways could offer therapeutic strategies for mitigating chronic lung diseases.

The main route of occupational exposure to nanomaterials is inhalation. Sputum and nasal lavage are the most important biological samples to analyze lung-specific biomarkers in occupational exposure. So, the aim of this study is to conduct a mixed-method systematic review with meta-synthesis and meta-analysis for assessment of sputum and nasal lavage lung-specific biomarkers in occupational exposure to nanomaterials. This systematic review was conducted through the end of June 2025. Search was done using 'Biomarkers', 'Occupational exposure', 'Sputum', 'Nanomaterials' and 'Nasal Lavage' keywords on PubMed, Scopus and WOS. After the data extraction, qualitative data was used to draw a qualitative model. Comprehensive Meta-Analysis Software (CMA) was used for meta-analysis and the pooled mean concentration of the biomarkers were calculated by the random effect model (REM). Thirty-three studies were primarily achieved, and six studies were finally analyzed. Pro-inflammatory, inflammatory, oxidative stress, cancer/fibrosis and cardiovascular biomarkers were the most important biomarkers investigated. Inflammatory biomarkers including IL-6, IL-8, IL-1β and TNF-α were involved better than other inflammatory biomarkers in nasal, in occupational exposure to nanomaterials. The pooled mean concentration of sputum inflammatory biomarkers interleukin including IL-1β, IL-2, IL-4, IL5, IL-6, IL-8 was estimated 404.76, 196.9, 156.47, 219.26, 33.98 and 2344.42 pg/mL, respectively. Moreover, concentration of Nasal lavage inflammatory biomarkers interleukin including IL-1β, IL-6, and IL-8 were 1.438, 0.911 and 17.847 pg/mL, respectively. Due to a lack of information about OEL for nanomaterials, evaluating the occupational exposure to them through measuring the level of specific biomarkers, especially in the upper respiratory system, requires more studies.

Inhalation of emissions from combustion events such as military burn pits and wildland-urban interface fires result in exposures to complex aerosols that may cause adverse health effects. A surrogate combustion generator was created to study these events. A pellet stove was modified to burn diverse fuels comprised of materials found in burn pits (plastic, rubber, and wood). Jet fuel (JF) was added during combustion. The purpose of this project was to: 1) operate the generator over diverse parameters; and 2) characterize the resultant emissions. Pellet combustion (8 g/minute; range: 1-34) ± JF (0.2 mL/minute; range: 0-1) was conducted at fixed rates. Real-time and off-line aerosol characterizations (size distributions, concentrations, morphology) and chemical measures (total and speciation of volatiles, organics, elementals) with subsequent analytic methodology were performed. Pellet combustion produced an average particle concentration of 7.0e+6±1.1e+6 #/cc, and a total volatile organic compound concentration (TVOC) of 0.97+0.41 parts per million (PPM). The addition of JF accelerated the combustion process and increased the total particle counts to 4.5e+7±8.3e+6 #/cc, but decreased the TVOC to 0.63±0.26 ppm. Ultrafine particles were predominantly generated with similar count median diameters (<100 nm) and polydisperse distributions (GSD>1.5). Chemical speciation revealed potential human carcinogens (formaldehyde, acetaldehyde) and the addition of JF resulted in a >40-fold drop in organic carbon constituents. Adding plastic and rubber into the pellet mixture resulted in emissions containing 4% methyl-methacrylate and 10% methyl-isobutyl-ketones. Future experiments will assess diverse wood varieties, synthetic building constituents, and asses the biological effects that follow these inhalation exposures.

Objective: Allergic rhinitis (AR), an allergen-driven chronic inflammatory disorder of nasal mucosa, is characterized by airway inflammation as its cardinal pathological manifestation. While acetylation is known to regulate airway inflammation, its mechanistic involvement in AR-related inflammation remains elusive. This study aims to investigate the acetylation-dependent mechanisms governing airway inflammation in AR.

Materials and methods: RNA-seq analysis identified differentially expressed genes in peripheral blood of AR patients and healthy controls. Ovalbumin-sensitized BALB/c mice were performed as the AR mouse model. Airway inflammation was assessed by measuring inflammatory cytokine levels, inflammatory cell numbers, macrophage counts in whole lung lavage fluid (WLLF), and specific IgE levels in plasma using ELISA and Diff-Quick staining. The underlying mechanism was investigated through Western blotting, immunoprecipitation (IP), and Co-IP.

Results: GNG3 expression was significantly increased in AR patients and the AR mouse model. Knockdown of GNG3 significantly reduced airway inflammation and inhibited NF-κB pathway activation in the AR mouse model. CREBBP overexpression enhanced GNG3 protein stability, and CREBBP mRNA expression was significantly increased in patients with AR and positively correlated with GNG3 expression. Furthermore, GNG3 overexpression restored airway inflammation that was suppressed by CREBBP knockdown in the AR mouse model.

Conclusion: These results demonstrate that CREBBP aggravated airway inflammation in AR by activating the NF-κB pathway via GNG3 upregulation mediated by GNG3 acetylation.

Objective: Iraqi automobiles use some of the poorest quality fuel in the world, characterized by extremely high sulfur content. In this study, we aim to investigate the immunological impact of traffic-related air pollution (TRAP) on individuals residing in the Kurdistan Region of Iraq.

Materials and methods: This prospective cross-sectional study (June 2021 and January 2022) assessed the immunological profile of 77 male participants in Sulaymaniyah Governorate who were grouped based on predefined exposure zones; High TRAP Group (n = 46) from urban areas with high exposure to TRAP and Low TRAP Group (n = 31) from rural areas with low exposure. An Aeroqual Series 500 monitor was used to estimate 24-hour arithmetic mean concentrations of PM1.0, PM2.5, and PM10 in the two exposure zones.

Results and discussion: Age distribution was comparable between the groups. Participants of High TRAP Group had significantly lower total lymphocyte counts (1.09 ± 0.36 vs. 1.90 ± 0.41, p < 0.001), T-cell (601.41 ± 60.02 vs. 799.80 ± 56.04; p < 0.001), B-cell levels (113.05 ± 48.23 vs. 230.68 ± 57.90; p < 0.001), IgG (11.94 ± 2.52 vs. 13.35 ± 2.77; p = 0.024), and IgM levels (0.96 ± 0.40 vs. 1.4 ± 0.66, p < 0.001) compared to Low TRAP Group. No significant differences were found in total WBC, granulocytes, or IgA levels (p > 0.05). The presence of inflammatory diseases (mostly thyroiditis) was significantly more common among the individuals of High TRAP Group (13, 28.26% vs. 3, 9.68%; p = 0.048).

Conclusion: Individuals with high exposure to TRAP are associated with significant reductions in lymphocyte count, IgM and IgG levels.

The mucosal origins hypothesis posits that environmental inhalant exposures, including cigarette smoke (CS) and crystalline silica (c-silica), trigger immune responses in the lung mucosa, an extra-articular site, which precede initiating events of rheumatoid arthritis (RA) pathogenesis in distant joints. Epidemiological data strongly associates these exposures with RA risk, especially in genetically susceptible individuals carrying HLA-DRB1 alleles, and with the production of autoantibodies such as anti-citrullinated peptide antibodies (ACPA) and rheumatoid factor (RF). However, establishing causality remains challenging due to unsynchronized exposure and disease onset and the lack of suitable animal models to study early disease events. This review synthesizes evidence linking inhalant exposures to RA, focusing on CS and c-silica, and evaluates experimental animal models used to investigate disease initiation and progression in the context of inhalant exposures. While models like collagen-induced arthritis (CIA) replicate joint pathology, they often fail to capture the lung-joint axis and gene-environment interactions critical for RA onset. We highlight the need for refined models with genetic susceptibility to subclinical autoimmunity to better mimic human RA, emphasizing the importance of standardized exposure protocols to address variability in outcomes. These advancements are crucial for elucidating mechanisms of inhalant exposure-induced RA and developing preventive strategies.

Objective: Lysosomal ion channel function in macrophages contributes to the development of silica-induced inflammation. Recent studies have shown that blocking K⁺ entry into the lysosome via the BK channel reduces silica-induced damage and inflammation in macrophages. This study aims to explore the mechanisms of particle-induced inflammation in BK^-/- macrophages. Methods: Bone marrow derived macrophages (BMdM) from C57BL/6 wildtype (WT) and BK^-/- mice were exposed in vitro to silica and IL-1β release and cell death assessed. The effect of BK^-/- on lysosomal pH, proteolytic activity, and cholesterol accumulation was evaluated. Results: BK^-/- BMdM failed to demonstrate a reduction in IL-1β or cell death following silica exposure. BK^-/- BMdM had comparable lysosome function to WT suggesting a compensatory mechanism was maintaining lysosome function. BK^-/- macrophages demonstrated an upregulation of a second lysosomal potassium channel, TMEM175. Inhibition of TMEM175 activity caused an increase in lysosomal pH and reduced silica-induced cell death and IL-1β release in both BK^-/- and WT BMdM. Conclusion: BK^-/- BMdM did not exhibit the same phenotype seen with pharmaceutical abrogation of BK channel activity and showed no differences from WT in response to silica exposure. Upregulation of TMEM175 in BK^-/- macrophages appears to prevent changes in lysosomal pH and cholesterol accumulation. Inhibiting TMEM175 activity in both BK^-/- and WT BMdM resulted in an increase in lysosomal pH and reduced silica-induced inflammation, suggesting that reduced particle-induced cell damage and inflammation is not dependent on the activity of a single lysosomal ion channel but rather on mechanisms that elevate lysosomal pH.

Objective: Pulmonary microvascular endothelial cell (PMEC) injury is a hallmark of septic acute lung injury (ALI). Elevation of chemokine C-X-C motif ligand 2 (CXCL2) is associated with inflammatory response in various diseases. Recent studies have demonstrated the involvement of CXCL2 in septic ALI. Herein, the role and mechanism of CXCL2 in regulating PMEC inflammation and apoptosis in septic ALI were explored.

Materials and methods: Human PMECs (HPMECs) were treated with lipopolysaccharide (LPS) for the establishment of in vitro septic ALI models. HPMEC viability was validated using CCK-8 assay. HPMEC apoptosis was evaluated by flow cytometry analysis. Measurement of proinflammatory cytokine concentration was conducted using enzyme-linked immunosorbent assay kits. RT-qPCR were required for determining gene levels. Western blotting was prepared for testing friend leukemia integration 1 (Fli1) and CXCL2 protein levels. The binding of Fli-1 to CXCL2 promoter was confirmed by chromatin immunoprecipitation and luciferase reporter assays.

Results: LPS upregulated CXCL2 expression in HPMECs. Moreover, LPS administration suppressed HPMEC viability and accelerated HPMEC inflammation and apoptosis, which was antagonized by CXCL2 depletion. Mechanistically, Fli1 served as a transcription factor and bound to CXCL2 promoter. In rescue assays, CXCL2 overexpression counteracted the restrictive impact of Fli1 deficiency on LPS-induced HPMEC apoptotic behaviors and inflammatory response.

Conclusions: The Fli1 transcription factor aggravates LPS-induced HPMEC dysfunction via binding to CXCL2 promoter in septic ALI.

Objective: The increasing frequency and intensity of wildfires pose significant environmental and public health risks. While existing research has highlighted the effects of wildfire smoke exposure on chronic diseases, the cellular and molecular mechanisms underlying these effects remain unclear. In vitro exposure systems are necessary to dissect the effects of wood smoke on various cell types, but current in vitro exposure systems are often expensive and technically complex. This study introduces the GunSmoke Exposure Chamber (GSEC), a cost-effective, user-friendly system for modeling wildfire smoke exposure.

Materials and methods: The GSEC consists of readily available components, including a 25 L egg incubator, a food service smoke infuser gun, and an at-home air quality monitor. The BEAS-2B human bronchial epithelial cell line was used to assess its effectiveness in activating wood smoke-responsive and xenobiotic signaling pathways.

Results: Gene expression analysis confirmed activation of the NRF2 and AhR xenobiotic response pathways after wood smoke exposure. The GSEC will allow researchers to model a variety of exposure conditions. The GSEC can also be adapted for more complex protocols, specialized culture systems and a variety of cell types.

Conclusion: The GSEC provides an affordable and practical approach for studying wildfire smoke exposure. Its adaptability and accessibility make it a valuable tool for investigating the public health impact of wildfire smoke under different experimental conditions.