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Published in final edited form as: Ann Allergy Asthma Immunol. 2024 Jan 20;132(4):426–432. doi: 10.1016/j.anai.2024.01.017

Effect of Air Pollution on Asthma

Xiaoying Zhou 1, Vanitha Sampath 1, Kari C Nadeau 1,*
PMCID: PMC10990824  NIHMSID: NIHMS1960638  PMID: 38253122

Abstract

Asthma is a chronic inflammatory airway disease characterized by respiratory symptoms, variable airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Exposure to air pollution has been linked to an increased risk of asthma development and exacerbation. This review aims to comprehensively summarize recent data on the impact of air pollution on asthma development and exacerbation. Specifically, we reviewed the effects of air pollution on the pathogenic pathways of asthma, including type 2 and non-type 2 inflammatory responses, as well as airway epithelial barrier dysfunction. Air pollution promotes the release of epithelial cytokines, driving Th2 responses, and induces oxidative stress and the production of pro-inflammatory cytokines. The enhanced type 2 inflammation, furthered by air pollution-induced dysfunction of the airway epithelial barrier, may be associated with the exacerbation of asthma. Disruption of the Th17/Treg balance by air pollutants is also related to asthma exacerbation. As the effects of air pollution exposure may accumulate over time, with potentially stronger impacts in the development of asthma during certain sensitive life periods, we also reviewed the effects of air pollution on asthma across the lifespan. Future research is needed to better characterize the sensitive period contributing to the development of air pollution-induced asthma, and to map air pollution-associated epigenetic biomarkers contributing to the epigenetic ages onto asthma-related genes.

Introduction

Air pollution is a complex mixture containing both particles and gases. The air pollutants for which the Environmental Protection Agency (EPA) has set National Ambient Air Quality Standards include particulate matter (PM), ground-level or tropospheric ozone (O3), carbon monoxide (CO), sulfur dioxide (SO2), and nitrogen dioxide (NO2)1, 2. Tropospheric ozone is created when nitrogen oxides and volatile organic compounds react in the presence of heat and sunlight. PM can be divided into three categories based on the diameter of particles: coarse PM10 (from 2.5 to 10 μm), fine PM2.5 (from 0.1 to 2.5 μm), ultrafine PM0.1 (UFPs) (less than 0.1 μm). 99% of the global population resided in areas where the air quality did not meet the WHO guidelines in 20192. Common sources of air pollution include household combustion devices, emissions from motor vehicles, industrial facilities, and forest fires3.

Asthma is a chronic inflammatory airway disease characterized by respiratory symptoms (such as wheezing, shortness of breath, and chest tightness), variable airflow obstruction, bronchial hyperresponsiveness, and airway inflammation4. There are several factors that can influence the development of asthma. The asthma associated loci across the genome are identified using Genome-wide association studies (GWAS) of asthma 5-8, suggesting genetic predisposition is one of the risk factors for developing asthma (Figure 1). Furthermore, epigenetic changes, including DNA methylation, chromatin remodeling, histone modifications and non-coding RNAs, are considered important additional mechanisms in the development of asthma and are highly influenced by environmental exposures9-11(Figure 1). Moreover, exposure to air pollution has been clearly demonstrated as a high-risk factor for the development and exacerbation of inflammatory disease of the lower airways, such as asthma12 (Figure 1). PM2.5 is one of the main components of air pollution and it can deposit deep in the bronchioles and alveoli of the lungs, sites proximal to asthma, where it induces the inflammatory responses 13-16. Outdoor PM originates from sources such as mineral dust, pollen, vehicle exhaust, and heating combustion. Indoor PM sources encompass smoking and incense burning, vacuum cleaning, sanitary and hygienic sprays, clothing residues and fiber breakage, friction, domestic animals, and cooking17. In addition to PM2.5, other major air pollutants related to asthma contain a significant portion of noxious gasses, including sulfur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3)12.

Figure 1: Risk factors contributing to the development of asthma.

Figure 1:

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PM2.5, particulate matter that have a diameter of 2.5μm or smaller; O3, ozone; SO2, sulfur dioxide; NO2, nitrogen dioxide; SNPs, Single nucleotide polymorphisms; TSLP, thymic stromal lymphopoietin; IL, interleukin; IL1RL1, Interleukin 1 receptor-like 1.

It has been demonstrated that climate change could worsen air quality, and the reduced air quality can have direct adverse impacts on human health 18. Climate change events have led to increased frequency, duration, severity of pollen exposures, as well as the formation and spread of air pollutants such as ground-level ozone , dust storms, infections, wildfires, and thunderstorms, all of which can exacerbate allergies and asthma18-20. Furthermore, wildfire smoke is a potent natural source of numerous air pollutants, including PM, CO, methane, NOx, formaldehyde, acrolein, polycyclic aromatic hydrocarbons, trace minerals and various other compounds21, 22. Wildfire smoke has been shown to have a positive impact on respiratory hospitalization such as asthma23.

The aim of this review is to summarize recent data on the effects of air pollution on the development and exacerbation of asthma, specifically the effects of air pollution on the pathogenic pathways of asthma, including type 2 and non-type 2 inflammatory responses, as well as airway epithelial barrier dysfunction. Given air pollution exposure effects may accumulate over the life course, with stronger impacts potentially during sensitive periods, we also review the effects of air pollution on asthma across the lifespan.

Air pollution and the development and exacerbation of asthma

Numerous published studies provide epidemiological evidence supporting the association between air pollutants exposure and the onset and progression of asthma. A study demonstrated that prolonged exposure to PM2.5 was associated with a higher risk of asthma in Chinese preschool children; those residing in suburban or rural areas in this survey were considerably more susceptible to PM2.5 exposure24. Carlsten et al.25 evaluated the associations between exposure to traffic-related air pollutants (NO, NO2, black carbon and PM2.5) at birth year and new onset asthma assessed asthma at age 7, and found that an interquartile range (IQR) of PM2.5 concentration at birth year of 4.1 μg/m3 was associated with a significantly increased risk of developing asthma in children (OR, 3.1; 95% CI: 1.3-7.4). Lavigne et al.26 conducted a population-based cohort study, including 1,130,855 singleton live births between 2006 and 2014 in the province of Ontario, Canada, and identified 167,080 children who developed asthma before the age of 6. In their adjusted models, outdoor PM2.5 mass concentrations during childhood were associated with an increased incidence of childhood asthma (Hazard Ratio [HR] for each 1 μg/m3 increase = 1.026, 95% CI: 1.021–1.031). A recent study involving 30,325 preschool children aged 3–6 years in China during 2019–2020 suggested that early-life exposure to PM2.5 was significantly associated with an increased risk of asthma and wheezing27.

Air pollutions exposure, such as PM2.5, O3, NO2 and SO2, has been also implicated in the exacerbation of asthma, as evidenced by increased hospitalization rates in patients with asthma due to air pollution exposure 12, 28-30. A previous study demonstrated that short-term exposure of PM2.5 had an adverse impact on asthma-related emergency department (ED) visits, especially in children who were a high-risk population, particularly during periods of elevated PM2.5 concentrations31. A study investigating the impact of O3 on asthma hospital admissions also demonstrated a significant association between O3 levels and asthma-related hospital admissions, and the susceptibility to O3 was found to be age-dependent, with children being at the highest risk28. These results suggest that children are at high-risk population for asthma exacerbation induced by air pollution exposure. This may be due to the unique anatomy and physiology of children. They breathe more quickly and inhale more air relative to their body weight than adults, which renders them more susceptible to the impacts of poor air quality 32.

Air pollution and asthma over life course

The health impact of air pollution can accumulate over time or have a stronger effect during certain sensitive periods throughout the life course. In an epidemiological study involving a cohort of 6501 children in Jinan, China, high-level of O3 exposure after birth was associated with asthma and wheezing (AW) in young children (Hazard ratio [HR]: 2.10, 95% CI: 1.31, 3.37)33. Specifically, this study demonstrated the existence of two sensitive windows in early life, identified correlated insults between high levels of O3 and other pollutants, as well as open windows contributing to the asthma-inducing effect33. While this report described the associations between air pollution exposure and the onset of asthma in early life and identified the sensitive period related to the onset of asthma, future studies should further explore how exposure at different epochs throughout life course are related to the development or exacerbation of asthma in young, adult, and older ages, and identify the sensitive period contributing to the development of asthma.

Previous studies showed that both long and short-term exposure to air pollution can impact telomere length (TL), but in different directions. Long-term exposure to PM is associated with a reduction in TL34, 35, while short-term exposure is linked to a rapid increase in blood TL36, 37. Miri et al38 conducted a meta-analysis, revealing a positive significant association between short-term exposure to PM2.5 and TL, whereas for long-term exposure to PM2.5 a negative association was observed. TL is a common biomarker of biological aging 39, 40. Telomeres progressively shorten with each cell cycle division and lead to cellular senescence due to the “end replication problem” which is incomplete replication at chromosomal ends by DNA polymerase41, 42. A study of the Coronary Artery Risk Development in Young Adults (CARDIA) cohort in the United States over 25 years demonstrated that the incidence of adult-onset asthma increased with age, and the prevalence trend over time for adult-onset asthma was greater among individuals with non-allergic asthma compared to those with allergic asthma43. Another study based on physician-diagnosed asthma data from questionnaires completed by 4,173 participants in Finland in 2016 also demonstrated that the incidence rate of non-allergic asthma increased after middle age, being highest in older age groups compared to children and young adults44. Additionally, a study of patients enrolled in the Severe Asthma Research Program (SARP) revealed that the probability of severe asthma increased with each year of life until 45 years, after which the age-related risk of severe asthma continued to rise in men but not in women45. While there is currently no conclusive evidence regarding the association between air pollution-induced changes in TL and age-related adult-onset asthma or severe asthma, further research to explore this relationship could provide insights into whether accelerated biological aging due to prolonged air pollution exposure-induced shortened telomeres during early life influences susceptibility to asthma phenotypes that typically emerge in adult groups.

Importantly, prolonged air pollution exposure can lead to epigenetic alteration46. Epigenetic modifications are associated with aging, and DNA methylation-based aging biomarkers are utilized to evaluate epigenetic age across various cells, tissues, and populations47. PM2.5 exposure has been shown to be associated with Horvath DNAmAge48, 49, which is an epigenetic age estimated using the Horvath multi-tissue age prediction model, based on the DNA methylation levels at the 353 CpG sites 50. Additionally, air pollution around a sensitive period in young-to-middle adulthood is linked to accelerated epigenetic aging, as demonstrated in a study encompassing a cohort of 525 older Scottish adults with life-course residential addresses linked to historical air pollution concentrations51. However, currently little is known about the life course during which air pollution might have a stronger impact on asthma-related epigenetic modifications, or whether the effect of air pollution on asthma accumulates over time. Further studies may investigate whether the air pollution associated CpGs contributing to the epigenetic ages are mapping to genes involved in the development of asthma.

Air pollution and type 2 inflammation in asthma

Extensive research has been conducted to examine the biological mechanisms underlying the effects of air pollution on asthma13, 52. The immune responses in both the adaptive and innate immune systems induced by exposure to air pollution associated with the pathogenesis of asthma have been investigated. Asthma can be mediated by type 2 and non-type 2 airway inflammations 53, 54. Type 2 inflammation is driven by CD4+ T helper 2 (Th2) cells, which secrete Th2 cytokines, such as IL-4, IL-5 and IL-13 and is involved in the activation and migration of eosinophils (Figure 2). These produced Th2 cytokines can promote the synthesis of immunoglobulin E (IgE) (Figure 2). In human in vitro studies, the air pollutants, such as PM2.5, diesel exhaust particles (DEP) and black carbon, have been shown to promote the productions of epithelial cytokines (IL-33 and thymic stromal lymphopoietin [TSLP]) in human bronchial epithelial cells (HBECs), and these epithelial cytokines can induce Th2-type cytokine synthesis55-58 (Figure 2). Furthermore, the genetic variations in the IL-33 and TSLP genes has reproducibly been found to be associated with asthma in genome-wide association studies (GWAS), suggesting that the effect of air pollution on asthma can be directly mediated by type 2 immune response 11, 59-62. In addition, the pro-inflammatory cytokines, such as IL-6, IL-8 and IL-1β, in human bronchial epithelial cells (HBECs) have been shown to be induced by PM2.563-65(Figure 2). In HBECs air liquid interface culture, IL-1 has been shown to trigger the production of type-2 inflammation cytokines, such as IL-33, TSLP, and GM-CSF 66-68, suggesting IL-1 signal pathway may contribute to type 2 inflammation in asthma (Figure 2). Additionally, the air pollutants, such as PM2.5 and O3, are potent oxidants and can induce oxidative stress initiated by reactive oxygen species (ROS) 69(Figure 2). The increased production of ROS can lead to direct oxidative damage and enhance intracellular calcium concentrations that precede IL-33 release in HBECs70(Figure 2). ROS can also induce the production of inflammatory cytokines, such as IL-6, IL-8 and IL-1β, by activating the redox-sensitive transcription factor NF-κB71, 72(Figure 2). These results suggest that air pollution induced ROS is associated with the development of type 2 inflammation in asthma.

Figure 2: Cellular pathways of type 2 inflammatory effects caused by PM exposure.

Figure 2:

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PM, particulate matter; ROS, reactive oxygen species; TSLP, thymic stromal lymphopoietin; IL, interleukin; ILC2, type 2 innate lymphoid cells; DC, dendritic cell; Th2, T helper 2 cell; IgE, Immunoglobulin E.

Air pollution and non-type 2 inflammation in asthma

In addition to the common type 2 asthma, non-type 2 inflammation is primarily associated with abnormal immune responses and neutrophilic inflammation, leading to severe asthma 73. Th1 pathway and Th17 pathway have been implicated in non-type 2 asthma. Previous study demonstrated a distinct immune response in severe asthma characterized by a dysregulated Th1 cytokine IFN-γ/secretory leukocyte protease inhibitor (SLPI) axis that affects lung function 74. The Th17 cytokine IL-17 plays a crucial role in neutrophilic inflammation73. Levels of this cytokine in bronchial biopsies correlate with airway neutrophil infiltration and are elevated in patients with severe asthma compared to those with milder disease73. In mice, the air pollutant O3 has been shown to induce neutrophilic airway inflammation and production of IL-1β, IL-18, IL-17A, granulocyte-colony-stimulating factor (G-CSF), and interferon-γ-inducible protein 10 (IP-10)75. A study in a rodent model demonstrated that the introduction of the IL-17 antagonist following PM2.5 exposure led to a significant decrease in inflammatory factor levels in bronchoalveolar lavage fluid (BALF) and pathological scores of lung tissues 76. A recent study in a mouse model suggests that PM2.5 could inhibit autophagy of bronchial epithelial cells and promote pulmonary inflammation and fibrosis by inducing the secretion of IL-17A in γδT and Th17 cells and regulating the PI3K/Akt/mTOR signaling pathway77. Piao et al.78 demonstrated that in an OVA-induced mouse model of combined allergic rhinitis and asthma syndrome (CARAS), exposure to PM2.5 can active the NF-κB signaling pathway and increase the production of cytokines, such as GATA3, RORγ, IL-4, IL-5, IL-13, and IL-17 in BALF. Although there is currently no convincing evidence to show the production of IL-17 in human airway epithelial cells in response to exposure to air pollutants, the results in mice and rodents models suggest that air pollution-induced IL-17 mediates non-type 2 inflammation in asthma.

Our published study demonstrated that asthma was associated with higher differentially methylated regions of Foxp3, and both short-term and long-term exposures to high levels of CO, NO2, and PM2.5 were associated with alterations in differentially methylated regions of Foxp3, suggesting the role of epigenetic modifications of regulatory T (Treg) cells in the effects of air pollution on asthma 79. Sun et al.80 demonstrated that in a mouse model, PM2.5 disrupted the balance of CD4+ T helper 17 (Th17) cells/Treg cells through aryl hydrocarbon receptor (AhR)-hypoxia-inducible factor 1α and AhR-glutamate oxaloacetate transaminase 1 (Got1) molecular pathways. PM2.5 impaired the differentiation of Treg cells, promoted the differentiation of Th17 cells, and exacerbated asthma in an AhR-dependent manner 80. This study also observed similar regulatory effects on Th17/Treg cell imbalance in human T cells after exposure to PM2.5 or polycyclic aromatic hydrocarbons (PAHs), and in a case-control design, PAHs exposure appeared to be a potential risk factor for asthma80. The imbalance of Th17/Treg cells induced by PM2.5 was further observed in a study using an ovalbumin (OVA)-sensitized rat model81. This study demonstrated that the STAT3/RORγt-STAT5/Foxp3 signaling pathway was involved in PM2.5-induced imbalance of Th17/Treg cells in asthma exacerbation81. Additionally, the alteration of DNA methylation in STAT3, STAT5, and RORγt genes may be involved in asthma exacerbation as well81. A recent study investigated the differential chromatin accessibilities in human lung epithelial cell line BEAS-2B cells before and after exposure to PM2.5 using assay for transposase-accessible chromatin with sequencing (ATAC-Seq) and RNA-seq, and PM2.5 induced up-regulated genes in the ferroptosis signaling pathway were identified82. Additionally, in an asthma mice model exposed to PM2.5, the airway inflammation was alleviated by inhibition of ferroptosis82. Ferroptosis has been demonstrated to facilitate Th17 responses83, suggesting that its role in PM2.5-induced asthma exacerbation may be mediated by Th17 response.

Air pollution and airway epithelial barrier

The disruption of airway epithelial function, along with the activation of type 2 immune responses, is considered to contribute to allergic airway inflammation84. Karki et al. 85 demonstrated that treatment with PM causes dose-dependent disruption of the endothelial cell barrier in human pulmonary endothelial cells. They also revealed a mechanism for the sustained dysfunction of the pulmonary endothelial cell barrier, driven by PM-induced generation of truncated products of phospholipid oxidation causing destabilization of cell junctions. PM-induced the increase of airway epithelial barrier permeability may lower the threshold of epithelial damage, activation of type 2 immune responses and production of inflammatory cytokines, which itself may disrupt the barrier function, thus generating a positive feedback loop of increased epithelial permeability. In addition, a group of genes associated with asthma has been reported to be related to epithelial function, such as ORMDL386-89, PCDH190, and CDHR391-93. Previous studies have reported on the regulatory role of these three genes in airway epithelial barrier dysfunction. ORMDL3 gene encodes a transmembrane protein localized in the endoplasmic reticulum (ER)94. A study in a mouse chronic asthma model induced by ovalbumin-respiratory syncytial virus (OVA-RSV) demonstrated upregulation of ORMDL3 and downregulation of the junction proteins Claudin-18 and E-cadherin95. Additionally, overexpression of ORMDL3 in human bronchial epithelial cells was shown to decrease transepithelial electrical resistance (TEER), further downregulate Claudin-18 and E-cadherin, and induce epithelial permeability95. The PCDH1 gene encodes an adhesion molecule localizes to cell-cell junctions96. The knockdown of PCDH1 gene in bronchial epithelial cells has been shown to disrupt both tight and adhesion junctions, resulting in increased epithelial permeability97. This suggests an important role for PCDH1 in maintaining airway epithelial barrier function. CDHR3 is a member of the cadherin family of transmembrane proteins98, and knockout of CDHR3 using CRISPR-Cas9 in human airway epithelial cells led to decreased transepithelial resistance and compromised epithelial integrity99. Further research on the association between the expression of these genes in human pulmonary cells and air pollutants is needed.

Conclusion

In conclusion, epidemiological studies provide evidence that exposure to air pollutants is associated with the development and exacerbation of asthma. Children may be more susceptible to the impact of air pollution due to their developing respiratory systems.

The effects of air pollution exposure may accumulate over time, and the air pollution may have stronger impacts in the development of asthma during certain sensitive life periods. Prolonged pollution exposure can induce epigenetic alterations. However, future research is needed to better characterize the sensitive period contributing to the development of air pollution-induced asthma, and to map air pollution-associated epigenetic biomarkers contributing to the epigenetic ages onto asthma-related genes.

Air pollutants can activate both type 2 and non-type 2 inflammatory pathways involved in asthma pathogenesis. They promote the release of epithelial cytokines that drive Th2 responses as well as induce oxidative stress and production of pro-inflammatory cytokines. The enhanced type 2 inflammation furthered by air pollution-induced dysfunction of the airway epithelial barrier may be associated with the exacerbation of asthma. The Th17/Treg balance can be disrupted by air pollutants and this imbalance is related to asthma exacerbation.

Overall, this review highlights the impacts of air pollution exposure on the development and exacerbation of asthma. Particularly, the effects of air pollution on the pathogenic pathways of asthma, including type 2 and non-type 2 inflammatory responses, as well as airway epithelial barrier dysfunction.

Funding Information:

This work was supported by grants from the following: NIEHS grant R01ES032253 (KN), NHLBI grant 5P01HL152953 (KN), and NIAID grant U01AI147462 (KN).

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Conflict of Interest: Dr. Nadeau reports grants from National Institute of Allergy and Infectious Diseases (NIAID), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Environmental Health Sciences (NIEHS), and Food Allergy Research & Education (FARE); Stock options from IgGenix, Seed Health, ClostraBio, Cour, Alladapt; Advisor at Cour Pharma; Consultant for Excellergy, Red tree ventures, Before Brands, Alladapt, Cour, Latitude, Regeneron, and IgGenix; Co-founder of Before Brands, Alladapt, Latitude, and IgGenix; National Scientific Committee member at Immune Tolerance Network (ITN), and National Institutes of Health (NIH) clinical research centers; patents include, “Mixed allergen com-position and methods for using the same,” “Granulocyte-based methods for detecting and monitoring immune system disorders,” and “Methods and Assays for Detecting and Quantifying Pure Subpopulations of White Blood Cells in Immune System Disorders”. Drs Zhou and Sampath have no conflicts of interest to report.

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