Inhalation Toxicology最新文献

Objective: The objectives are to develop inhalation dosimetry models of the flavoring agents diacetyl, 2, 3-pentanedione, and acetoin to predict uptake throughout the rat and human respiratory tracts and use the results with histopathology data from 2-week, nose-only inhalation exposures in Sprague-Dawley rats to assess relationships between predicted dose and in vivo responses.

Methods: Computational fluid dynamics (CFD) models of the nasal passages were used to simulate inspiratory airflow and vapor uptake and mechanistic models of the lung airways were used to simulate vapor uptake during a breathing cycle.

Results: Diacetyl and 2, 3-pentanedione demonstrated similar uptake and wall mass flux patterns throughout the respiratory tract. Acetoin, being more soluble, was rapidly absorbed in the nasal and upper lung airways. At a 10 ppm exposure concentration and resting breathing conditions, nasal uptake of diacetyl, 2, 3-pentanedione, and acetoin was 30.9, 30.3, and 73.6% in the rat, and 8.7, 9.3, and 32.5% in the human, respectively; total respiratory tract uptake was 76.5, 76.8, and 93.0% in the rat and 79.6, 81.1, and 85.9% in the human, respectively. Wall mass flux patterns aligned with previously reported in vivo observations of histopathological effects in the rat respiratory tract following 8.75, 17.5, or 35 ppm diacetyl or 2, 3-pentanedione exposure and can be used to evaluate dose-response behavior.

Conclusions: Dose-response assessment of inhaled vapors demonstrates the utility of dosimetry models for interspecies extrapolation and chemical comparisons and how their use is an important part of risk characterization as non-animal alternatives are more widely considered.

Occupational exposure to crystalline silica (CS) is known to induce silicosis, a chronic lung disease characterized by the formation of granulomas and severe lung fibrosis. Specifically, individuals exposed to low doses of CS may develop silicosis after a decade or more of exposure. Similarly, in rat silicosis models exposed to occupationally relevant doses of α-quartz, there is an initial phase characterized by minimal and well-controlled pulmonary inflammation, followed by the development of robust and persistent inflammation. During the initial phase, the inflammation provoked by α-quartz is subdued by two mechanisms. Firstly, α-quartz particles are engulfed by alveolar macrophages (AMs) of the alternatively activated (M2) subtype and interstitial macrophages (IMs), limiting their interaction with other lung cells. Secondly, the anti-inflammatory cytokine, interleukin (IL)-10, is constitutively expressed by these macrophages, further dampening the inflammatory response. In the later inflammatory phase, IL-10-dependent anti-inflammatory state is disrupted by Type I interferons (IFNs), leading to the production of pro-inflammatory cytokines in response to α-quartz, aided by lipopolysaccharides (LPS). This review delves into the complex pathways involving IL-10, LPS, and Type I IFNs in α-quartz-induced pulmonary inflammation, offering a detailed analysis of the underlying mechanisms and identifying areas for future research.

Objectives: The adverse effects of fine particulate matter (PM_2.5), including cardiovascular outcomes, are well established. This review and meta-analysis investigates the association between long-term exposure to low concentration PM_2.5 (<12 µg/m³) and CVD mortality in U.S. and Canadian populations.

Methods: We conducted a literature search and completed random effect meta-analyses.

Results: Twenty-four studies were reviewed, with 12 from each of the U.S. and Canada. Fifteen of eighteen studies that reported hazard ratios (HRs) for total CVD mortality reported statistically significant positive associations with low concentration PM_2.5. For cause-specific CVD mortality, more consistent results were shown for ischemic heart disease (IHD) mortality, with all eleven studies reporting statistically significant associations (HR = 1.09 to 2.48). Only three of 12 studies evaluating cerebrovascular mortality reported statistically significant associations (HR = 1.10 to 1.27). Studies that restricted analyses to participants with mean exposures <12 µg/m³ found statistically significant associations between PM_2.5 and at least some of the CVD mortality outcomes of interest. However, the shape of the concentration-response functions varied widely. Only six studies controlled for at least one additional air pollutant, and multi-pollutant models generally showed an attenuated impact of PM_2.5. Despite existing gaps in understanding the association between low concentrations of PM_2.5 and cardiovascular mortality, this review highlights the critical importance of ongoing efforts to improve air quality for public health benefits.

Conclusions: Continued focus on understanding the shape of the concentration-response function for PM_2.5, the impact of co-pollutants on observed effects, and how particle composition may impact effect estimates, is recommended.

Purpose: Pulmonary exposure to emissions from manipulating solid surface composite (SSC) materials has been associated with adverse health effects in humans and laboratory animals. Previous in vitro and in vivo investigations of SSC toxicity have been limited by particle delivery methods that do not fully recapitulate the workplace environment. This study sought to determine the acute SSC-induced pulmonary responses via whole-body inhalation exposure. Materials and Methods: A chamber for dust particle generation and an exposure system for characterization and animal exposures was constructed. The system successfully generated SSC at a concentration of 19.9 ± 1.5 mg/m³. The aerosol count median aerodynamic diameter was 820 nm. First, C57BL/6 mice were exposed to SSC particles for 4 h (n = 6) or filtered air control followed by euthanasia either immediately or 24 h post-exposure. Lungs were analyzed for aluminum (Al) content using inductively coupled plasma atomic emission spectroscopy (ICP-AES) which measured a lung deposition of 19.13 ± 5.03 µg/g elemental Al, or approximately 64 µg/g SSC dust. Second, a group of mice (n = 9) was exposed to SSC particles at 20 mg/m³ for 4 days, 4 h/day to assess the acute and sub-chronic pulmonary effects of SSC inhalation. Animals were euthanized at 1- and 56-days post-exposure. Results: Total estimated pulmonary deposition for these animals was 49.2 µg SSC dust/animal. No histopathologic changes were observed at any post-exposure time point; however, BALF total protein was increased at 1-day post-exposure. Conclusions: We conclude that exposure to dust from cutting SSC at this dose and post-exposure durations induces mild, transient inflammation.

Objective: The present study evaluated urinary oxidative stress (OxS) biomarkers to explain the extrapulmonary effect of renal function decline due to subchronic inhalation exposure to particles smaller than 2.5 μm, as well as the correlation of the biomarkers with the particles' endotoxin content.

Materials and methods: Adult male Sprague-Dawley rats were exposed to subchronic inhalation of particles smaller than 2.5 μm (8 weeks, 4 days/week, 5 h/day). The control group was exposed to filtered air. MiniVol and HiVol samplers were used to estimate the concentration and collected particles, respectively. Biomarkers were assessed in weekly urine samples harvested by the metabolic cage. The OxS biomarkers assessed were methylglyoxal, non-esterified fatty acids, malondialdehyde, advanced oxidative protein products, arginase, myeloperoxidase, glutathione S-transferase, and gamma-glutamyl transferase, all of which were evaluated by colorimetric assays. Creatinine was evaluated by the Jaffe reaction, and cystatin-C (Cys-C) and neutrophil gelatinase-associated lipocalin-2 were quantified using Luminex technology. Endotoxin content was analyzed with the Limulus Amebocyte Lysate Pyrochrome Chromogenic Test Kit.

Results and discussion: Subchronic exposure to PM_2.5 increased OxS biomarkers in urine. Endotoxin content showed a positive correlation with the urinary OxS biomarkers evaluated. Additionally, urinary OxS biomarkers correlated with creatinine and the early kidney damage biomarkers Cys-C and neutrophil gelatinase-associated lipocalin-2, where the strongest and positive correlations were observed with the latter two biomarkers.

Conclusions: Inhalation of environmental airborne particles smaller than 2.5 μm increased urinary OxS biomarkers, correlated with endotoxin content and early kidney damage biomarkers. This finding corroborates the extrapulmonary nephrotoxic effect of inhaled particles.

Purpose: In the past decade, microplastics (MPs) have drawn significant attention as widespread environmental contaminants, with research increasingly highlighting their harmful effects on respiratory health in aquatic and terrestrial organisms. Findings revealed microplastics in human lung tissues, raising concerns about their potential role in damaging lung tissue integrity and contributing to pulmonary fibrosis-a chronic inflammatory condition characterized by scarring of lung epithelial tissues due to accumulated extracellular matrix, triggered by factors such as alcohol, pathogens, genetic mutations, and environmental pollutants.

Objective: In this review, we explore both well-studied and lesser-studied mechanisms and signaling pathways, aiming to shed light on how microplastics might act as mediators that activate distinct, often overlooked signaling cascades.

Materials and methods: This review searched PubMed and Google Scholar using keywords like "plastic," "microplastic," "lung fibrosis," "pulmonary system," "exposure route," and "signaling pathways," combined with "OR" and "AND" in singular and plural forms.

Results: These pathways could not only induce lung damage but also play a significant role in the development of pulmonary fibrosis.

Discussion and conclusions: These signaling pathways could also be targeted to reduce microplastic-induced pulmonary fibrosis, opening new avenues for future treatments.

Objective: Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation, with cigarette smoke being a major contributor to epithelial injury. Recent studies have shown that abnormal mitochondrial function is closely linked to the onset and progression of airway inflammation. This study aims to explore the role and underlying molecular mechanisms of mitochondrial dynamics in cigarette smoke-induced airway inflammation.

Materials and methods: Human bronchial epithelial (HBE) cells were exposed to cigarette smoke extract (CSE) to assess the expression of mitochondrial fusion markers MFN2 and OPA1, the fission marker DRP1, and the glucose-regulated protein GRP78. The siRNA and pharmaceutics targeting DRP1, MFN2, and GRP78 were employed. Both cells and supernatants were analyzed for inflammatory factor levels and the related signaling pathways.

Results: In this study, HBE cells exposed to CSE showed a significant decrease in the proteins MFN2 and OPA1 and an increase in DRP1. The inhibition of DRP1 expression mitigated inflammation while silencing MFN2 exacerbated it. This was similarly corroborated by the use of the DRP1 inhibitor mdivi-1 and the MFN2 activator leflunomide. Additionally, we proved that GRP78 played an important regulatory role as an essential endoplasmic reticulum protein, regulating the mitochondrial fusion/fission process and subsequently activating the NF-κB pathway to regulate airway inflammation.

Discussion and conclusion: Taken together, these results suggested that the GRP78-mediated mitochondrial fusion and fission process played a vital role in cigarette smoke-induced airway inflammation and might be a potential therapeutic target in this regard.

Objective: PM_2.5 is closely linked to vascular endothelial injury and has emerged as a major threat to human health. Our previous research indicated that exposure to PM_2.5 induced an increased release of miR-421 from the bronchial epithelium. However, the role of miR-421 in PM_2.5-induced endothelial injury remains elusive.

Materials and methods: We utilized a subacute PM_2.5-exposure model in mice in vivo and an acute injury cell model in vitro to simulate PM_2.5-associated endothelial injury. We also used quantitative real-time polymerase chain reaction, western blot, enzyme-linked immunosorbent assay, and immunohistochemistry to investigate the role of miR-421 in PM_2.5-induced endothelial injury.

Results: Our findings reveal that inhibition of miR-421 attenuated PM_2.5-induced endothelial injury and hypertension. Mechanistically, miR-421 inhibited the expression of angiotensin-converting enzyme 2 (ACE2) in human umbilical vein endothelial cells and upregulated the expression of the downstream molecule inducible nitric oxide synthase (iNOS), thereby exacerbating PM_2.5-induced endothelial injury.

Conclusions: Our results indicate that PM_2.5 exposure facilitates crosstalk between bronchial epithelial and endothelial cells via miR-421/ACE2/iNOS signaling pathway, mediating endothelial damage and hypertension. MiR-421 inhibition may offer a new strategy for the prevention and treatment of PM_2.5-induced vascular endothelial injury.

Objective: Chlorine (Cl₂) is a widely used industrial chemical and toxic human exposures have occurred from Cl₂ releases. No approved medical countermeasures (MCMs) exist for Cl₂-induced lung injuries. The objective of this study was to develop and characterize swine Cl₂ inhalation injuries to understand lung injury and histopathological sequalae.

Materials and methods: Male swine (approximately 14 weeks old) were anesthetized, paralyzed, intubated, and exposed to clean air or Cl₂ while connected to a ventilator. The exposed LD_50/24 hr of 1.8 mg/kg was delivered within a 15-20-minute timeframe. Scheduled terminal timepoints were 6 h, 7- and 30-days post-exposure.

Results: Following Cl₂ exposure, 46% of the animals succumbed with an average time to death of 1.42 h. Dynamic lung compliance at 6 h post-exposure was reduced 45%. Clinical observations demonstrated respiratory abnormalities similar to Cl₂ exposed humans. Compared to air shams, Cl₂-exposed animals had decreased SpO₂, arterial blood pH, pO₂, sO₂, increased blood lactate levels and deoxyhemoglobin levels at early timepoints. Increased neutrophils 6 h post- exposure occurred concurrent with increased inflammatory cytokines, bronchiolar epithelial necrosis with alveolar edema, cellular infiltrates, and lobular atelectasis.

Discussion/conclusions: Potentially relevant biomarkers involved in the progression and recovery from acute Cl₂ lung injury in this model include lung compliance, select cytokines/chemokines, arterial blood gas parameters, and histopathological evaluation. Normal lung histopathological observations beyond 7- days indicates that histopathological evaluations should occur earlier. This animal model delivers accurate and consistent Cl₂ exposures resulting in a human-relevant lung injury for evaluating MCM efficacy against Cl₂-mediated acute lung injury.

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.