Cigarette smoke-induced dysbiosis: comparative analysis of lung and intestinal microbiomes in COPD mice and patients.

BACKGROUND: The impact of cigarette smoke (CS) on lung diseases and the role of microbiome dysbiosis in chronic obstructive pulmonary disease (COPD) have been previously reported; however, the relationships remain unclear. METHODS: Our research examined the effects of 20-week cigarette smoke (CS) exposure on the lung and intestinal microbiomes in C57BL/6JNarl mice, alongside a comparison with COPD patients' intestinal microbiome data from a public dataset. RESULTS: The study found that CS exposure significantly decreased forced vital capacity (FVC), thickened airway walls, and induced emphysema. Increased lung damage was observed along with higher lung keratinocyte chemoattractant (KC) levels by CS exposure. Lung microbiome analysis revealed a rise in Actinobacteriota, while intestinal microbiome showed significant diversity changes, indicating dysbiosis. Principal coordinate analysis highlighted distinct intestinal microbiome compositions between control and CS-exposed groups. In the intestinal microbiome, notable decreases in Patescibacteria, Campilobacterota, Defferibacterota, Actinobacteriota, and Desulfobacterota were observed. We also identified correlations between lung function and dysbiosis in both lung and intestinal microbiomes. Lung interleukins, interferon-É£, KC, and 8-isoprostane levels were linked to lung microbiome dysbiosis. Notably, dysbiosis patterns in CS-exposed mice were similar to those in COPD patients, particularly of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 4 patients. This suggests a systemic impact of CS exposure. CONCLUSION: In summary, CS exposure induces significant dysbiosis in lung and intestinal microbiomes, correlating with lung function decline and injury. These results align with changes in COPD patients, underscoring the important role of microbiome in smoke-related lung diseases.

Exposure and health risk assessment of volatile organic compounds among drivers and passengers in long-distance buses.

Exposure to volatile organic compounds (VOCs) such as benzene, toluene, ethylbenzene, xylene, and formaldehyde from long-distance buses has been reported to adversely affect human health. This study investigates the concentrations of these five VOCs and evaluates their health risks to drivers and passengers on board. Ten trips from Taipei to Taichung were performed during the warm and cold seasons of 2021-2022. Two locations inside the bus were established to collect air samples by a 6-liter canister for drivers and passengers. Exposure concentrations of benzene, toluene, ethylbenzene, and xylene were analyzed via gas chromatography with a flame ionization detector and the formaldehyde concentration was monitored using a formaldehyde meter. Subsequently, a Monte Carlo simulation was conducted to evaluate the carcinogenic and non-carcinogenic risks of the five VOCs. Formaldehyde emerged as the highest detected compound (9.06 ± 3.77 µg/m3), followed by toluene (median: 6.11 µg/m3; range: 3.86-14.69 µg/m3). In particular, formaldehyde was identified to have the significantly higher concentration during non-rush hours (10.67 ± 3.21 µg/m3) than that during rush hours (7.45 ± 3.41 µg/m3) and during the warm season (10.71 ± 2.97 µg/m3) compared with that during the cold season (7.41 ± 4.26 µg/m3). Regarding non-carcinogenic risks to drivers and passengers, the chronic hazard indices for these five VOCs were under 1 to indicate an acceptable risk. In terms of carcinogenic risk, the median risks of benzene and formaldehyde for drivers were 2.88 × 10-6 (95% confidence interval [CI]: 2.11 × 10-6 - 5.13 × 10-6) and 1.91 × 10-6 (95% CI: 4.54 × 10-7 - 3.44 × 10-6), respectively. In contrast, the median carcinogenic risks of benzene and formaldehyde for passengers were less than 1 × 10-6 to present an acceptable risk. This study suggests that benzene and formaldehyde may present carcinogenic risks for drivers. Moreover, the non-carcinogenic risk for drivers and passengers is deemed acceptable. We recommended that the ventilation frequency be increased to mitigate exposure to VOCs in long-distance buses.

Effects of occupational exposure to metal fume PM2.5 on lung function and biomarkers among shipyard workers: a 3-year prospective cohort study.

OBJECTIVE: This study investigates the associations of α1-antitrypsin, inter-α-trypsin inhibitor heavy chain (ITIH4), and 8-isoprostane with lung function in shipyard workers exposed to occupational metal fume fine particulate matter (PM2.5), which is known to be associated with adverse respiratory outcomes. METHODS: A 3-year follow-up study was conducted on 180 shipyard workers with 262 measurements. Personal exposure to welding fume PM2.5 was collected for an 8-h working day. Pre-exposure, post-exposure, and delta (∆) levels of α1-antitrypsin, ITIH4, and 8-isoprostane were determined in urine using enzyme-linked immunosorbent assays. Post-exposure urinary metals were sampled at the beginning of the next working day and analyzed by inductively coupled plasma-mass spectrometry. Lung function measurements were also conducted the next working day for post-exposure. RESULTS: An IQR increase in PM2.5 was associated with decreases of 2.157% in FEV1, 2.806% in PEF, 4.328% in FEF25%, 5.047% in FEF50%, and 7.205% in FEF75%. An IQR increase in PM2.5 led to increases of 42.155 µg/g in ∆α1-antitrypsin and 16.273 µg/g in ∆ITIH4. Notably, IQR increases in various urinary metals were associated with increases in specific biomarkers, such as post-urinary α1-antitrypsin and ITIH4. Moreover, increases in ∆ α1-antitrypsin and ∆ITIH4 were associated with decreases in FEV1/FVC by 0.008% and 0.020%, respectively, and an increase in ∆8-isoprostane resulted in a 1.538% decline in FVC. CONCLUSION: Our study suggests that urinary α1-antitrypsin and ITIH4 could indicate early lung function decline in shipyard workers exposed to metal fume PM2.5, underscoring the need for better safety and health monitoring to reduce respiratory risks.

Characterization of airborne endotoxin in personal exposure to fine particulate matter (PM2.5) and bioreactivity for elderly residents in Hong Kong.

The heavy metals and bioreactivity properties of endotoxin in personal exposure to fine particulate matter (PM2.5) were characterized in the analysis. The average personal exposure concentrations to PM2.5 were ranged from 6.8 to 96.6 µg/m3. The mean personal PM2.5 concentrations in spring, summer, autumn, and winter were 32.1±15.8, 22.4±11.8, 35.3±11.9, and 50.2±19.9 µg/m3, respectively. There were 85 % of study targets exceeded the World Health Organization (WHO) PM2.5 threshold (24 hours). The mean endotoxin concentrations ranged from 1.086 ± 0.384-1.912 ± 0.419 EU/m3, with a geometric mean (GM) varied from 1.034 to 1.869. The concentration of iron (Fe) (0.008-1.16 µg/m3) was one of the most abundant transition metals in the samples that could affect endotoxin toxicity under Toll-Like Receptor 4 (TLR4) stimulation. In summer, the interleukin 6 (IL-6) levels showed statistically significant differences compared to other seasons. Spearman correlation analysis showed endotoxin concentrations were positively correlated with chromium (Cr) and nickel (Ni), implying possible roles as nutrients and further transport via adhering to the surface of fine inorganic particles. Mixed-effects model analysis demonstrated that Tumor necrosis factor-α (TNF-α) production was positively associated with endotoxin concentration and Cr as a combined exposure factor. The Cr contained the highest combined effect (0.205-0.262), suggesting that Cr can potentially exacerbate the effect of endotoxin on inflammation and oxidative stress. The findings will be useful for practical policies for mitigating air pollution to protect the public health of the citizens.

Alteration in branching morphogenesis via YAP/TAZ in fibroblasts of fetal lungs in an LPS-induced inflammation model.

BACKGROUND: Chorioamnionitis is a common cause of preterm birth and leads to serious complications in newborns. The objective of this study was to investigate the role of the Hippo signaling pathway in lung branching morphogenesis under a lipopolysaccharide (LPS)-induced inflammation model. MATERIALS AND METHODS: IMR-90 cells and ex vivo fetal lungs were treated with 0, 10, 30, or 50 µg/ml LPS for 24 and 72 h. Supernatant levels of lactate dehydrogenase (LDH), interleukin (IL)-6, IL-8, Chemokine (C-X-C motif) ligand 1(CXCL1), branching and the surface area ratio, Yes-associated protein (YAP), transcription coactivator with PDZ-binding motif (TAZ), fibroblast growth factor 10 (FGF10), fibroblast growth factor receptor II (FGFR2), SRY-box transcription factor 2 (SOX2), SOX9, and sirtuin 1 (SIRT1) levels were examined. Differentially expressed genes in fetal lungs after LPS treatment were identified by RNA-sequencing. RESULTS: LPS at 50 µg/ml increased IL-6 and IL-8 in IMR-90 cells and increased IL-6, CXCL1 and LDH in fetal lungs. The branching ratio significantly increased by LPS at 30 µg/ml compared to the control but the increased level had decreased by 50 µg/ml LPS exposure. Exposure to 50 µg/ml LPS increased phosphorylated (p)-YAP, p-YAP/YAP, and p-TAZ/TAZ in IMR-90 cells, whereas 50 µg/ml LPS decreased FGF10 and SOX2. Consistently, p-YAP/YAP and p-TAZ/TAZ were increased in fibronectin+ cells of fetal lungs. Moreover, results of RNA-sequencing in fetal lungs showed that SMAD, FGF, IκB phosphorylation, tissue remodeling and homeostasis was involved in branching morphogenesis following exposure to 50 µg/ml LPS. The p-SIRT1/SIRT1 ratio increased in IMR-90 cells by LPS treatment. CONCLUSIONS: This study showed that regulation of the Hippo pathway in fibroblasts of fetal lungs was involved in branching morphogenesis under an inflammatory disease such as chorioamnionitis.

Role of DCLK1/Hippo pathway in type II alveolar epithelial cells differentiation in acute respiratory distress syndrome.

BACKGROUND: Delay in type II alveolar epithelial cell (AECII) regeneration has been linked to higher mortality in patients with acute respiratory distress syndrome (ARDS). However, the interaction between Doublecortin-like kinase 1 (DCLK1) and the Hippo signaling pathway in ARDS-associated AECII differentiation remains unclear. Therefore, the objective of this study was to understand the role of the DCLK1/Hippo pathway in mediating AECII differentiation in ARDS. MATERIALS AND METHODS: AECII MLE-12 cells were exposed to 0, 0.1, or 1 µg/mL of lipopolysaccharide (LPS) for 6 and 12 h. In the mouse model, C57BL/6JNarl mice were intratracheally (i.t.) injected with 0 (control) or 5 mg/kg LPS and were euthanized for lung collection on days 3 and 7. RESULTS: We found that LPS induced AECII markers of differentiation by reducing surfactant protein C (SPC) and p53 while increasing T1α (podoplanin) and E-cadherin at 12 h. Concurrently, nuclear YAP dynamic regulation and increased TAZ levels were observed in LPS-exposed AECII within 12 h. Inhibition of YAP consistently decreased cell levels of SPC, claudin 4 (CLDN-4), galectin 3 (LGALS-3), and p53 while increasing transepithelial electrical resistance (TEER) at 6 h. Furthermore, DCLK1 expression was reduced in isolated human AECII of ARDS, consistent with the results in LPS-exposed AECII at 6 h and mouse SPC-positive (SPC+) cells after 3-day LPS exposure. We observed that downregulated DCLK1 increased p-YAP/YAP, while DCLK1 overexpression slightly reduced p-YAP/YAP, indicating an association between DCLK1 and Hippo-YAP pathway. CONCLUSIONS: We conclude that DCLK1-mediated Hippo signaling components of YAP/TAZ regulated markers of AECII-to-AECI differentiation in an LPS-induced ARDS model.

Uteroplacental insufficiency decreases leptin expression and impairs lung development in growth-restricted newborn rats.

BACKGROUND: The study aimed to analyze the effect of uteroplacental insufficiency (UPI) on leptin expression and lung development of intrauterine growth restriction (IUGR) rats. METHODS: On day 17 of pregnancy, time-dated Sprague-Dawley rats were randomly divided into either an IUGR group or a control group. Uteroplacental insufficiency surgery (IUGR) and sham surgery (control) were conducted. Offspring rats were spontaneously delivered on day 22 of pregnancy. On postnatal days 0 and 7, rats' pups were selected at random from the control and IUGR groups. Blood was withdrawn from the heart to determine leptin levels. The right lung was obtained for leptin and leptin receptor levels, immunohistochemistry, proliferating cell nuclear antigen (PCNA), western blot, and metabolomic analyses. RESULTS: UPI-induced IUGR decreased leptin expression and impaired lung development, causing decreased surface area and volume in offspring. This results in lower body weight, decreased serum leptin levels, lung leptin and leptin receptor levels, alveolar space, PCNA, and increased alveolar wall volume fraction in IUGR offspring rats. The IUGR group found significant relationships between serum leptin, radial alveolar count, von Willebrand Factor, and metabolites. CONCLUSION: Leptin may contribute to UPI-induced lung development during the postnatal period, suggesting supplementation as a potential treatment. IMPACT: The neonatal rats with intrauterine growth restriction (IUGR) caused by uteroplacental insufficiency (UPI) showed decreased leptin expression and impaired lung development. UPI-induced IUGR significantly decreased surface area and volume in lung offspring. This is a novel study that investigates leptin expression and lung development in neonatal rats with IUGR caused by UPI. If our findings translate to IUGR infants, leptin may contribute to UPI-induced lung development during the postnatal period, suggesting supplementation as a potential treatment.

Climate change and mortality rates of COPD and asthma: A global analysis from 2000 to 2018.

BACKGROUND: Climate change plays a significant role in global health threats, particularly with respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma, but the long-term global-scale impact of climate change on these diseases' mortality remains unclear. OBJECTIVE: This study aims to investigate the impact of climate change on the age-standardized mortality rates (ASMR) of COPD and asthma at national levels. METHODS: We used Global Burden of Disease (GBD) data of ASMR of COPD and asthma from 2000 to 2018. The climate change index was represented as the deviance percentage of temperature (DPT) and relative humidity (DPRH), calculated based on 19-year temperature and humidity averages. Annual temperature, RH, and fine particulate matter (PM2.5) levels in 185 countries/regions were obtained from ERA5 and the OECD's environmental statistics database. General linear mixed-effect regression models were used to examine the associations between climate change with the log of ASMR (LASMR) of COPD and asthma. RESULTS: After adjusting for annual PM2.5, SDI level, smoking prevalence, and geographical regions, a 0.26% increase in DPT was associated with decreases of 0.016, 0.017, and 0.014 per 100,000 people in LASMR of COPD and 0.042, 0.046, and 0.040 per 100,000 people in LASMR of asthma for both genders, males, and females. A 2.68% increase in DPRH was associated with increases of 0.009 and 0.011 per 100,000 people in LASMR of COPD. We observed a negative association of DPT with LASMR for COPD in countries/regions with temperatures ranging from 3.8 to 29.9 °C and with LASMR for asthma ranging from -5.3-29.9 °C. However, we observed a positive association of DPRH with LASMR for both COPD and asthma in the RH range of 41.2-67.2%. CONCLUSION: Climate change adaptation and mitigation could be crucial in reducing the associated COPD and asthma mortality rates, particularly in regions most vulnerable to temperature and humidity fluctuations.

A mobile platform for characterizing on-road tailpipe emissions and toxicity of ultrafine particles under real driving Conditions.

Acute exposure to fresh traffic-related air pollutants (TRAPs) can be high for road users, including motorbike drivers, cyclists, and pedestrians. However, evaluating the toxicity of fresh traffic emissions from on-road vehicles is challenging since pollution properties can change dynamically within a short distance and time. This study demonstrated a mobile platform equipped with an On-Board Diagnostic II (OBDII) system, a tailor-made portable emission measurement system, and an electrostatic air-liquid interface exposure system with human monocytic THP-1 cells to characterize on-road tailpipe emissions under real driving conditions. High number concentrations up to 106-107 # cm-3 of ultrafine particles (UFPs) were observed for a gasoline engine at the cold-start stage and a diesel engine during particulate filter regeneration. In particular, a substantial fraction of freshly emitted UFPs within the size less than 23 nm were observed and should be cautioned. The potential toxicity of fresh TRAPs was quantified by cell viability, cytotoxicity, oxidative stress, and inflammatory biomarkers. Results show that the decreased cell viability, increased lactate dehydrogenase (LDH) activity, and high oxidative stress induced by the fresh TRAPs were potentially contributed by gaseous pollutants as well as particles, especially driving with the high idling frequency. Moreover, the dominant contributor to the toxicity is different for gasoline's and diesel's TRAPs. Characterizing on-road air pollutant toxicity as well as physicochemical properties using an innovative mobile platform can fill this knowledge gap.

Associations of overnight changes in body composition with positional obstructive sleep apnea.

PURPOSE: Body composition is considered to be associated with obstructive sleep apnea (OSA) severity. This cross-sectional study aimed to examine associations of overnight body composition changes with positional OSA. METHODS: The body composition of patients diagnosed with non-positional and positional OSA was measured before and after overnight polysomnography. Odds ratios (ORs) of outcome variables between the case (positional OSA) and reference (non-positional OSA) groups were examined for associations with sleep-related parameters and with changes in body composition by a logistic regression analysis. RESULTS: Among 1584 patients with OSA, we used 1056 patients with non-positional OSA as the reference group. We found that a 1-unit increase in overnight changes of total fat percentage and total fat mass were associated with 1.076-fold increased OR (95% confidence interval (CI): 1.014, 1.142) and 1.096-fold increased OR (95% CI: 1.010, 1.189) of positional OSA, respectively (all p < 0.05). Additionally, a 1-unit increase in overnight changes of lower limb fat percentage and upper limb fat mass were associated with 1.043-fold increased OR (95% CI: 1.004, 1.084) and 2.638-fold increased OR (95% CI: 1.313, 5.302) of positional OSA, respectively (all p < 0.05). We observed that a 1-unit increase in overnight changes of trunk fat percentage and trunk fat mass were associated with 1.056-fold increased OR (95% CI: 1.008, 1.106) and 1.150-fold increased OR (95% CI: 1.016, 1.301) of positional OSA, respectively (all p < 0.05). CONCLUSION: Our findings indicated that nocturnal changes in the body's composition, especially total fat mass, total fat percentage, lower limb fat percentage, upper limb fat mass, trunk fat percentage, and trunk fat mass, may be associated with increased odds ratio of positional OSA compared with non-positional OSA.

Association between ambient BTEX mixture and neurological hospitalizations: A multicity time-series study in Taiwan.

BACKGROUND: Benzene, toluene, ethylbenzene, and xylenes, collectively known as BTEX, are hazardous chemical mixtures, and their neurological health effects have not been thoroughly evaluated. We examined the association between BTEX exposure and neurological hospital admissions. METHODS: This was a multicity time-series study conducted in five major Taiwanese cities. Daily hospital admission records for diseases of the nervous system from January 1, 2016, to December 31, 2017, were collected from the National Health Insurance Research Database. Ambient BTEX and criteria pollutant concentrations and weather factors were collected from Photochemical Assessment Monitoring Stations. We applied a Poisson generalized additive model (GAM) and weighted quantile sum regression to calculate city-specific effect estimates for BTEX and conducted a random-effects meta-analysis to pool estimates. RESULTS: We recorded 68 neurological hospitalizations per day during the study period. The daily mean BTEX mixture concentrations were 22.5 µg/m3, ranging from 18.3 µg/m3 in Kaohsiung to 27.0 µg/m3 in Taichung, and toluene (13.6 µg/m3) and xylene (5.8 µg/m3) were the dominant chemicals. Neurological hospitalizations increased by an average of 1.6 % (95 % CI: 0.6-2.6 %) for every interquartile range (15.8 µg/m3) increase in BTEX at lag 0 estimated using a GAM model. A quartile increase in the weighted sum of BTEX exposure was associated with a 1.7 % (95 % CI: 0.6-2.8 %) increase in daily neurological hospitalizations. CONCLUSION: We found consistent acute adverse effects of BTEX on neurological hospitalizations in Taiwan, with toluene and xylene as the dominant chemicals. These findings aid the development of more targeted public health interventions.

Assessing traffic-related air pollution-induced fiber-specific white matter degradation associated with motor performance declines in aged rats.

Fine particulate matter (PM2.5) is thought to exacerbate Parkinson's disease (PD) in the elderly, and early detection of PD progression may prevent further irreversible damage. Therefore, we used diffusion tensor imaging (DTI) for probing microstructural changes after late-life chronic traffic-related PM2.5 exposure. Herein, 1.5-year-old Fischer 344 rats were exposed to clean air (control), high-efficiency particulate air (HEPA)-filtered ambient air (HEPA group), and ambient traffic-related PM2.5 (PM2.5 group, 9.933 ± 1.021 µg/m3) for 3 months. Rotarod test, DTI tractographic analysis, and immunohistochemistry were performed in the end of study period. Aged rats exposed to PM2.5 exhibited motor impairment with decreased fractional anisotropy and tyrosine hydroxylase expression in olfactory and nigrostriatal circuits, indicating disrupted white matter integrity and dopaminergic (DA) neuronal loss. Additionally, increased radial diffusivity and lower expression of myelin basic protein in PM2.5 group suggested ageing progression of demyelination exacerbated by PM2.5 exposure. Significant production of tumor necrosis factor-α was also observed after PM2.5 exposure, revealing potential inflammation of injury to multiple fiber tracts of DA pathways. Microstructural changes demonstrated potential links between PM2.5-induced inflammatory white matter demyelination and behavioral performance, with indication of pre-manifestation of DTI-based biomarkers for early detection of PD progression in the elderly.

Downregulation of TAZ elicits a mitochondrial redox imbalance and ferroptosis in lung epithelial cells exposed to diesel exhaust particles.

Mitochondrial dysfunction was reported to be involved in the development of lung diseases including chronic obstructive pulmonary disease (COPD). However, molecular regulation underlying metabolic disorders in the airway epithelia exposed to air pollution remains unclear. In the present study, lung bronchial epithelial BEAS-2B and alveolar epithelial A549 cells were treated with diesel exhaust particles (DEPs), the primary representative of ambient particle matter. This treatment elicited cell death accompanied by induction of lipid reactive oxygen species (ROS) production and ferroptosis. Lipidomics analyses revealed that DEPs increased glycerophospholipid contents. Accordingly, DEPs upregulated expression of the electron transport chain (ETC) complex and induced mitochondrial ROS production. Mechanistically, DEP exposure downregulated the Hippo transducer transcriptional co-activator with PDZ-binding motif (TAZ), which was further identified to be crucial for the ferroptosis-associated antioxidant system, including glutathione peroxidase 4 (GPX4), the glutamate-cysteine ligase catalytic subunit (GCLC), and glutathione-disulfide reductase (GSR). Moreover, immunohistochemistry confirmed downregulation of GPX4 and upregulation of lipid peroxidation in the bronchial epithelium of COPD patients and Sprague-Dawley rats exposed to air pollution. Finally, proteomics analyses confirmed alterations of ETC-related proteins in bronchoalveolar lavage from COPD patients compared to healthy subjects. Together, our study discovered that involvement of mitochondrial redox dysregulation plays a vital role in pulmonary epithelial cell destruction after exposure to air pollution.

Association of air pollution exposure with exercise-induced oxygen desaturation in COPD.

BACKGROUND: There is a link between exposure to air pollution and the increased prevalence of chronic obstructive pulmonary disease (COPD) and declining pulmonary function, but the association with O2 desaturation during exercise in COPD patients with emphysema is unclear. Our aims were to estimate the prevalence of O2 desaturation during exercise in patients with COPD, and determine the association of exposure to air pollution with exercise-induced desaturation (EID), the degree of emphysema, and dynamic hyperinflation (DH). METHODS: We assessed the effects of 10-year prior to the HRCT assessment and 7 days prior to the six-minute walking test exposure to particulate matter with an aerodynamic diameter of < 10 µm (PM10) or of < 2.5 µM (PM2.5), nitrogen dioxide (NO2), and ozone (O3) in patients with emphysema in this retrospective cohort study. EID was defined as a nadir standard pulse oximetry (SpO2) level of < 90% or a delta (△)SpO2 level of ≥ 4%. Ambient air pollutant (PM2.5, PM10, O3, and NO2) data were obtained from Taiwan Environmental Protection Administration (EPA) air-monitoring stations, usually within 10 km to each participant's home address. RESULTS: We recruited 141 subjects with emphysema. 41.1% of patients with emphysema exhibited EID, and patients with EID had more dyspnea, worse lung function, more severe emphysema, more frequent acute exacerbations, managed a shorter walking distance, had DH, and greater long-term exposure to air pollution than those without EID. We observed that levels of 10-year concentrations of PM10, PM2.5, and NO2 were significantly associated with EID, PM10 and PM2.5 were associated with the severity of emphysema, and associated with DH in patients with emphysema. In contrast, short-term exposure did not have any effect on patients. CONCLUSION: Long-term exposure to ambient PM10, PM2.5 and NO2, but not O3, was associated with EID.

Lnc-IL7R alleviates PM2.5-mediated cellular senescence and apoptosis through EZH2 recruitment in chronic obstructive pulmonary disease.

BACKGROUND: Long-term exposure to PM2.5 (particulate matter with an aerodynamic diameter of ≤ 2.5 µm) is associated with pulmonary injury and emphysema in patients with chronic obstructive pulmonary disease (COPD). We investigated mechanisms through which the long noncoding RNA lnc-IL7R contributes to cellular damage by inducing oxidative stress in COPD patients exposed to PM2.5. METHODS: Associations of serum lnc-IL7R levels with lung function, emphysema, and previous PM2.5 exposure in COPD patients were analyzed. Reactive oxygen species and lnc-IL7R levels were measured in PM2.5-treated cells. The levels of lnc-IL7R and cellular senescence-associated genes, namely p16INK4a and p21CIP1/WAF1, were determined through lung tissue section staining. The effects of p16INK4a or p21CIP1/WAF1 regulation were examined by performing lnc-IL7R overexpression and knockdown assays. The functions of lnc-IL7R-mediated cell proliferation, cell cycle, senescence, colony formation, and apoptosis were examined in cells treated with PM2.5. Chromatin immunoprecipitation assays were conducted to investigate the epigenetic regulation of p21CIP1/WAF1. RESULTS: Lnc-IL7R levels decreased in COPD patients and were negatively correlated with emphysema or PM2.5 exposure. Lnc-IL7R levels were upregulated in normal lung epithelial cells but not in COPD cells exposed to PM2.5. Lower lnc-IL7R expression in PM2.5-treated cells induced p16INK4a and p21CIP1/WAF1 expression by increasing oxidative stress. Higher lnc-IL7R expression protected against cellular senescence and apoptosis, whereas lower lnc-IL7R expression augmented injury in PM2.5-treated cells. Lnc-IL7R and the enhancer of zeste homolog 2 (EZH2) synergistically suppressed p21CIP1/WAF1 expression through epigenetic modulation. CONCLUSION: Lnc-IL7R attenuates PM2.5-mediated p21CIP1/WAF1 expression through EZH2 recruitment, and its dysfunction may augment cellular injury in COPD.

Real-time chemical composition of ambient fine aerosols and related cytotoxic effects in human lung epithelial cells in an urban area.

Particulate matter with aerodynamic diameters ≤1 µm (PM1) in the atmosphere, especially that which is emitted from anthropogenic sources, can induce considerable negative effects on the cardiopulmonary system. To investigate the chemical emission characteristics and organic sources in Yuen Long (Hong Kong), both offline and online approaches for PM1 samples were applied by filter-based samplers and a Quadrupole Aerosol Chemical Speciation Monitor (Q-ACSM), respectively. The toxicological effects on human A549 lung alveolar epithelial cells were investigated, and associations between cytotoxicity and organic sources and compositions were evaluated. The organics from the Q-ACSM measurement were the largest contributor to submicron aerosols in both seasons of our study, and the mass fraction was higher in winter (60%) than it was in autumn (46%). Regarding organic sources, the mass fraction of hydrocarbon-like organics (HOA) increased from 7% in autumn to 38% in winter, whereas cooking organics (COA) decreased from 30% in autumn to 18% in winter, and oxygenated organics (OOA) decreased from 63% to 45%. Organic compounds contributed more during pollution episodes, and more secondary ions were formed by means of the oxidation process. Oxidative and inflammatory responses in A549 cells were found with PM1 exposures; the differences in chemical compositions resulted in the higher cytotoxicity in winter than autumn. The cooking organic aerosol in residential area was significantly correlated with cell inflammation. Both elemental carbon and specific inorganic ions (SO42- and Mg2+) contributed to the intracellular cytotoxicity. This study demonstrated that specific atmospheric particulate matter chemical properties and sources can trigger distinct cell reactions; the inorganic ions from cooking emissions cannot be disregarded in terms of their pulmonary health risks in residential areas.

Exposure and health risk assessment of indoor volatile organic compounds in a medical university.

Many volatile organic compounds (VOCs) are used for experiments at universities, and most of them contain benzene, toluene, ethylbenzene, xylene, and an extraction solvent of dichloromethane. This study aimed to investigate the indoor concentrations of these five compounds in different locations on campus and to evaluate possible health risks for faculty members and students in a medical university. We selected 10 locations as sampling sites to conduct 4-h monitoring sessions on weekdays each season during 2019-2020. We used a 6-liter canister to collect air samples and analyzed these five VOCs via gas chromatography with a flame ionization detector. Monte Carlo simulation was performed to evaluate the carcinogenic and noncarcinogenic risks of these five VOCs. We found that dichloromethane was the most highly detected compound (median: 621.07 µg/m3; range: 44.01-8523.91 µg/m3), and the Department of Medicine had the highest concentration of the total of these VOCs among all of the locations (median: 5595.29 µg/m3; range: 1565.67-7398.66 µg/m3). The median carcinogenic risks of dichloromethane and benzene were 6.36 × 10-5 (95% confidence interval [CI]: 6.83 × 10-6-7.37 × 10-4) and 5.47 × 10-6 (95% CI: 4.03 × 10-7-2.42 × 10-5), respectively, for faculty members, and the lower risks of 3.14 × 10-5 (95% CI: 3.39 × 10-6-3.64 × 10-4) and 2.69 × 10-6 (95% CI: 1.97 × 10-7-1.19 × 10-5) were estimated for the students. The chronic noncarcinogenic risks of four VOCs were less than one, except for dichloromethane with a median hazard index of 1.92 (95% CI: 2.11 × 10-1-2.22 × 101). This study observed the spatial variation in the concentrations of the total of five VOCs and dichloromethane. The carcinogenic risks were classified as being at the possible level, and the noncarcinogenic risk of dichloromethane was greater than the acceptable level. Increasing local exhaust ventilation during the experiment and reducing the using amount of dichloromethane are recommended actions to reduce VOCs exposures in the medical university.

Benzo[a]pyrene exposure in muscle triggers sarcopenia through aryl hydrocarbon receptor-mediated reactive oxygen species production.

BACKGROUND: Benzo[a]pyrene (BaP), a toxic carcinogen, is associated with various adverse effects but is rarely discussed in muscle-related disorders. This study investigated in vitro and in vivo effects triggered by BaP exposure in muscles and hypothesized that exposure might induce conditions similar to sarcopenia due to the shared mechanism of oxidative stress. In vitro experiments used C2C12 mouse myoblasts to examine effects induced by BaP exposure in control (untreated) and BaP-treated (10 µM/ml) muscle cells. An established TNF-α-treated sarcopenia model was utilized to verify our results. In vivo experiments compared immunohistochemical staining of sarcopenia-related markers in rats exposed to clean air and polluted air. RESULTS: In C2C12 cells, after 2-72 h of BaP exposure, elevated mRNA and protein expressions were observed in aryl hydrocarbon receptor (AhR) and cytochrome P450 1A1, subsequently in ROS (NOX2 and NOX4) production, inflammatory cytokines (IL-6, TNF-α, and NF-kB), and proteins mediating apoptotic cell death (caspase-3 and PARP). Two myokines also altered mRNA and protein expressions akin to changes in sarcopenia, namely decreased irisin levels and increased myostatin levels. In addition, N-acetylcysteine, a well-known antioxidant, led to decrease in oxidative markers induced by BaP. The validation by TNF-α-treated sarcopenia model revealed comparable biological responses in either TNF-α or BaP treated C2C12 cells. In vivo experiments with rats exposed to air pollution showed increased expression of BaP, AhR, 8-hydroxydeoxyguanosine, and myostatin and decreased irisin expression in immunohistochemical staining. CONCLUSIONS: Our results suggest that BaP exerts deleterious effects on the muscle, leading to conditions indicative of sarcopenia. Antioxidant supplementation may be a treatment option for BaP-induced sarcopenia, but further validation studies are needed.

Effects of antibiotics and metals on lung and intestinal microbiome dysbiosis after sub-chronic lower-level exposure of air pollution in ageing rats.

We investigated the effects of antibiotics, drugs, and metals on lung and intestinal microbiomes after sub-chronic exposure of low-level air pollution in ageing rats. Male 1.5-year-old Fischer 344 ageing rats were exposed to low-level traffic-related air pollution via whole-body exposure system for 3 months with/without high-efficiency particulate air (HEPA) filtration (gaseous vs. particulate matter with aerodynamic diameter of ≤2.5 µm (PM2.5) pollution). Lung functions, antibiotics, drugs, and metals in lungs were examined and linked to lung and fecal microbiome analyses by high-throughput sequencing analysis of 16 s ribosomal (r)DNA. Rats were exposed to 8.7 µg/m3 PM2.5, 10.1 ppb NO2, 1.6 ppb SO2, and 23.9 ppb O3 in average during the study period. Air pollution exposure decreased forced vital capacity (FVC), peak expiratory flow (PEF), forced expiratory volume in 20 ms (FEV20), and FEF at 25∼75% of FVC (FEF25-75). Air pollution exposure increased antibiotics and drugs (benzotriazole, methamphetamine, methyl-1 H-benzotriazole, ketamine, ampicillin, ciprofloxacin, pentoxifylline, erythromycin, clarithromycin, ceftriaxone, penicillin G, and penicillin V) and altered metals (V, Cr, Cu, Zn, and Ba) levels in lungs. Fusobacteria and Verrucomicrobia at phylum level were increased in lung microbiome by air pollution, whereas increased alpha diversity, Bacteroidetes and Proteobacteria and decreased Firmicutes at phylum level were occurred in intestinal microbiome. Lung function decline was correlated with increasing antibiotics, drugs, and metals in lungs as well as lung and intestinal microbiome dysbiosis. The antibiotics, drugs, and Cr, Co, Ca, and Cu levels in lung were correlated with lung and intestinal microbiome dysbiosis. The lung microbiome was correlated with intestinal microbiome at several phylum and family levels after air pollution exposure. Our results revealed that antibiotics, drugs, and metals in the lung caused lung and intestinal microbiome dysbiosis in ageing rats exposed to air pollution, which may lead to lung function decline.

Reduction of Emphysema Severity by Human Umbilical Cord-Derived Mesenchymal Stem Cells in Mice.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality in chronic lung disease patients throughout the world. Mesenchymal stem cells (MSCs) have been shown to regulate immunomodulatory, anti-inflammatory, and regenerative responses. However, the effects of human-umbilical-cord-derived mesenchymal stem cells (hUC-MSCs) on the lung pathophysiology of COPD remain unclear. We aimed to investigate the role of hUC-MSCs in emphysema severity and Yes-associated protein (Yap) phosphorylation (p-Yap) in a porcine-pancreatic-elastase (PPE)-induced emphysema model. We observed that the emphysema percentages (normalized to the total lung volume) measured by chest computed tomography (CT) and exercise oxygen desaturation were significantly reduced by hUC-MSCs at 107 cells/kg body weight (BW) via intravenous administration in emphysematous mice (p < 0.05). Consistently, the emphysema index, as assessed by the mean linear intercept (MLI), significantly decreased with hUC-MSC administration at 3 × 106 and 107 cells/kg BW (p < 0.05). Changes in the lymphocytes, monocytes, and splenic cluster of differentiation 4-positive (CD4+) lymphocytes by PPE were significantly reversed by hUC-MSC administration in emphysematous mice (p < 0.05). An increasing neutrophil/lymphocyte ratio was reduced by hUC-MSCs at 3 × 106 and 107 cells/kg BW (p < 0.05). The higher levels of tumor necrosis factor (TNF)-α, keratinocyte chemoattractant (KC), and lactate dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF) were significantly decreased by hUC-MSC administration (p < 0.05). A decreasing p-Yap/Yap ratio in type II alveolar epithelial cells (AECII) of mice with PPE-induced emphysema was significantly increased by hUC-MSCs (p < 0.05). In conclusion, the administration of hUC-MSCs improved multiple pathophysiological features of mice with PPE-induced emphysema. The effectiveness of the treatment of pulmonary emphysema with hUC-MSCs provides an essential and significant foundation for future clinical studies of MSCs in COPD patients.