Inhalation Toxicology最新文献

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.

Background: Saikosaponin D (SSD), a triterpenoid saponin extracted from Bupleurum chinensis, has many pharmacological properties. The goal of our study is to assess the roles and mechanisms of SSD in septic acute lung injury (ALI).

Methods: ALI in mice was induced by cecal ligation and puncture (CLP). After CLP surgery, mice were intragastrically administered with SSD (4 mg/kg) or vehicle for five consecutive days. Alveolar epithelial barrier function was detected by measuring total protein in BALF and tight junction proteins in lung tissues. Morphological changes of lung tissues were examined by hematoxylin-eosin staining. ROS content in lung tissues was measured by DHE staining. GSH and MDA levels were estimated to evaluate oxidative stress. Western blotting was used to evaluate protein levels. An in vitro model of septic lung injury was established in MLE-12 cells via LPS stimulation. Cytotoxicity, TEER values, and FITC-dextran flux were detected. Intracellular ROS content was evaluated by DCFH-DA staining.

Results: SSD improved alveolar epithelial barrier function and suppressed ferroptosis in CLP-induced septic mice. SSD activated Nrf2/HO-1 signaling in CLP mice and LPS-exposed MLE-12 cells. ML385 (an Nrf2 inhibitor) attenuated SSD-mediated protective effects against ferroptosis and alveolar epithelial cell barrier dysfunction in vitro.

Conclusion: SSD ameliorates septic ALI by maintaining alveolar epithelial barrier integrity and suppressing ferroptosis via the activation of Nrf2 signaling.

Introduction: Carcinogenic potential of elongate particles depends on many characteristics, with dimensional parameters playing an important role at all stages of disease origination and progression. It is important to develop quantitative metrics of mesothelial carcinogenicity for particles in order to predict their behavior within biological systems. It would be especially valuable if such metrics could be developed for both carbon nanotubes (CNTs) and elongate mineral particles (EMPs) to demonstrate similarities and differences in the estimations of mesothelioma risk.

Methods: The database is organized with dimensional characteristics of EMPs, containing 570,950 records for 246 asbestiform, non-asbestiform, and mixed datasets. A database on carbon nanotubes (CNTs) with various toxicological outcomes of animal experiments, including mesothelioma, was also created. Mathematical modeling was used to determine the best metric of mesotheliomagenicity that would work for CNTs and EMPs.

Results: The dimensional coefficient of carcinogenicity (DCC) was introduced with the formula DCC = 1-exp(-AxSA/(BxWidth³+C)), where SA - surface area of the elongate particle, Width - particle width, A, B, C - coefficients. It was demonstrated that DCC can efficiently determine mesotheliomagenic varieties of CNTs and EMPs, with a threshold for carcinogenic potential of 0.05 with A = 0.11, B = 1000, C = 1.

Discussion: The new quantitative metric of carcinogenicity can be used for the purposes of mineralogical evaluation and toxicological analysis. It was confirmed that DCC-based models predict negligible mesothelioma potency for non-asbestiform amphiboles.

Background: Increasing evidence suggests that exposure to fine particulate matter (PM_2.5) is associated with an elevated risk of respiratory diseases. However, the precise mechanisms by which PM_2.5 influences inflammatory processes in allergic rhinitis (AR) remain insufficiently understood. The STAT pathway has been identified as a critical mediator of immune and inflammatory responses, but its specific role in modulating PM_2.5-induced effects in the nasal mucosa of AR remains unclear. This study aims to investigate the impact of PM_2.5 on the STAT pathway in the inflammatory response of the nasal mucosa during AR.

Methods: We analyzed mRNA expression profiles (GSE215411) from the Gene Expression Omnibus (GEO) database to investigate the effects of PM_2.5 on human nasal mucosa-derived fibroblasts. Differential expression analysis identified differential expression genes (DEGs), which were visualized through hierarchical clustering and radar plots. GO/KEGG enrichment and Gene Set Enrichment Analysis (GSEA) identified key pathways, focusing on STAT pathway enrichment. Protein-protein interactions (PPIs) within the STAT pathway were analyzed using STRING and Cytoscapedatabase, revealing immune response and cytokine signaling as predominant functional pathways. An AR model, induced by ovalbumin sensitization and whole-body ambient PM_2.5 exposure, was utilized to assess the activation of the STAT pathway in nasal mucosal tissue.

Results: A total of 426 DEGs were identified in human nasal mucosa-derived fibroblasts following PM_2.5 exposure, emphasizing STAT pathway involvement. Validation in an AR mouse model confirmed that allergens and PM_2.5 activate the STAT pathway, modulating Th2 and inflammatory cytokines.

Conclusion: PM_2.5 exposure significantly activates the STAT pathway in the nasal mucosa of AR, amplifying Th2-related inflammatory cytokine response.

Background: Cigarette smoking stands as a prominent contributor to global mortality rates, and its impact spans both immediate and long-term effects on hematological parameters; however, in addition to controversial results in previous studies, its effect on novel inflammatory indices has yet to be thoroughly investigated. Thus, this study aims to assess the impact of various smoking profiles on total white blood cell (WBC) count, WBC differentials, and novel hematologic-inflammatory indices among males.

Methods: This cross-sectional study was conducted on 4039 male adults from the enrollment phase data of the TABARI cohort population in Iran. WBC, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count (AMC), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), platelet-to-HDL ratio (PHR), RDW-to-platelet ratio (RPR), lymphocyte-to-HDL ratio (LHR), monocyte-to-HDL ratio (MHR), and neutrophil-to-HDL ratio (NHR) were compared between smokers and nonsmokers and also within smokers with different smoking intensities (pack/year). Comparisons were made by Chi-square test and one-way ANOVA, and further done using multivariate linear regression after adjustment for confounders.

Results: WBC, ANC, ALC, AMC, LMR, PLR, PHR, LHR, MHR, and NHR were significantly higher in smokers compared to nonsmokers in a dose-dependent manner (p < 0.05). The multivariate linear regression showed that among smokers, WBC was 25.3% higher, ANC and ALC were 19.7% higher, and AMC was 12.2% higher compared to nonsmokers (all p < 0.001).

Conclusion: Our results demonstrated that WBC, ANC, ALC, AMC, PHR, LHR, MHR, and NHR exhibit significant dose-dependent elevations in smokers.

Background: Chemicals released during cigarette smoking disrupt the structure, function and physiological capacity of the cardiovascular system. Detoxification of these harmful chemicals is done by Glutathione S-transferase (GST) isoenzymes (GSTM1 and GSTT1). GST gene polymorphisms may have a role in conferring susceptibility to coronary artery disease. This case-control study aims to evaluate the relationship between GSTM1 and GSTT1 gene polymorphisms, smoking habits, and coronary artery disease (CAD) in the Northern Indian population of Jammu and Kashmir, strengthened by a meta-analysis based on previously published studies.

Methods: The current study involved 220 patients with CAD and 240 healthy controls from the Jammu region in the Union Territory of Jammu and Kashmir. Whole blood DNA was isolated, followed by genotyping using the polymerase chain reaction (PCR) technique.

Results: Smoking, a non-vegetarian diet, and lipid levels were found to be significantly associated with coronary artery disease (CAD). The frequency of the GSTM^null genotype was significantly higher in patients than in controls (48.2% vs. 33.3%), while both groups showed comparable frequencies of the GSTT^null genotype. Combined genotype analysis indicated that the GSTM1 T^null genotype was associated with an increased risk of CAD, with an adjusted odds ratio (AOR) of 1.70 and a 95% confidence interval (CI) of 1.30-2.27(p = 0.05). Patients who were smokers and had the GSTM^null genotype, as well as those with the GSTM1T^null or GSTM^nullT1 genotypes, were at a significantly higher risk of developing CAD. The results of the meta-analysis supported the findings of the case-control association study.

Conclusion: The GSTM1 null genotype, either independently or in conjunction with smoking, is linked to the incidence of CAD among North Indians in Jammu and Kashmir.

Purpose: Dysfunction of pulmonary microvascular endothelial cells (PMVECs) is an important feature of pulmonary embolism (PE) in sepsis. This study aimed to explore the impact of caspase recruitment domain-containing protein 9 (CARD9) on sepsis-induced PE. Materials and Methods: Proteomic analysis was performed on serum of sepsis patients with PE to identify differentially expressed proteins. Wild-type (WT) and CARD9 knockout (KO) mice were used to establish PE in sepsis mouse model. In vitro and in vivo sepsis models were established to evaluate PMVEC function. Tiliroside (TIS) was tested for its therapeutic effects via modulation of the CARD9-mediated MAPK/NF-κB pathway. Results: In the pulmonary vascular endothelial tissues of mice with sepsis, a total of 46 proteins exhibited differential expression, and CARD9 was one of the changes proteins. Both CARD9 knockout (KO) and silencing were found to effectively ameliorate sepsis-induced dysfunction of PMVECs in both in vivo and in vitro models of sepsis. Tiliroside (TIS), an active constituent derived from Buddleja officinalis Maxim, demonstrated a significant capacity to enhance the function of PMVECs in sepsis by modulating the CARD9-mediated MAPK/NF-κB signaling pathway. Conclusion: In summary, CARD9 emerges as a potential molecular target for the treatment of sepsis-associated PE dysfunction.