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Establishment of Repeated In Vitro Exposure System for Evaluating Pulmonary Toxicity of Representative Criteria Air Pollutants Using Advanced Bronchial Mucosa Models.

ABSTRACT: There is mounting evidence that shows the association between chronic exposure to air pollutants (particulate matter and gaseous) and onset of various respiratory impairments. However, the corresponding toxicological mechanisms of mixed exposure are poorly understood. Therefore, in this study, we aimed to establish a repeated exposure setting for evaluating the pulmonary toxicological effects of diesel exhaust particles (DEP), nitrogen dioxide (NO₂), and sulfur dioxide (SO2) as representative criterial air pollutants. Single, combined (DEP with NO₂ and SO₂), and repeated exposures were performed using physiologically relevant human bronchial mucosa models developed at the air-liquid interface (bro-ALI). The bro-ALI models were generated using human primary bronchial epithelial cells (3-4 donors; 2 replicates per donor). The exposure regime included the following: 1. DEP (12.5 µg/cm²; 3 min/day, 3 days); 2. low gaseous (NO₂: 0.1 ppm + SO₂: 0.2 ppm); (30 min/day, 3 days); 3. high gaseous (NO₂: 0.2 ppm + SO₂: 0.4 ppm) (30 min/day, 3 days); and 4. single combined (DEP + low gaseous for 1 day). The markers for pro-inflammatory (IL8, IL6, NFKB, TNF), oxidative stress (HMOX1, GSTA1, SOD3,) and tissue injury/repair (MMP9, TIMP1) responses were assessed at transcriptional and/ or secreted protein levels following exposure. The corresponding sham-exposed samples under identical conditions served as the control. A non-parametric statistical analysis was performed and p < 0.05 was considered as significant. Repeated exposure to DEP and single combined (DEP + low gaseous) exposure showed significant alteration in the pro-inflammatory, oxidative stress and tissue injury responses compared to repeated exposures to gaseous air pollutants. The study demonstrates that it is feasible to predict the long-term effects of air pollutants using the above explained exposure system.

SUBMITTER: Upadhyay S

PROVIDER: S-EPMC9228979 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Establishment of Repeated In Vitro Exposure System for Evaluating Pulmonary Toxicity of Representative Criteria Air Pollutants Using Advanced Bronchial Mucosa Models.

Upadhyay Swapna S Chakraborty Ashesh A Thimraj Tania A TA Baldi Marialuisa M Steneholm Anna A Ganguly Koustav K Gerde Per P Ernstgård Lena L Palmberg Lena L

Toxics 20220524 6

There is mounting evidence that shows the association between chronic exposure to air pollutants (particulate matter and gaseous) and onset of various respiratory impairments. However, the corresponding toxicological mechanisms of mixed exposure are poorly understood. Therefore, in this study, we aimed to establish a repeated exposure setting for evaluating the pulmonary toxicological effects of diesel exhaust particles (DEP), nitrogen dioxide (NO2), and sulfur dioxide (SO2) as representative cr ...[more]

PMID: 35736886

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Project description:BackgroundChronic obstructive pulmonary disease (COPD) has the highest increased risk due to household air pollution arising from biomass fuel burning. However, knowledge on COPD patho-mechanisms is mainly limited to tobacco smoke exposure. In this study, a repeated direct wood smoke (WS) exposure was performed using normal- (bro-ALI) and chronic bronchitis-like bronchial (bro-ALI-CB), and alveolar (alv-ALI) lung mucosa models at air-liquid interface (ALI) to assess broad toxicological end points.MethodsThe bro-ALI and bro-ALI-CB models were developed using human primary bronchial epithelial cells and the alv-ALI model was developed using a representative type-II pneumocyte cell line. The lung models were exposed to WS (10 min/exposure; 5-exposures over 3-days; n = 6-7 independent experiments). Sham exposed samples served as control. WS composition was analyzed following passive sampling. Cytotoxicity, total cellular reactive oxygen species (ROS) and stress responsive NFkB were assessed by flow cytometry. WS exposure induced changes in gene expression were evaluated by RNA-seq (p ≤ 0.01) followed by pathway enrichment analysis. Secreted levels of proinflammatory cytokines were assessed in the basal media. Non-parametric statistical analysis was performed.Results147 unique compounds were annotated in WS of which 42 compounds have inhalation toxicity (9 very high). WS exposure resulted in significantly increased ROS in bro-ALI (11.2%) and bro-ALI-CB (25.7%) along with correspondingly increased NFkB levels (bro-ALI: 35.6%; bro-ALI-CB: 18.1%). A total of 1262 (817-up and 445-down), 329 (141-up and 188-down), and 102 (33-up and 69-down) genes were differentially regulated in the WS-exposed bro-ALI, bro-ALI-CB, and alv-ALI models respectively. The enriched pathways included the terms acute phase response, mitochondrial dysfunction, inflammation, oxidative stress, NFkB, ROS, xenobiotic metabolism of AHR, and chronic respiratory disorder. The enrichment of the 'cilium' related genes was predominant in the WS-exposed bro-ALI (180-up and 7-down). The pathways primary ciliary dyskinesia, ciliopathy, and ciliary movement were enriched in both WS-exposed bro-ALI and bro-ALI-CB. Interleukin-6 and tumor necrosis factor-α were reduced (p < 0.05) in WS-exposed bro-ALI and bro-ALI-CB.ConclusionFindings of this study indicate differential response to WS-exposure in different lung regions and in chronic bronchitis, a condition commonly associated with COPD. Further, the data suggests ciliopathy as a candidate pathway in relation to WS-exposure.

Project description:Chronic obstructive pulmonary disease (COPD) has the highest increased risk due to household air pollution arising from biomass fuel burning. However, knowledge on COPD patho-mechanisms is mainly limited to tobacco smoke exposure. In this study, a repeated direct wood smoke (WS) exposure was performed using normal- (bro-ALI) and chronic bronchitis-like bronchial (bro-ALI-CB), and alveolar (alv-ALI) lung mucosa models at air-liquid interface (ALI) to assess broad toxicological end points. The bro-ALI and bro-ALI-CB models were developed using human primary bronchial epithelial cells and the alv-ALI model was developed using a representative type-II pneumocyte cell line. The lung models were exposed to WS (10 minutes/exposure; 5-exposures over 3-days; n=6-7 independent experiments). Sham exposed samples served as control. WS composition was analyzed following passive sampling. Cytotoxicity, total cellular reactive oxygen species (ROS) and stress responsive NFkB were assessed by flow cytometry. WS exposure induced changes in gene expression were evaluated by RNA-seq (p≤0.01) followed by pathway enrichment analysis. Secreted levels of proinflammatory cytokines were assessed in the basal media. Non-parametric statistical analysis was performed. 147 unique compounds were annotated in WS of which 42 compounds have inhalation toxicity (9 very high). WS exposure resulted in significantly increased ROS in bro-ALI (11.2%) and bro-ALI-CB (25.7%) along with correspondingly increased NFkB levels (bro-ALI: 35.6%; bro-ALI-CB: 18.1%). A total of 1262 (817-up and 445-down), 329 (141-up and 188-down), and 102 (33-up and 69-down) genes were differentially regulated in the WS-exposed bro-ALI, bro-ALI-CB, and alv-ALI models respectively. The enriched pathways included the terms acute phase response, mitochondrial dysfunction, inflammation, oxidative stress, NFkB, ROS, xenobiotic metabolism of AHR, and chronic respiratory disorder. The enrichment of the ‘cilium’ related genes was predominant in the WS-exposed bro-ALI (180-up and 7-down). The pathways primary ciliary dyskinesia, ciliopathy, and ciliary movement were enriched in both WS-exposed bro-ALI and bro-ALI-CB. Interleukin-6 and tumor necrosis factor-α were reduced (p<0.05) in WS-exposed bro-ALI and bro-ALI-CB.

Project description:As a result of the lockdown (LD) control measures enacted to curtail the COVID-19 pandemic in Wuhan, almost all non-essential human activities were halted beginning on January 23, 2020 when the total lockdown was implemented. In this study, changes in the concentrations of the six criteria air pollutants (PM2.5, PM10, SO2, NO2, CO, and O3) in Wuhan were investigated before (January 1 to 23, 2020), during (January 24 to April 5, 2020), and after the COVID-19 lockdown (April 6 to June 20, 2020) periods. Also, the relationships between the air pollutants and meteorological variables during the three periods were investigated. The results showed that there was significant improvement in air quality during the lockdown. Compared to the pre-lockdown period, the concentrations of NO2, PM2.5, PM10, and CO decreased by 50.6, 41.2, 33.1, and 16.6%, respectively, while O3 increased by 149% during the lockdown. After the lockdown, the concentrations of PM2.5, CO and SO2 declined by an additional 19.6, 15.6, and 2.1%, respectively. However, NO2, O3, and PM10 increased by 55.5, 25.3, and 5.9%, respectively, compared to the lockdown period. Except for CO and SO2, WS had negative correlations with the other pollutants during the three periods. RH was inversely related with all pollutants. Positive correlations were observed between temperature and the pollutants during the lockdown. Easterly winds were associated with peak PM2.5 concentrations prior to the lockdown. The highest PM2.5 concentrations were associated with southwesterly wind during the lockdown, and northwesterly winds coincided with the peak PM2.5 concentrations after the lockdown. Although, COVID-19 pandemic had numerous negative effects on human health and the global economy, the reductions in air pollution and significant improvement in ambient air quality likely had substantial short-term health benefits. This study improves the understanding of the mechanisms that lead to air pollution under diverse meteorological conditions and suggest effective ways of reducing air pollution in Wuhan.

Dataset Information

Establishment of Repeated In Vitro Exposure System for Evaluating Pulmonary Toxicity of Representative Criteria Air Pollutants Using Advanced Bronchial Mucosa Models.

Publications

Establishment of Repeated In Vitro Exposure System for Evaluating Pulmonary Toxicity of Representative Criteria Air Pollutants Using Advanced Bronchial Mucosa Models.

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