The stress-responsive cytotoxic effect of diesel exhaust particles on lymphatic endothelial cells.

Diesel exhaust particles (DEPs) are very small (typically < 0.2 µm) fragments that have become major air pollutants. DEPs are comprised of a carbonaceous core surrounded by organic compounds such as polycyclic aromatic hydrocarbons (PAHs) and nitro-PAHs. Inhaled DEPs reach the deepest sites in the respiratory system where they could induce respiratory/cardiovascular dysfunction. Additionally, a previous study has revealed that a portion of inhaled DEPs often activate immune cells and subsequently induce somatic inflammation. Moreover, DEPs are known to localize in lymph nodes. Therefore, in this study we explored the effect of DEPs on the lymphatic endothelial cells (LECs) that are a constituent of the walls of lymph nodes. DEP exposure induced cell death in a reactive oxygen species (ROS)-dependent manner. Following exposure to DEPs, next-generation sequence (NGS) analysis identified an upregulation of the integrated stress response (ISR) pathway and cell death cascades. Both the soluble and insoluble components of DEPs generated intracellular ROS. Three-dimensional Raman imaging revealed that DEPs are taken up by LECs, which suggests internalized DEP cores produce ROS, as well as soluble DEP components. However, significant cell death pathways such as apoptosis, necroptosis, ferroptosis, pyroptosis, and parthanatos seem unlikely to be involved in DEP-induced cell death in LECs. This study clarifies how DEPs invading the body might affect the lymphatic system through the induction of cell death in LECs.

Differential Pattern of Cell Death and ROS Production in Human Airway Epithelial Cells Exposed to Quinones Combined with Heated-PM2.5 and/or Asian Sand Dust.

The combined toxicological effects of airborne particulate matter (PM), such as PM2.5, and Asian sand dust (ASD), with surrounding chemicals, particularly quinones, on human airway epithelial cells remain underexplored. In this study, we established an in vitro combination exposure model using 1,2-naphthoquinones (NQ) and 9,10-phenanthroquinones (PQ) along with heated PM (h-PM2.5 and h-ASD) to investigate their potential synergistic effects. The impacts of quinones and heated PM on tetrazolium dye (WST-1) reduction, cell death, and cytokine and reactive oxygen species (ROS) production were examined. Results revealed that exposure to 9,10-PQ with h-PM2.5 and/or h-ASD dose-dependently increased WST-1 reduction at 1 µM compared to the corresponding control while markedly decreasing it at 10 µM. Higher early apoptotic, late apoptotic, or necrotic cell numbers were detected in 9,10-PQ + h-PM2.5 exposure than in 9,10-PQ + h-ASD or 9,10-PQ + h-PM2.5 + h-ASD. Additionally, 1,2-NQ + h-PM2.5 exposure also resulted in an increase in cell death compared to 1,2-NQ + h-ASD and 1,2-NQ + h-PM2.5 + h-ASD. Quinones with or without h-PM2.5, h-ASD, or h-PM2.5 + h-ASD significantly increased ROS production, especially with h-PM2.5. Our findings suggest that quinones, at relatively low concentrations, induce cell death synergistically in the presence of h-PM2.5 rather than h-ASD and h-PM2.5 + h-ASD, partially through the induction of apoptosis with increased ROS generation.

Effects of styrene monomer on a mouse model of atopic dermatitis.

Aim: Styrene monomer (SM) is a basic chemical used as a raw material for polystyrene and unsaturated polyester resins and in the production of synthetic resins, synthetic rubbers, paints, and adhesives. To date, it is unclear whether SM is associated with the aggravation of atopic dermatitis. The aim was to investigate the effects of SM on atopic dermatitis-like skin lesions induced by mite allergen in NC/Nga mice.Methods: Male mice were injected intradermally with mite allergen on their right ears. In the presence of an allergen, SM (3.5 or 350 µg/animal/week) was administered by intraperitoneal injection. We evaluated clinical scores, ear thickening, histologic findings, and the protein expressions of cytokines and chemokines.Results: Macroscopic and microscopic examinations demonstrated that exposure to SM at a dose of 3.5 µg caused an exacerbation of atopic dermatitis-like skin lesions related to mite allergen. These changes were consistent with the level of histamine in the ear tissue as an overall trend. In contrast, 350-µg SM did not show significant enhancement effects.Conclusion: These results indicate that SM exacerbated atopic dermatitis-like skin lesions at hundred-fold lower levels than the level that causes no observed adverse effects as determined by histologic changes in rodent livers. SM could be at least partly responsible for the recent increase in atopic dermatitis.Impact statementStyrene monomer (SM) is classified as an International Agency for Research on Cancer group 2B carcinogen and includes neurotoxicity and respiratory disorders. However, the effects of SM as a chemical substance on existing allergic pathophysiology have not been elucidated yet. This study demonstrated that SM exacerbated murine atopic dermatitis-like skin lesions at hundred-fold lower levels than the level that causes no observed adverse effects as determined by histologic changes in rodent livers, which was concomitant with the local level of histamine. These data hasten a need for comprehensive research to clarify the chemical pollutants' effects of doses much lower than NOAEL on vulnerable pathophysiologies such as allergy/atopy.

Effect modification by temperature on the association between O3 and emergency ambulance dispatches in Japan: A multi-city study.

Numerous epidemiological studies have reported that ozone (O3) and temperature are independently associated with health outcomes, but modification of the effects of O3 on health outcomes by temperature, and vice versa, has not been fully described. This study aimed to investigate effect modification by temperature on the association between O3 and emergency ambulance dispatches (EADs) in Japan. Data on daily air pollutants, ambient temperature, and EADs were obtained from eight Japanese cities from 2007 to 2015. A distributed lag non-linear model combined with Poisson regression was performed with temperature as a confounding factor and effect modifier to estimate the effects of O3 on EADs at low (<25th percentile), moderate (25th-75th percentile), and high (>75th percentile) temperature for each city. The estimates obtained from each city were pooled by random-effects meta-analysis. When temperature was entered as a confounder, the estimated effects of O3 on EADs for all acute, cardiovascular, and respiratory illnesses were largest at lag 0 (current-day lag). Therefore, this lag was used to further estimate the effects of O3 on EADs in each temperature category. The estimated effects of O3 on EADs for all acute, cardiovascular, and respiratory illnesses in all eight Japanese cities increased with increasing temperature. Specifically, a 10 ppb increase in O3 was associated with 0.80 % (95 % CI: 0.25 to 1.35), 0.19 % (95 % CI: -0.85 to 1.25), and 1.14 % (95 % CI: -0.01 to 2.31) increases in the risk of EADs for all acute, cardiovascular, and respiratory illnesses, respectively, when city-specific daily temperature exceeded the 75th percentile. Our findings suggest that the association between O3 and EADs for all acute, cardiovascular, and respiratory illnesses is the highest during high temperature. Finding of this study can be used to develop potential mitigation measures against O3 exposure in high temperature environment to reduce its associated adverse health effects.

Effects of Streamer Discharge on PM2.5 Containing Endotoxins and Polyaromatic Hydrocarbons and Their Biological Responses In Vitro.

Experimental and epidemiological studies have demonstrated that fine particulate matter with a diameter of <2.5 µm (PM2.5) affects both the respiratory and immune systems. However, effective approaches to reduce PM2.5-induced hazardous effects have not been discovered yet. Streamer discharge is a category of plasma discharge in which high-speed electrons collide with oxygen and nitrogen molecules. Although streamer discharge can reportedly eliminate bacteria, molds, chemical substances, and allergens, its ability to decontaminate PM2.5 has not been previously demonstrated. The present study explored whether streamer discharge treatment could reduce PM2.5-induced inflammatory responses by employing an in vitro system. PM2.5 was collected under four conditions (Bangkok (Sep.−Dec.), Bangkok (Dec.−Mar.), Singapore, and Taipei). Airway epithelial cells and antigen-presenting cells exposed to non-treated PM2.5 in several conditions resulted in inflammatory responses. Streamer-discharged PM2.5 (Bangkok (Sep.−Dec.)) decreased the expression of interleukin (IL)-6 and IL-8 compared to non-treated PM2.5. Moreover, composition analysis demonstrated that streamer discharge reduced some compounds, such as endotoxins and polycyclic aromatic hydrocarbons, included in PM2.5 that can elicit inflammatory responses. Streamer discharge treatment can reduce endotoxins, polycyclic aromatic hydrocarbons, and the subsequent inflammatory responses induced by PM2.5 in vitro.

Estimation of hospital visits for respiratory diseases attributable to PM10 from vegetation fire smoke and health impacts of regulatory intervention in Upper Northern Thailand.

The air quality in Upper Northern Thailand (UNT) deteriorates during seasonal vegetation fire events, causing adverse effects especially on respiratory health outcomes. This study aimed to quantitatively estimate respiratory morbidity from vegetation fire smoke exposure, and to assess the impact of a burning ban enforced in 2016 on morbidity burden in UNT. We computed daily population exposure to fire-originated PM10 and estimated its health burden during a 5-year period from 2014 to 2018 using daily fire-originated PM10 concentration and the concentration-response function for short-term exposure to PM10 from vegetation fire smoke and respiratory morbidity. In subgroups classified as children and older adults, the health burden of respiratory morbidity was estimated using specific effect coefficients from previous studies conducted in UNT. Finally, we compared the health burden of respiratory morbidity before and after burning ban enforcement. Approximately 130,000 hospital visits for respiratory diseases were estimated to be attributable to fire-originated PM10 in UNT from 2014 to 2018. This estimation accounted for 1.3% of total hospital visits for respiratory diseases during the 5-year period, and 20% of those during burning events. Age-specific estimates revealed a larger impact of PM10 in the older adult group. The number of hospital visits for respiratory diseases attributable to fire-originated PM10 decreased from 1.8% to 0.5% after the burning ban policy was implemented in the area. Our findings suggest that PM10 released from vegetation fires is a health burden in UNT. The prohibition of the burning using regulatory measure had a positive impact on respiratory morbidity in this area.

Post-staining Raman analysis of histological sections following decolorization.

Hematoxylin and eosin (HE) staining of tissue sections is a powerful tool for observing changes in the tissue structure and is used as the most fundamental and vital technique in histology. However, xenobiotics such as polymers and inorganic or organic materials have low dyeability, making it difficult to observe the distribution of materials across tissues. Raman spectroscopy is an advantageous technique for identifying materials in tissues using spectroscopic fingerprints by laser irradiation without staining. In this study, we developed a combined method for morphological observation and Raman spectral acquisition on the identical tissue slide by employing a decolorization step to remove eosin-induced fluorescence in HE-stained samples. Our method eliminated the fluorescence background and allowed the identical-field pathological observation, enabling simultaneous identification of biological responses and materials in tissues.

Everolimus for Treating Hormone Receptor-positive Metastatic Breast Cancer Previously Treated With Cyclin-dependent Kinase 4/6 Inhibitors.

BACKGROUND/AIM: Cyclin-dependent kinase (CDK) 4/6 inhibitors have become the standard of care as the first- and second-line treatments for hormone receptor-positive (HR+) or human epidermal growth factor receptor 2 (HER2)-negative metastatic and recurrent breast cancers. Although CDK 4/6 inhibitors can markedly prolong progression-free survival, there is no clear evidence of their post-treatment effects. The option of developing mammalian target of rapamycin (mTOR) inhibitors, such as everolimus, has been discussed as a post-treatment option for such patients. This study aimed at determining everolimus' efficacy as a post-treatment option following CDK4/6 inhibitor administration in clinical settings. PATIENTS AND METHODS: Thirteen patients who received everolimus as a post-treatment after CDK4/6 inhibitor therapy from December 2017 to July 2021 were retrospectively reviewed. The primary endpoint was progression-free survival; the secondary endpoints were overall response rate, clinical benefit rate, and overall survival. RESULTS: The median patient age, progression-free survival, and overall survival were 59 years (range=44-76 years), 9.1 months (95% confidence interval=2.3 to not reached), and 37.4 months (95% confidence interval=12.3-37.4), respectively. The overall response rate and clinical benefit rate were 15.3% (2/13) and 46.2% (6/13), respectively. CONCLUSION: Considering there is a mechanism of resistance to CDK4/6 inhibitors, everolimus would be important as an effective post-treatment for HR+ or HER2-negative metastatic and recurrent breast cancers treated with CDK4/6 inhibitors in clinical settings.

Effect of a vegetation fire event ban on hospital visits for respiratory diseases in Upper Northern Thailand.

BACKGROUND: Upper Northern Thailand (UNT) has been episodically affected by air pollution from vegetation burning, which causes adverse respiratory health effects. However, no study has evaluated the effect of regulatory actions to prohibit vegetation burning on respiratory morbidity. We examined the effect of a burning ban enforced in May 2016 on hospital visits for respiratory diseases in UNT. METHODS: This study used data from eight provinces in UNT. Analyses were conducted for January to April of 2014-2016 (before ban enforcement) and January to April of 2017-2018 (after ban enforcement). Particulate matter of 10 microns in diameter or smaller (PM10) concentrations, numbers of satellite fire hotspots and age-standardized rates of hospital visits for respiratory diseases before and after ban enforcement were compared. The effect of the ban on hospital visits for respiratory diseases was evaluated using an interrupted time-series analysis controlled for season-specific temporal trends, day of week, public holiday, temperature, relative humidity, number of hospitals and offset population, with gastrointestinal diseases as a negative control. A meta-analysis was performed to pool province-specific effect estimates. RESULTS: The daily average PM10 concentration and the number of fire hotspots decreased after ban enforcement in all provinces in UNT, with percent changes ranging from 5.3 to 34.3% and 14.3 to 81.5%, respectively. The adjusted pooled effect estimates of hospital visits for respiratory diseases decreased by 9.1% (95% CI: 5.1, 12.9), whereas a null association was observed for gastrointestinal diseases. CONCLUSION: The burning ban had a positive impact on both air pollution levels and rates of hospital visits for respiratory diseases in UNT.

Distribution of Severe Fever with Thrombocytopenia Syndrome Virus and Antiviral Antibodies in Wild and Domestic Animals in Oita Prefecture, Japan.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging life-threatening infectious disease caused by the tickborne SFTS virus (SFTSV), first identified in China in 2009 and then in Japan in 2013. Human SFTS cases were reported to be concentrated in western Japan, but the epidemiological conditions of SFTSV infection in a specific region are still obscure. We performed an epidemiological study of SFTSV in Oita Prefecture on the island of Kyushu, located in western Japan. For our research, we collected sera from wild and domestic animals (deer, wild boars, raccoons, cats, and dogs) and ticks from January 2010 to November 2020 in Oita. The anti-SFTSV antibody positivity rate of deer in 2014 was significantly higher than that in 2011 (65% versus 27%, P < 0.001). The anti-SFTSV antibody positivity rates of deer, wild boars, raccoons, wild dogs, domestic dogs, and domestic cats were 55%, 12%, 27%, 1.8%, 0.53%, and 1.4%, respectively. Moreover, RT-PCR could not detect SFTSV in any tick sample. Of the six areas of Oita Prefecture, only the Eastern area showed no incidence or possibility of SFTSV infection among wild and domestic animals, ticks, and human beings. Further investigation is required to assess whether local seroepidemiology in animals will help assess the risk of SFTSV infections in inhabitants.

Long-term air pollution exposure and decreased kidney function: A longitudinal cohort study in Bangkok Metropolitan Region, Thailand from 2002 to 2012.

BACKGROUND: Kidney dysfunction is considered a cardiovascular risk factor. However, few longitudinal studies have examined the effects of air pollution on kidney function. We evaluated associations between long-term air pollution exposure and estimated glomerular filtration rate (eGFR) using data from a cohort of the Electricity Generating Authority of Thailand (EGAT) study in Bangkok Metropolitan Region, Thailand. METHODS: This longitudinal study included 1839 subjects (aged 52-71 years in 2002) from the EGAT1 cohort study during 2002-2012. eGFR, based on creatinine, was measured in 2002, 2007, and 2012. Annual mean concentrations of air pollutants (i.e., particulate matter with an aerodynamic diameter ≤10 µm (PM10), ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO)) prior to a measurement of creatinine were assessed with the ordinary kriging method. Mixed-effect linear regression models were used to assess associations between air pollutants and eGFR, while controlling for potential covariates. eGFR values are expressed as percent change per interquartile range (IQR) increments of each pollutant. RESULTS: Lower eGFR was associated with higher concentrations of PM10 (-1.99%, 95% confidence interval (CI): -3.33, -0.63), SO2 (-4.89%, 95%CI: -6.69, -3.07), and CO (-0.97%, 95%CI: -1.96, 0.03). However, after adjusting for temperature, relative humidity, PM10, and SO2, no significant association was observed between CO and eGFR. CONCLUSIONS: Our findings support the hypothesis that long-term exposure to high concentrations of PM10 and SO2 is associated with the progression of kidney dysfunction in subjects of the EGAT cohort study.

Investigation of association between smoke haze and under-five mortality in Malaysia, accounting for time lag, duration and intensity.

BACKGROUND: Studies on the association between smoke haze (hereafter 'haze') and adverse health effects have increased in recent years due to extreme weather conditions and the increased occurrence of vegetation fires. The possible adverse health effects on under-five children (U5Y) is especially worrying due to their vulnerable condition. Despite continuous repetition of serious haze occurrence in Southeast Asia, epidemiological studies in this region remained scarce. Furthermore, no study had examined the association accounting for three important aspects (time lag, duration and intensity) concurrently. OBJECTIVE: This study aimed to examine the association between haze and U5Y mortality in Malaysia, considering time lag, duration and intensity of exposure. METHODS: We performed a time-stratified case-crossover study using a generalized additive model to examine the U5Y mortality related to haze in 12 districts in Malaysia, spanning from 2014 to 2016. A 'haze day' was characterized by intensity [based on concentrations of particulate matter (PM)] and duration (continuity of haze occurrence, up to 3 days). RESULTS: We observed the highest but non-significant odds ratios (ORs) of U5Y mortality at lag 4 of Intensity-3. Lag patterns revealed the possibility of higher acuteness at prolonged and intensified haze. Stratifying the districts by the 95th-percentile of PM distribution, the 'low' category demonstrated marginal positive association at Intensity-2 Duration-3 [OR: 1.210 (95% confidence interval: 1.000, 1.464)]. CONCLUSIONS: We found a null association between haze and U5Y mortality. The different lag patterns of the association observed over different duration and intensity suggest consideration of these aspects in future studies.

Application of three-dimensional Raman imaging to determination of the relationship between cellular localization of diesel exhaust particles and the toxicity.

A diesel exhaust particle (DEP) is a type of particulate matter that is easily produced from combustion in a diesel power engine. It has been reported that DEPs can cause short- and long-term health problems. This is because DEPs are complex mixtures that are highly inhalable through the airways due to their small particle size. However, the relationship between intracellular localization of DEPs after their deposition in the lungs and the subsequent biological responses remains to be clarified. This is due to difficulties in distinguishing particles that are inside the cells from those that are outside. In this study, A549 human lung epithelial cells were exposed to DEPs at concentrations of 0, 25, 75, or 200 µg/mL for different periods, after that particles in the A549 cells were analyzed by three-dimensional (3D) images obtained from a Raman microscope. The cytotoxic effects of DEPs on the A549 cells were investigated by measuring cell viability, the levels of intracellular reactive oxygen species (ROS) and cell death. The Raman microscopy revealed that the particles invaded the A549 cells, and at a concentration of 200 µg/mL, they markedly decreased cell viability, increased intracellular ROS production, triggered late apoptosis/necrosis and induced nuclear damage. These results suggest that intracellular DEPs exposed at a high concentration may be highly toxic and can impair the viability of A549 cells. Furthermore, the 3D images from the Raman microscopy can be used to evaluate intracellular particle dynamics.

Di-(2-ethylhexyl) phthalate enhances cytokine release from group 2 innate lymphoid cells in the presence of interleukin-33.

Epidemiological and experimental studies have shown that di-(2-ethylhexyl) phthalate (DEHP), a plasticizer, can aggravate allergic diseases. DEHP promotes adaptive immune responses, although its effect on the innate immune system remains largely unknown. The present study investigated the effects of DEHP on group 2 innate lymphoid cells (ILC2) that produce Th2 cytokines in response to epithelial cell-derived cytokines, such as interleukin (IL)-33. ILC2 (lineage-negative, CD45.2+, Sca1+, KLRG1+) were isolated from the lungs of C57BL/6 J mice. Co-exposure to DEHP and IL-33 significantly increased IL-5 release from ILC2, whose level was higher than that of the vehicle and IL-33 alone. The effects of DEHP in the presence of IL-33 showed an inverted-U dose-response. The present is the first report showing that DEHP exacerbates allergy through the innate immune system.

Effects of long-term air pollution exposure on ankle-brachial index and cardio-ankle vascular index: A longitudinal cohort study using data from the Electricity Generating Authority of Thailand study.

BACKGROUND: Ankle-brachial index (ABI) and cardio-ankle vascular index (CAVI) are surrogate measures of atherosclerosis based on the functional performance of vessels, and are highly related to cardiovascular events. However, only a few longitudinal studies have been conducted on their associations with long-term air pollution exposure. OBJECTIVE: This study aimed to examine whether long-term air pollution exposure is associated with ABI and CAVI in workers of the Electricity Generating Authority of Thailand (EGAT) in the Bangkok Metropolitan Region (BMR). METHODS: This longitudinal study included 1261 participants (age range, 57-76 years as of 2007) of the EGAT study (2007-2017). ABI and CAVI were measured in 2007, 2012, and 2017. Annual mean concentrations of particulate matter ≤10 µm in diameter (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3), and carbon monoxide (CO) were estimated by ordinary kriging using data from 22 background and 7 traffic monitoring stations in BMR between 2002 and 2017. Linear mixed-effects models were used to assess associations between air pollution (expressed as 1-year, 3-year, and 5-year average concentration) and ABI and CAVI (expressed as percent changes per interquartile range (IQR) increase in PM10, O3, NO2, SO2, and CO). We also applied the mixed-effect ordinal logistic models to calculate odds ratios (ORs) of having high or moderate CAVI per an IQR increase in air pollution. RESULTS: After controlling for potential confounders, 1-year average CO was negatively associated with ABI, but not significantly (-0.48%, 95% CI: -1.03, 0.07). Three-year average NO2 was positively associated with CAVI (6.67%, 95% CI: 0.21, 13.1). In contrast, 1-year average PM10 was inversely associated with CAVI although the association was not significant. Although not significantly, 1-year average NO2 and CO were positively associated with prevalence of high or moderate CAVI. CONCLUSIONS: Although not statistically significant, long-term NO2 and CO exposure was associated with ABI and CAVI in the participants of the EGAT study.

Association between ambient temperature and intentional injuries: A case-crossover analysis using ambulance transport records in Japan.

BACKGROUND: Epidemiological studies based on mortality and crime data have indicated that short-term exposure to higher temperature increases the risk of suicide and violent crimes. However, there are few studies on non-fatal intentional injury, especially on non-fatal self-harm which is much more common than suicide. OBJECTIVES: We aimed to clarify how short-term exposure to temperature is associated with emergency ambulance transport caused by intentional injuries including acts of self-harm and assault. METHOD: We applied a time-stratified case-crossover design using a conditional quasi-Poisson regression model for each of the 46 prefectures. All temperatures were converted to percentile value for each prefecture, to account for the varied climate across Japan. A Distributed Lag Non-Linear Model was used to explore the temperature percentile and lag pattern. The prefecture-specific results were combined using a meta-analysis with the random effects model. RESULT: Between 2012 and 2015, the number of acts of self-harm and assault across all 46 prefectures totaled 151,801 and 95,861, respectively. We found that as the temperature increased, the relative risk (RRs) for both self-harm and assault behaviors increased in a nearly linear manner. The pooled relative risk at the 99th percentile temperature for self-harm behavior was 1.11 (95% CI: 1.07, 1.15) compared with the risk at the 1st percentile temperature, and that for assault was 1.12 (95% CI: 1.08, 1.16) at lag 0. The RRs were highest at lag0 and less than 1 at lag7-20. CONCLUSION: The present study found that short-term exposure to higher temperature promotes the risk of emergency ambulance transport due to acts of self-harm and assault. The lag pattern indicates a possible "displacement" effect. These results suggest that exposure to high temperatures may potentially function as a trigger for intentional injuries.

Exposure to particulate matter upregulates ACE2 and TMPRSS2 expression in the murine lung.

Coronavirus disease (COVID-19) is currently a serious global issue. Epidemiological studies have identified air pollutants, including particulate matter (PM), as a risk factor for COVID-19 infection and severity of illness, in addition to numerous factors such as pre-existing conditions, aging and smoking. However, the mechanisms by which air pollution is involved in the manifestation and/or progression of COVID-19 is still unknown. In this study, we used a mouse model exposed to crude PM, collected by the cyclone method, to evaluate the pulmonary expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine type 2 (TMPRSS2), the two molecules required for the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells. Multiplex immunohistochemical analysis revealed that exposure to PM increased the expression of these two molecules at the same site. Furthermore, image cytometry analysis revealed increased expression of these proteins, particularly, in the alveolar type 2 cells and macrophages, which are potential targets for SARS-CoV-2. Our findings provide an experimental evidence that exposure to PM may adversely affect the manifestation and progression of COVID-19, mediated by the impact of SARS-CoV-2 on the site of entry. The study results suggest that examining these effects might help to advance our understanding of COVID-19 and aid the development of appropriate social interventions.

Role of necroptosis of alveolar macrophages in acute lung inflammation of mice exposed to titanium dioxide nanoparticles.

Titanium dioxide (TiO2) nanoparticles are indispensable for daily life but induce acute inflammation, mainly via inhalation exposure. TiO2 nanoparticles can be phagocytosed by alveolar macrophages (AMs) in vivo and cause necroptosis of exposed cells in vitro. However, the relationship between localization of TiO2 nanoparticles in the lungs after exposure and their biological responses including cell death and inflammation remains unclear. This study was conducted to investigate the intra/extracellular localization of TiO2 nanoparticles in murine lungs at 24 h after intratracheal exposure to rutile TiO2 nanoparticles and subsequent local biological reactions, specifically necroptosis of AMs and lung inflammation. We found that TiO2 exposure induced leukocyte migration into the alveolar region and increased the secretion of C-C motif ligand (CCL) 3 in the bronchoalveolar lavage (BAL) fluid. A combination of Raman spectroscopy and staining of cell and tissue samples confirmed that AMs phagocytose TiO2. AMs that phagocytosed TiO2 nanoparticles showed necroptosis, characterized by the expression of phosphorylated mixed lineage kinase domain-like protein and translocation of high mobility group box-1 from the cell nucleus to the cytoplasm. In primary cultured AMs, TiO2 also induced necroptosis and increased the secretion of CCL3. Necroptosis inhibitors suppressed the increase in CCL3 secretion in both the BAL fluid and culture supernatant of AMs and suppressed the increase in leukocytes in the BAL fluid. These data suggest that necroptosis of AMs that phagocytose TiO2 nanoparticles is involved as part of the mechanism by which TiO2 induces acute lung inflammation.

Long-term air pollution exposure and self-reported morbidity: A longitudinal analysis from the Thai cohort study (TCS).

BACKGROUND: Several studies have shown the health effects of air pollutants, especially in China, North American and Western European countries. But longitudinal cohort studies focused on health effects of long-term air pollution exposure are still limited in Southeast Asian countries where sources of air pollution, weather conditions, and demographic characteristics are different. The present study examined the association between long-term exposure to air pollution and self-reported morbidities in participants of the Thai cohort study (TCS) in Bangkok metropolitan region (BMR), Thailand. METHODS: This longitudinal cohort study was conducted for 9 years from 2005 to 2013. Self-reported morbidities in this study included high blood pressure, high blood cholesterol, and diabetes. Air pollution data were obtained from the Thai government Pollution Control Department (PCD). Particles with diameters ≤10 µm (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3), and carbon monoxide (CO) exposures were estimated with ordinary kriging method using 22 background and 7 traffic monitoring stations in BMR during 2005-2013. Long-term exposure periods to air pollution for each subject was averaged as the same period of person-time. Cox proportional hazards models were used to examine the association between long-term air pollution exposure with self-reported high blood pressure, high blood cholesterol, diabetes. Results of self-reported morbidity were presented as hazard ratios (HRs) per interquartile range (IQR) increase in PM10, O3, NO2, SO2, and CO. RESULTS: After controlling for potential confounders, we found that an IQR increase in PM10 was significantly associated with self-reported high blood pressure (HR = 1.13, 95% CI: 1.04, 1.23) and high blood cholesterol (HR = 1.07, 95%CI: 1.02, 1.12), but not with diabetes (HR = 1.05, 95%CI: 0.91, 1.21). SO2 was also positively associated with self-reported high blood pressure (HR = 1.22, 95%CI: 1.08, 1.38), high blood cholesterol (HR = 1.20, 95%CI: 1.11, 1.30), and diabetes (HR = 1.21, 95%CI: 0.92, 1.60). Moreover, we observed a positive association between CO and self-reported high blood pressure (HR = 1.07, 95%CI: 1.00, 1.15), but not for other diseases. However, self-reported morbidities were not associated with O3 and NO2. CONCLUSIONS: Long-term exposure to air pollution, especially for PM10 and SO2 was associated with self-reported high blood pressure, high blood cholesterol, and diabetes in subjects of TCS. Our study supports that exposure to air pollution increases cardiovascular disease risk factors for younger population.