Authors: Matthew J. Mears (1Dorothy M. Davis Heart and Lung Research Institute; College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, OH;), Eleanor J. Mohler (1Dorothy M. Davis Heart and Lung Research Institute; College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, OH;; 2Division of Cardiac Surgery, Department of Surgery, Wexner Medical Center and The Ohio State University, Columbus, OH), Priya Bandaru (1Dorothy M. Davis Heart and Lung Research Institute; College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, OH;), Evan W. Neczypor (1Dorothy M. Davis Heart and Lung Research Institute; College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, OH;), Matthew W. Gorr (1Dorothy M. Davis Heart and Lung Research Institute; College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, OH;; 2Division of Cardiac Surgery, Department of Surgery, Wexner Medical Center and The Ohio State University, Columbus, OH), Loren E. Wold (1Dorothy M. Davis Heart and Lung Research Institute; College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, OH;; 2Division of Cardiac Surgery, Department of Surgery, Wexner Medical Center and The Ohio State University, Columbus, OH)
Categories: Article, air pollution, particulate matter, wildfire smoke, cardiovascular, pulmonary, immune system
Source: Physiology (Bethesda, Md.)
Authors: Matthew J. Mears, Eleanor J. Mohler, Priya Bandaru, Evan W. Neczypor, Matthew W. Gorr, Loren E. Wold
Ninety-nine percent of the global population breathes air containing elevated levels of air pollutants, exceeding the World Health Organization (WHO) air quality limits. Among these pollutants, WHO has identified particulate matter (PM) as a top ten killer, causing injurious effects on many organ systems. In recent years, wildfire events have increased in severity, duration, and frequency, eliciting hazardous air pollutants including PM that have been known to cause adverse health effects. Therefore, the purpose of this comprehensive review is to dissect and summarize the known systemic effects of PM and wildfire exposure, covering pathways and mechanisms through which these effects occur. Notably, both PM and wildfire exposures increase cytokine release and oxidative stress, associated with a heightened risk of dysfunction within several organ systems, such as cardiovascular, respiratory, and even the development of autoimmune diseases. This manuscript will discuss the interconnection between systems and identify areas for further studies.
Where you live and what you are exposed to can play a considerable role in the progression of many diseases. Environmental exposure is comprised of both indoor and outdoor pollutants, with a large portion in the form of ambient particulate matter (PM). Ambient particulate matter is classified into three categories by its coarse (PM10), fine (PM2.5) or ultrafine (PM0.1). In addition to ambient particulate matter, the surge in wildfire events, linked to alterations in forest management practices and climate changes, leads to high levels of PM2.5 emissions that pose significant health risks (1). Various clinical and epidemiological investigations have demonstrated that exposure to PM2.5 increases the risk for cardiovascular (CVD) and metabolic disease (2). Exposure to PM2.5 correlates with arrhythmia, hypertension, myocardial infarction, and cardiac remodeling, resulting in heart failure (2), as well as increased obesity and insulin resistance. Other reports have shown that PM2.5 inhalation elicits both fetal (3) and systemic vascular inflammation with impaired vascular reactivity, leading to CVD (4, 5). While many studies (including those from our laboratory) have focused on cardiovascular implications of PM2.5 exposure, all other organ systems have been shown to be impacted by exposure to various components of pollutants. Epidemiological studies have also indicated that exposure to PM in utero alters fetal programming and increases the risk of heart and metabolic disease during adulthood (6, 7). Recently, the World Health Organization (WHO) declared that the impact of environmental pollution is more than double what was originally assumed, placing PM exposure as a top ten killer(8).
In this comprehensive review, we will describe the various sources of PM, including those originating from wildfires, as well as the organ-specific effects of PM and wildfire exposure. There are numerous interactions between organ systems that we will address throughout this manuscript and are briefly summarized in Figure 1. Understanding how these air pollutants can play a role in disease progression will allow us to design effective mitigation strategies, with a goal of setting new policy for safe exposures.
Ambient air pollution is a prominent cause of non-communicable diseases globally. PM is one of the most prevalent pollutants and is often considered the agent of greatest concern to human health. Sources of PM stem from primary and secondary sources (9): primary PM is generated from the combustion of fossil fuels, both organic and inorganic. Organic primary sources include wildfires, wood burning, cooking, and other biological particles such as pollen. Inorganic (man-made) primary sources of PM include the combustion of fossil fuels, diesel exhaust particles (DEP), waste disposal and burn pits, wear on road surfaces and automobile brakes, and resuspension of crustal matter (i.e. dust) (9, 10). Secondary sources form through photo-chemical reactions of PM in the atmosphere with nucleation of pollutant gases such as ammonium nitrate and sulfur dioxides (9).
PM is composed of both solid particulates and gaseous components (GCs) suspended in the air. PM can consist of various combinations of organic and elemental carbon, polycyclic aromatic hydrocarbons (PAH), inorganic ions (i.e., Na^+^, K^+^, Ca^2+^, Mg^2+^, Cl^−^), ammonium (NH4^+^) carbon monoxide (CO), nitrogen oxides (NOx), ozone (O3), sulfates (SOx), volatile organic compounds (VOC), and metals (i.e., Cd, Cu, Ni, V, Zn)(11). PM has also been shown to contain various components of infectious microbes such as lipopolysaccharide (LPS), fungal spores, and other allergens bound to particulates (12).
PM can be broken down into subtypes characterized by particulate size, known as aerodynamic equivalent diameter (AED) (13). Particulates with AED greater than 10 μm have a relatively small suspension half-life and are filtered out by the nose and upper airways, thus they are unlikely to reach lower airways and the bloodstream (14). Particulates with AED less than 10 μm are known as coarse PM (PM10). PM10 has been shown to deposit chiefly in proximal airways, whereas particulates of smaller AED are thought to deposit into deeper airways, the terminal bronchioles and alveoli, promoting inflammatory processes that may progress into disease states. These smaller particulates include fine PM (PM2.5) and ultra-fine PM (PM0.1, or UFP) with AEDs of less than 2.5 μm and 0.1 μm, respectively (14). The duration for which PM is suspended in the air is size-dependent (15). PM10 has an atmospheric lifetime ranging from minutes to hours and travels distances ranging from 1 to 10 km. PM2.5 has a much longer atmospheric lifetime ranging from days to weeks and travels distances ranging from 100 to 1,000 km (16, 17). Thus, PM2.5 is capable of widespread atmospheric travel, permitting the potential for PM to cause disease in seemingly “clean” atmospheric conditions and can affect cities far from wildfires. As such, understanding the sources, composition, and characteristics of PM is of utmost importance to elucidate the mechanisms by which PM induces disease and inform policies that potentially mitigate pollution and its effects on health.
Worldwide, ambient air pollution levels are highly variable. Globally, the average population-weighted PM2.5 concentration is 46 μg/m^3^, which is far above the 9 μg/m^3^ annual average standard set by the Environmental Protection Agency (EPA) (18). From 1990 to 2011, this global average increased by 13% before returning to near-1990 levels. Collectively, Asian PM2.5 levels mirror and are largely responsible for this global trend, with average concentrations well above the global average (19). Africa is also above the global average and has a 20% increase in population-weighted PM2.5 from 2014 to 2017(19). European, American, and Australian averages have slowly declined since 1990, and their current population-weighted PM2.5 concentrations are 17, 13, and 8.6 μg/m^3^, respectively(19). Generally, ambient air pollution spikes due to urban sprawl without careful planning and environmental management (20). Developed countries see reduced emissions due to strict environmental policies, transfer of heavily polluting industries to developing nations, and implementation of clean energy sources (20).
According to the WHO, there are 7 million deaths attributable to air pollution exposure each year. The economic cost of these deaths is estimated to be $4.09 trillion, as measured by the loss of value of statistical life-years (21). Ambient outdoor air pollution, as opposed to indoor air pollution, accounts for 3.3 to 4.2 million worldwide of pollution-related deaths, with approximately 59% of these deaths occurring in South and East Asia; China and India have far higher pollution-associated mortalities than any other nation (22). Per geographical area, vast regions across India and China have pollution-associated mortality rates that are mirrored only in small hotspots near other major cities. The major contributors in some regions include indoor heating and cooking in China and India, traffic and power generation from fossil fuels in much of the United States, agricultural emissions in the Eastern United States, East Asia, and Russia, and burning of biomass fuels in remote or developing regions of Canada, Siberia, Africa, and South America (22).
Large-scale epidemiological studies have provided estimates for the health impact of a wide range of pollutants of varying concentrations. A meta-analysis analyzing 110 studies published prior to 2011 found that for every 10 μg/m^3^ increase in ambient PM2.5, all-cause risk of death increased by 1.04% on average, with substantial regional variation (23). Considering several of the most heavily polluted nations have PM2.5 averages around 100 μg/m^3^, compared to United States averages below 10 μg/m^3^, this data suggests upwards of a 10% increase in risk of death from PM2.5 in these nations compared to that of the USA (24). A 2019 study of 652 cities worldwide found a slightly lower mortality increase of 0.68% for each 10 μg/m^3^ PM2.5 increase (25). Increasing PM concentrations are concerning for developed nations with relatively clean air, as subtle concentration changes can have substantial impacts on mortality.
PM10 is associated with a 0.44% mortality increase per 10 μg/m^3^ increase (25). Along with particulate size, the composition of PM can greatly impact associated mortality. A 2018 meta-analysis found that black carbon and organic carbon emissions are most robustly and consistently associated with mortality, while nitrates, sulfates, and various metals are associated with adverse respiratory or cardiovascular outcomes (26). Non-PM air pollution from nitrogen dioxide and ozone also pose significant health risks, with 10 μg/m^3^ increases resulting in 0.60% and 0.26% increases in mortality, respectively (27, 28). Air pollution mortality risks are greatly heighted for elderly a 10 μg/m^3^ PM2.5 increase is associated with a 7.3% increase of all-cause mortality for older subjects, and the economic cost of air pollution per capita is 10 times higher for individuals older than 60 compared to younger individuals worldwide (21). Concentration-dependent estimates of mortality are subject to regional variability in demographics, pollutant sources, compositions, and concentrations, highlighting the need for location-specific analyses.
Mortality from air pollution is predicted to double by 2050 (22). However, preventative measures could blunt this a 2012 study estimated that worldwide implementation of 14 emission control measures could prevent 0.64 to 4.92 million premature deaths annually after 20 years, indicating the potential for significant mitigation from existing technologies and policies (29).
Humans typically spend approximately 90% of their time indoors, and indoor air quality can be a major determinant to health (30). Pollutants of indoor and outdoor origin contribute similarly to the estimated 7 million premature deaths each year (8). Sources of indoor air pollution include indoor human activity (e.g. cooking), as well as infiltration of ambient air pollution from the outdoors (31). Indoor-outdoor sampling methods have provided data on pollutant severity and composition that can be used to make population risk assessments. Pollutant sensors that can be worn or carried throughout the day have rapidly advanced in price and accuracy in recent years (32). This technology has been used for novel personal exposure sampling methods which have highlighted local heterogeneity of exposure based on personal behavior and demographics (33).
In Beijing, China, the infiltration of outdoor pollution has been extensively studied with a recent study using vacant apartments to model a system free from indoor pollutant sources. The study found that the indoor to outdoor (I/O or infiltration) PM2.5 ratio was 0.53 on average, suggesting that approximately half of outdoor PM can penetrate indoor spaces (34). The makeup of I/O PM was different, with substances such as volatile organic matter having a high I/O, and larger particles such as crustal dust having a relatively low I/O. Other Beijing studies using occupied residences reported a wide range of estimated pollutant infiltration, ranging from 10% to 82% of outdoor pollution penetrating indoors (35, 36). This wide range of variability can be attributed to differences in seasonal outdoor air quality, sampling of residential areas with different window types, or building age (37). Indoor PM of outdoor origin has been estimated to account for 81% to 89% of the total mortality increases due to outdoor pollutant sources in the United States, Europe, and China (38, 39).
A global study of PM-induced mortality found that emissions from indoor heating and cooking have the largest impact on premature mortality (22). Even in the most polluted cities, I/O pollutant ratios can exceed 1.0 when outdoor PM2.5 drops below 100 mg/m^3^ (40). In New York City, indoor sources were reported to account for 54% of residential PM (41). Indoor air pollution derived from kitchens in rural areas and developing countries are a major contributor to morbidity worldwide; use of solid biomass fuels contributes four times more harmful pollutants than cleaner sources (42). In addition to personal residences, other highly trafficked areas of concern include schools, with reports suggesting 47% of pollution is generated indoors, and hospitals, with medications and sample transport systems, reportedly contributing other hazardous aerosols (43, 44).
National Ambient Air Quality Standards (NAAQS) for the concentrations of PM2.5, PM10, NO2, O3, lead, SO2, and CO (45) are set by the EPA and include primary standards which are meant to be public health measures and secondary standards which are meant to be public welfare measures (46). All states are required to file State Implementation Plans (SIP), which contain regulations and documentation of plans to adhere to the NAAQS (47). If a region or multiple regions within a given state fail to meet the NAAQS (nonattainment areas), the state is required to include additional plans in their SIP to reduce pollution in these areas. If a state fails to implement SIP requirements for nonattainment areas, the EPA can threaten sanctions in the form of withholding federal highway funding in nonattainment areas (48). In addition to enforcing the NAAQS, the EPA has the authority to regulate emissions released from a variety of sources. When the EPA identifies an emission violation, they can choose to issue monetary penalties or file civil lawsuits against offenders (49).
Globally, numerous regions are witnessing shifts in wildfire patterns, driven by an interplay of climatic factors and human-induced influences (50) leading to an increase in the severity and frequency of wildfires observed over the last two decades (51). In Canada, the estimated total wildfire emissions for 2023 were projected to reach a record-high of nearly 410 megatons, significantly surpassing the previous high of 138 megatons in 2014 (52). Additionally, as of November 6, 2023, California had reported 6,375 wildland fires affecting nearly 319,070 acres of land in the year 2023 alone (53). However, effects from wildfire emissions are not confined solely to their original locations; smoke particles from extensive fires travel thousands of miles (depending on wind speed and direction), affecting air quality in regions distant from the point of origin of the fire (54).
Wildfire emissions typically consist of fine PM2.5, black carbon, carbon dioxide (CO2), carbon monoxide (CO), and various trace gases; however, the variable nature of wildfires influenced by factors like fuel type, temperature, and combustion conditions introduces variability in the composition of particles and gases in these emissions (38, 39). Regardless of composition, these small particles can remain in the atmosphere for weeks to months at a time. Delay of smoke removal mechanisms such as precipitation, impaction scavenging, and nucleation, can result in an extended atmospheric lifespan and long-distance transport for these particles (39).
Recent analysis of PM2.5 measurements from the US EPA’s ground monitoring sites from 1988 to 2016 confirmed that wildfires are a major contributor to the increasing PM2.5 concentration in the Northwestern United States (1). A modeling system to estimate daily PM2.5 concentrations(54)and found that wildfire smoke has the greatest impact on air quality in the West Coast, followed by the Southeastern United States. Another study on wildfire impact in the Southeastern United States found that during a November 2016 wildfire episode, the contribution of wildfire to PM2.5 was 45% (55).
This section will review potential mechanisms that contribute to the development of PM-induced inflammation contributing to specific pathologies. As the upper and lower airways are the first organ systems exposed to PM, the innate immune cells that reside there are the first to be impacted. Following an environmental insult, an immune response is mounted, and inflammatory cells and pathways are activated, leading to systemic inflammation.
Research has shown that PM deposition within airways may activate immune cells via multiple host defense pathways such as toll-like receptors (TLR) and activation by reactive oxygen species (ROS) and poly-aromatic hydrocarbons (PAH), leading to pro-inflammatory intracellular signaling cascades such as extracellular signal-regulated kinase 1/2 (ERK1/2), Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB), and mitogen-activated protein kinases (MAPK) (56–58). Particulate-depleted air pollution can still cause immunological effects (59, 60). PM can stimulate receptors as it may contain various PAMPs, such as LPS and fungal spores. PM may even act directly on TLRs as an alternative agonist (61). PM has been shown to activate cells directly through TLR2, TLR4, and TLR9 with varying degrees of stimulation dependent up cell type and particulate size and could involve systemic inflammatory responses (62–67).
PM may contain heavy metals and organic compounds that can generate ROS, depleting antioxidants and inducing oxidative stress (68, 69). Oxidative stress can induce NF-κB signaling and AP-1 activity, both promoters of antioxidant gene transcription (70). Oxidative stress induces NF-κB and AP-1 activity, yet PM has been shown to downregulate their activity (65). ROS generation may also disrupt pulmonary smooth muscle contraction with increased airway contraction and hyperresponsiveness, potentially via PM-induced production of TNF-α from monocytes and suppressed CXCL8 from pulmonary epithelial cells (71, 72). Beyond altering inflammatory pathways, ROS can directly damage proteins and DNA and generate intracellular danger signals, including systemic inflammatory responses (66). PM may also contain PAHs and other persistent organic pollutants that induce oxidative stress (73). The overexpression of CYP enzymes after exposure to PAHs has also been shown to stimulate the production of ROS, providing some insight into oxidative regulation after exposure (74, 75). Exposure to PM and PAHs can induce inflammatory responses that may lead to chronic inflammatory diseases such as asthma, CVD, and increased cancer risk (74, 75).
As fine and ultra-fine PM traverse the lower airways, particulates interact with lung epithelial tissues and other innate lung immune cells (e.g., alveolar macrophages). Activation of a multitude of cell signaling pathways has been described. As a result, the potential for PM-induced pathologies may be a product of either an inadequate immune response to the insult, allowing the particulates to linger and elicit further inflammation, or an inappropriate and excessive immune response, causing collateral damage to host body tissues. The following subsections will discuss the current understanding of the response of various immune cell types to PM exposure.
The respiratory epithelium contains alveolar macrophages (AM), dendritic cells (DC), granulocytes, innate lymphoid cells (ILC), NK cells, and T-cells. Bronchial epithelial cells have a multitude of functions, including forming the physical barrier facing the airway lumen, producing the mucus component of respiratory tract lining fluid, secreting cytokines, chemokines, and other signaling molecules to promote airway inflammation (e.g., IL-6, CXCL8, and GM-CSF), sensing particle deposition in the airways, and clearing the airways via mucociliary action. Following PM damage and activation, epithelial-derived cytokines are released and activate ILCs, granulocytes, AMs, and DCs. The immune response associated with PM can be summarized in Figure 2.
Cell culture studies of PM and epithelial cell dysfunction have played a key role in understanding the mechanisms that may be the initial steps inciting the PM-induced inflammation. PM2.5 exposure to human bronchial epithelial cell (HBEC) increases transforming growth factor-β (TGF-β) and IL-8 levels following exposure (76). IL-8 mainly induces chemotaxis and migration of neutrophils to the site of inflammation to initiate the acute and chronic inflammatory processes (77, 78). TGF-β, alongside epidermal growth factor (EGF), induces the growth of fibroblasts, but TGF-β may also induce the phenotypic transformation of fibroblasts independent of EGF and has also been identified as a growth inhibitor (79). TGF-β is a bifunctional regulator of cell proliferation, with both inhibitory and stimulatory roles. Ambient PM2.5 and DEP have shown to upregulate the expression of amphiregulin (AR), an agonist of EGFR, in HBEC (80). In vitro PM2.5 and DEP exposure also demonstrated that AR secretion could be mediated with the antioxidant N-acetyl cysteine, suggesting that EGFR transactivation may be mediated by oxidative stress (80).
The resident macrophages of the lungs, alveolar macrophages (AM), phagocytize cell debris, microbes, and other particles as an initial step to clearing the lungs (81). PM and other particles are also phagocytized by AM, potentially leading to dysfunctional PM-laden macrophages with deficiencies in phagocytosis (82). Macrophage exposure to PM2.5 (NIST SRM 2786) in vitro led to phagocytic dysfunction via disruption of autophagy-related processes (82). That is, PM2.5 induces autophagic dysfunction via activated ERK1/2 signaling, upregulated expression of ATG2A (autophagy-related 2A), and generation of ROS, leading to disrupted lysosomal activity further leading to autophagy flux inhibition and reduced proteolytic activity (82). These findings suggest that the disruption of lysosomal activity plays a role in PM-induced macrophage phagocytotic dysfunction.
A collection of compact mature macrophages, with or without accessory features such as necrosis, infiltrating leukocytes, or multinucleated giant cells, is the hallmark feature of granuloma development (83). Granulomatous inflammation has been reported in diseases of almost every body system and initially presents with persistent and poorly degradable antigens, including PM2.5, that lead to a variety of inflammatory responses. Within the lungs, granulomas contribute to a spectrum of pathologies with non-specific clinical manifestations and outcomes (83–85). Pulmonary granulomatous diseases remain challenging to diagnose but are strongly linked to occupational exposures, including specific inhaled particulates rather than ambient PM broadly. (85, 86). PM exposure may result in pulmonary granulomas, similar to the pathophysiology of pulmonary sarcoidosis, demonstrated by AM deficiency of ATP-binding cassette (ABC) lipid transporter ABCG1-promoted pulmonary granulomatosis and exacerbated by additional deletion of ABCA1 (85). While PM has been shown to disrupt AM phagocytosis, there are multiple signaling pathways and cell types responsible for phagocytic responses, and further research is necessary (82).
Neutrophils eliminate pathogens via phagocytosis, release of granular contents, or ROS generation via respiratory burst(Bosch et al., 2013). There is evidence that inhalation of engineered carbon nanoparticles, representing the ultrafine carbon core of ambient PM, by healthy non-smoker human subjects of reproductive age has been associated with dose-dependent increases in blood neutrophils; however, these effects remain understudied in females (88). Granular contents of neutrophils include members of the serine protease family such as neutrophil elastase (NE), cathepsin, and proteinase, as well as matrix metalloproteinases (MMP), such as neutrophil collagenase (MMP-8) and gelatinase (MMP-9), which are all involved in inflammatory pathogenesis (i.e., airway and parenchymal lung diseases) (89). Exposure to DEP can induce immune responses and augment allergic inflammation synergistically with allergen exposure (90), resulting in augmented CD4, IL-4, CD138, and NE levels, contributing to neutrophil accumulation and infiltration of tissues as well as remodeling and degradation of elastin and collagens (90, 91). ROS production is initially generated as superoxide anion or hypochlorous acid via neutrophil expression of NADPH oxidase and myeloperoxidase, respectively (92). Transition metals such as Fe, Cu, Ni, Pd and Zn within PM can induce redox cycling of ROS reactions, and therefore illicit oxidative damage within host tissues; however, the exact components of PM influencing this remains undetermined (93). Short-term exposure to PM has also been associated with increased MMP-9 and IL-8 neutrophilic secretions, mitigated by gamma tocopherol (94, 95). Omega-3 polyunsaturated fatty acid and vitamin C supplementation resulted in decreased plasma docosahexaenoic acid, improved symptoms, and marked decreases in neutrophil counts in animal models of exposure (96). Selenium (Se) is a vital antioxidant and exhibits anti-inflammatory functions and animal models demonstrate that supplementation with dietary Se prior to PM exposure can inhibit the inflammation and oxidative stress induced by PM when compared to controls (97). The protective effects of Se supplementation were characterized by decreased number of neutrophils and blunted levels of TNF-α, IL-1β, and sICAM-1 in a dose-dependent manner compared to controls.
The basophilic inflammatory response to PM exposure is poorly understood. Circulating basophils are similar to large tissue mast cells (MC), located immediately outside capillaries. Basophils and MCs both play a major role in allergic reactions due to their propensity to attach to IgE-coated pathogens via high-affinity FcεRI (98). Basophils and MCs release histamine, bradykinin, serotonin, chymase, tryptase, eicosanoids, and lysosomal enzymes causing local vascular and tissue changes (99). AhR controls murine MC homeostasis in a calcium- and ROS-dependent manner and that the addition of AhR agonists (i.e., PAHs) can lead to exacerbated MC activation (100). It may be the case that PAHs within air pollution are able to cause a similar dysregulation of MC homeostasis in humans, but this potential link remains understudied.
Eosinophils also act as effector cells characteristic of a Th2 response from CD4+ naïve T cells (101). There is evidence that ambient PM may lead to changes in eosinophil homeostasis characterized by increased IL-13, eotaxin-1, and eosinophil accumulation (102). Therefore, responses to components of PM could be much more influential in disease progression than previously thought, but further research is needed (103).
While dendritic cells (DC) are innate immune cells, in nature, they aid in bridging the gap between the innate and adaptive immune systems as antigen-presenting cells. DCs are located throughout the body with the main role of phagocytizing pathogens, digesting pathogen into recognizable antigens, and presenting antigen to T cells via MHC proteins. The following section, summarized in Figure 2, discusses how PM influences the interaction between DC and T cells, and how this skews immunomodulatory effects on the activation of CD4+ and CD8+ T cells. Most research regarding PM-induced adaptive immune dysfunction focuses on T lymphocytes, however there is emerging evidence of potential B lymphocyte dysfunction following PM exposure.
PM has been shown to have mixed actions on antigen presenting cells, such as dendritic cells (DCs), exhibiting both stimulatory and inhibitory effects in a seemingly pathway-dependent manner, potentially inducing DCs to favor a Th2 response from naïve CD4+ T cells as opposed to a Th1 response (62, 65, 104). DEP has been shown to induce DC maturation via the upregulation of co-stimulatory molecules CD40, CD80, and CD86 as well as enhanced MHC-II (HLA-DR) expression (62). PM- and DEP-exposed DCs have also been shown to induce the secretions of pro-inflammatory chemokine, CCR7, which directs localization of naïve CD4+ T cells within lymph nodes (62, 105).
Toll-like receptor (TLR) 9 plays an important role in inducing Th1 activation. PM2.5 has been shown to downregulate secretions of the cytokines IL-12, IL-6, and TNF-α from TLR9 stimulated DCs (65). In the same study, PM2.5 downregulated ERK1/2, MAPK, and NF-κB pathways via decreased TLR9-dependent NF-κB and AP-1 activities, suppressing MAPK phosphorylation in the TLR9 pathway. Therefore, PM2.5-induced downregulation of TLR9 activity may be a key component in favoring a skewed Th2/Th1 response (65, 104, 106). DEP has been demonstrated to downregulate TLR2 and TLR4; both play an important role in DC-induction of Th1 response alongside TLR9 (62–65). However, the authors suggest that TLR9 plays a greater role in DC-induced Th1 activation than TLR2 and synergistically functions alongside other enzymes, coenzymes, and cofactors, necessitating further research on other pathways involved in PM-induced DC-lymphocyte immunomodulation (106). Further, PM-exposure has been shown to reduce DC secretions of anti-inflammatory cytokines IL-13 and IL-5 and reduce Th1 secretions of IFN-γ, together inducing naïve CD4+ T cell proliferation, preferential to a skewed Th2/Th1 response (107–110).
PM induced the differentiation of IFN-γ, IL-13, and IL-17A-secreting effector cells in both healthy control patients and asthmatic patients in a manner dependent on MHC II availability (111). Studies investigating the interaction between PM and allergens showed that inhalation of traffic-related PM during secondary challenge with allergen resulted in more Th2 and Th17 effectors with symptoms (111, 112). In contrast, chronic inhalation of PM alone favored the generation of Th1 and Th17 cells (113). Contradictions of in vitro studies may be a result of the PM constituents used in each study, as PM alone may promote Th1 responses while the presence of allergens or microbial byproducts may promote skew towards Th2 differentiation. While PM exposure induces Th17 cell population expansion and asthma exacerbations, Th17 expansion without allergen exposure does not result in asthma symptoms (114). Similarly, a study of urban ambient PM from Baltimore and New York City resulted in the stimulation of a mixed Th2/Th17 inflammatory response accompanied by eosinophilic and neutrophilic influx, mucus production, and airway hyperresponsiveness (115). Baltimore PM was associated with more robust airway inflammation, hyperresponsiveness, and production of Th2 cytokines potentially as the result of increased metal content as an additional irritant of PM (115). These findings suggest a common mechanism of CD4+ T effector generation following PM exposure independent of asthma status and that the presence of additional irritants may result in the DC-induced favoring of a Th2 response following PM exposure.
The effects of PM on B cells and their immunoglobulin secretions remain largely understudied in comparison to PM effects on T cells. Regardless, this is a growing area of interest and is necessary to refine our understanding of PM-induced immunologic dysfunction. One study following traffic policemen found that PM was associated with increases in IgM, IgG, IgE, and hs-CRP and decreases in IgA and CD8+ T cells, suggesting the activation of the humoral immune response (116).
Deficiencies of IgA have been linked with several autoimmune diseases such as Grave’s disease, systemic lupus erythematosus, type 1 diabetes, celiac disease, and rheumatoid arthritis (RA)(117). Rheumatoid factor (RF), used in the diagnosis of RA, is an autoantibody of any isotype, predominately encountered as IgM, that binds to IgG Fc, but an association between tobacco smoke (which contains PM) and the production of IgA RF has been demonstrated (118). Smoke-induced IgA RF appears to have an even stronger association with smoke-induced lung damage than IgM RF, perhaps due to mucus membrane damage inducing abnormalities in IgA secretions in mucus membranes.
IgE primes allergic responses via binding to MCs and basophils and plays a major role in the immune response to parasitic infections (119). Excessive IgE production, as seen following PM exposure, is characteristic of type I hypersensitivity reactions, giving rise to increased antigen-IgE binding and heightened inflammatory responses when bound to MCs and basophils (116). This heightened reactivity is associated with atopic diseases of exaggerated IgE-mediated immune responses such as asthma, rhinitis, conjunctivitis, and dermatitis (120). While PM is not consistently associated with IgE sensitization to any common allergen up to age 16 years, it is associated with increased risks of sensitization to Phleum pratense 1 (major timothy grass allergen) and Felis domesticus (cat allergen), and increased exposure to NO2 was associated with increased risk of sensitization to birch (121). These findings demonstrate that PM may not increase the overall risk of allergic IgE sensitization but rather poses risks for increased sensitization to specific allergens. Adding to this, PM exposure has been associated with increased incidence of type I hypersensitivity reactions, especially those reactions involved in allergic inflammatory airways diseases (122–126). Effects of PM on inflammatory airways diseases are characterized further in the pulmonary section.
IgG is the most common antibody isotype in human serum and binds pathogens such as viruses, bacteria, and fungi via agglutination, opsonization, neutralization, activation of complement system and is a characteristic component of type II and type III hypersensitivity reactions, alongside IgM (127, 128). Not only have IgG levels been shown to increase following PM exposure but IgG antibodies have also been shown to extravasate the blood-brain barrier (BBB), after being coupled with bilateral carotid artery stenosis in mice, and deposit in white matter (129). IgG extravasation signifies the potential for other blood-derived molecules to cross compromised BBB capillary networks and elicit toxic effects such as those seen in neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis, dementia, and chronic traumatic encephalopathy (129, 130). Similar studies utilizing cigarette smoke (with some cigarettes producing PM levels of over 3,000 μg/m^3^) found increased bronchial epithelial damage, mucus and airspace enlargement, and increased IgA and IgG production in BAL fluid (131, 132).
Agricultural operations, such as cattle farms, are important sources of organic dust containing PM and other pathogens (133). A study has shown that dairy farmers exposed to high levels of organic dust with repeated inhalation had increased levels of IgG against farm-specific pathogens (i.e., fungi and bacteria antigens contained in dust)(134). In contrast, another study found that PM exposure led to no significant differences in IgG levels in mice, but that the ratio of albumin to IgG (i.e., the percentage of albumin, or A/G) decreased(135)(L. Song et al., 2021) Initially, IgG increased rapidly, however, by the end of the study no difference was observed following PM exposure. Still, further insight is necessary to fill current gaps in knowledge regarding potential PM-induced IgG immunopathologies.
IgM is the largest of the antibody isotypes and is the first antibody to respond to initial antigen exposure. Thus, elevated IgM serum levels may indicate recent infection. However, IgM antibodies display broad antigen specificity and high avidity allowing for multiple cross-reactions to antigens, however weak they may be (137). Given the increased IgM levels following PM exposure, it may be possible that IgM levels are upregulated to agglutinate particulates following entry into airways (116). The potential relevance of IgM elevations in response to PM exposure remains unstudied.
While investigating the effects of each cell type may elucidate potential mechanisms by which PM may induce immunological dysfunction, immune cells do not respond to insults in an isolated manner. Rather, coordination of multiple cell and tissue types is necessary to mount an insult-appropriate response. Further, considering that cytokines, chemokines, and white blood cells themselves are transported throughout the body via blood and lymphatic vessels, exacerbation of immune responses may not always be localized and contained to the initial site. Alongside circulating inflammatory mediators, fractions of PM also translocate into systemic circulation and directly interact with extrapulmonary organ systems (138).
Pro-inflammatory cytokines following PM inhalation in the lungs further perturb immune regulation and may even spill over into the rest of the body and progress to chronic inflammatory or autoimmune diseases. PM has been strongly linked to respiratory disease (i.e., lung cancer, asthma, and COPD), CVD (i.e., hypertension, atherosclerosis, myocardial infarction, and stroke), autoimmune disease (i.e., systemic lupus erythematosus and RA), neurological disease (Alzheimer’s and Parkinson’s disease), and many other disorders of various organ systems (139). Chronic inflammation is a hallmark in the development and progression of these diseases and will be discussed in an organ-specific manner throughout the remainder of this review.
Systemic inflammation is a clear mechanism that links PM exposure to increased risk of CVD (139, 140). Previously, CVD has been demonstrated to coincide with PM-induced increases of acute phase reactants such as CRP, fibrinogen, and D-dimer, as well as perturbed blood coagulability and endothelium function, in a manner dependent on exposure duration and age of individual (141). Increases in these mediators have been associated with acute exacerbations of CVD, as they are linked with the destabilization of atherosclerotic plaques, predisposing to rupture, thrombosis formation, and impaired endogenous fibrinolysis (142). While the direct impact of individual PM constituents has not been extensively studied, it is likely that certain heavy metals, for example, could have individual effects on the heart (and lungs) upon direct exposure through the circulation.
Smaller particles can cross the blood-air barrier, potentially impacting other organ systems (139). Therefore, it has long been studied as the human organ system most directly affected by ambient air pollution. There is a mass of epidemiological evidence for the detrimental effects of long-term and short-term exposures to air pollutants such as PM, ozone, and nitrogen oxides on the pulmonary system, as these contaminants are associated with respiratory mortality (24, 143, 144). Air pollutants not only affect the lungs after lifelong exposure, but also negatively affect the lungs when exposed at younger ages, to such an extent that it is strongly associated with childhood asthma rates (145). Outdoor air pollutants during childhood inhibit the rate of lung function growth and increases the likelihood of acute illnesses like respiratory infections, bronchiolitis and asthma (146). This exposure can eventually contribute to long-term consequences such as COPD and reduced lung function in adulthood (147, 148).
In a comprehensive multi-city study in China spanning from 2016 to 2019, researchers investigated the impact of short-term air pollutants on hospitalizations of children (aged 0–18 years) for acute upper and lower respiratory infections (149). Results showed that a 10 mg/m^3^ increase in CO and a 10 ug/m^3^ increase in NO2, SO2, and O3 were linked to 1.65%, 0.54%, 0.60%, and 0.23% increases in hospitalizations for all respiratory causes, respectively (149). Another multi-city study covering the period from January 2000 to December 2020 in China similarly found that a 10 ug/m^3^ increase in PM2.5 and PM10 were associated with a 0.75% and 0.70% elevated risk of respiratory disease in children (150, 151). Consistent results were also observed in focused single-city studies in Zhoushan and Wuhan, China (152, 153).
Wildfire events pose a significant acute pollutant exposure that multiple epidemiological studies have demonstrated to contribute to asthma, COPD, acute bronchitis, pneumonia, and other respiratory illnesses (154, 155). A systematic review of health impact data from wildfires revealed connections between respiratory symptoms and exposure to wildfire smoke (156). The review identified significant associations, including declines in lung function among non-asthmatic children, increases in physician visits, emergency department visits, and hospitalizations for respiratory issues linked to wildfire smoke exposure.
Research on the impact of wildfires on asthma symptoms has yielded conflicting results. While some studies found no associations, others reported a statistically significant rise in hospitalizations, emergency department visits, and admissions for asthma linked (157–161). Some studies that observed no associations suggested that, despite no acute changes in lung function among individuals with asthma exposed to wildfires, significant declines were noted in those without asthma and those with bronchial hyper-reactivity (160, 162). Researchers speculated that the asthma group might have mitigated the effects through medication when perceiving deteriorating air quality, potentially influencing the outcomes (163). Other studies conclude strong associations between wildfire exposure and exacerbations of asthma(155, 164).
Studies on wildfire smoke exposure and COPD are more consistent, showing a strong association (155, 165, 166). Research investigating the mechanisms behind these effects, using small airway epithelial cell cultures and primary bronchial epithelial cell cultures exposed to wildfire smoke extract, reveal that wildfire exposure leads to dysfunction of the respiratory epithelium, significantly contributing to respiratory diseases (167). Post-exposure, researchers observed apoptosis and blocked autophagic flux (a key controller of cellular repair, survival, and inflammatory processes) in small airway epithelial cells (167). Additionally, there was a notable downregulation of tight junction proteins ZO-1 and Claudin-1, along with increased secretion of IL-6 from primary bronchial epithelial cells during wildfire exposure (167). The secretion of IL-6 is known to contribute to inflammation, a frequent phenotype of the epithelium in those with COPD (167).
Additionally, numerous in vivo studies have shown that acute exposure to PM2.5 triggers acute lung inflammation, marked by elevated inflammatory cells, heightened epithelial permeability, and oxidative stress. This impacts airway function and resistance to viruses and bacteria, elevating the risk of infections such as upper respiratory tract infections, bronchitis, and pneumonia. This response, although not completely known, is thought to be associated with the activation of the TLR4/MyD88 pathway and the NLRP3 inflammasome, leading to the secretion of IL-1β (168). Studies have also observed alveolar collapse, neutrophilic inflammation, and an increase in TNF-α production following acute exposure to PM (169). Elevated TNF-α production is recognized for inducing inflammation, resulting in elastin degradation and alveolar destruction (170).
Chronic exposure to air pollutants induces significant structural and functional alterations in the lungs, such as inflammation, emphysema, small airway remodeling, airway mucus hypersecretion, reduced lung function, and a systemic inflammatory response (139) Specifically, inflammatory markers such as PMNs, leukocytes, alveolar macrophages, and various cytokines (IL-13, IL-17, MIP-3α, MIP-1α, MCP-1, IL-1α, IL-1β, RANTES, IL-6, TNF-α, and IFN-γ) were up-regulated in bronchoalveolar lavage fluid (BALF) and serum following acute exposure to air pollutants (170). A study investigating chronic exposure to ambient particulate matter utilized motor vehicle exhaust (MVE) and biomass fuel (BMF) exposures found an increased recruitment of phagocytic cells, including neutrophils and macrophages, leading to compromised clearance and respiratory injury. Moreover, the study found that exposure to MVE resulted in neutrophilic airway inflammation, heightened lung inflammation, increased goblet epithelial cells, and thicker small airway walls with collagen deposition (170). BMF exposure led to a rise in phagocytic inflammatory cells, primarily macrophages, an elevated incidence of emphysema, more pronounced apoptosis of alveolar septal cells, greater epithelial cell hyperplasia, and enhanced squamous metaplasia. These responses initiated by alveolar macrophages and airway epithelial cells induce oxidative stress and systemic inflammation, leading to cellular and tissue damage across multiple organs (171). Our understanding of the mechanisms of insult that occur upon exposure are paramount to determining their impact on other co-exposures, lung diseases, and lung injury.
The effects of PM exposure have not only been a large focus of study for our group(172) (173–178) but also the subject of many cardiovascular researchers. This section of the review will discuss the mechanisms by which PM elicits cardiovascular dysfunction, including inflammation and ROS, endothelial dysfunction, autonomic nervous system and hemodynamic changes, altered hemostasis, calcium dysregulation, and epigenetic modifications.
PM can induce inflammation in the cardiovascular system by activating immune cells with resultant release of inflammatory mediators, outlined within the immune system section above. Similarly, PM also induces inflammation via the release of ROS contained within PM, which leads to oxidative stress in cardiovascular tissue, promoting lipid peroxidation, protein oxidation, and DNA damage which contribute to cardiovascular dysfunction (179–181). Chronic exposure to PM2.5 in mice has been shown to increase the oxidation of phospholipids, resulting in the activation and mobilization of macrophages from the bone marrow to the circulation and vascular wall via TLR-4 (182). ROS-induced lipid peroxides have been shown to promote the production of malondialdehyde, which also induces the activation and foaming of macrophages (i.e., foam cells) (183). These foam cells propagate the formation of atherosclerotic plaques in the aorta, coronary arteries, and carotid arteries (181). PM2.5 has also been shown to induce the oxidation of low-density lipoproteins (LDL) cholesterol which, in combination with PM2.5-induced lipid peroxidation, is also implicated in the propagation of arterial atherosclerotic plaques. PM2.5 exposure was associated with an increase in 7-ketocholesterol (7-KCh), a key oxysterol, in LDL fraction of plasma lipoproteins within aortic plaques(181).
Further, endothelial dysfunction reduces nitric oxide (NO) bioavailability resulting in increased vasoconstriction and thrombosis which are both risk factors for CVD (184). In vitro studies of DEP on vascular function, NO availability, and the generation of oxygen-free radicals in rat aortic rings found that DEP exposure decreased the release of NO from the endothelium. Similarly, PM also decreases the expression of inducible NO synthase (iNOS) (185). The impact of air pollution, chemical composition, and biological activity on iNOS levels is complex. However, the downregulation of iNOS is likely due to three hypothesized altered phosphorylation, uncoupling of NO synthase (NOS), and/or upregulation of endogenous NO synthase inhibitors (184, 186, 187). The altered phosphorylation hypothesis is particularly variable when considering the composition of PM exposure. PM exposure containing DEP and PAH has been shown to stimulate the phosphorylation of MAPK, AKT, and endothelial NOS (eNOS) when the exposures were associated with higher levels of PAHs. Conversely, PM exposures had no effect on MAPK alone, but inhibited estradiol-induced MAPK and eNOS phosphorylation when the exposures were associated with lower levels of PAHs (184). Saline and inhaled DEP enhanced vasoconstriction in veins but not arteries and this vasoconstriction could be normalized with the addition of L-nitro-arginine-methyl-ester, a NOS inhibitor, indicating an uncoupling of eNOS as a mechanism for DEP-induced vasoconstriction (186). The upregulation of endogenous NOS inhibitors has demonstrated asymmetric dimethylarginine (ADMA), a circulating endogenous inhibitor of NOS, is associated with impaired vascular function and increased risk for cardiovascular events (188, 189). Rats exposed to PM showed increased levels of plasma levels of ADMA. One of the major enzymes responsible for the clearance of ADMA is dimethylarginine dimethylaminohydrolase II (DDAH II) (190). DDAH II is sensitive to and inhibited by oxidative stress, hence ADMA is elevated in conditions that induce oxidative stress, such as PM exposure. Recently, a study demonstrated evidence that all three of these proposed mechanisms may occur simultaneously, utilizing human umbilical vein endothelial cells (HUVEC) exposed to PM2.5 over a 24-hour duration (191). PM2.5 exposure also resulted in the increased levels of superoxide anion and hydrogen peroxide with upregulation of NADPH oxidase (NOX). PM exposure resulted in increased ADMA levels and reduced NO production, as well as the downregulation of phosphorylation of eNOS and AKT with increased iNOS levels. PM exposure in HUVECs resulted in elevated tissue-type plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), and endothelin-1 (191).
As mentioned, PM may induce alterations to hemostasis via the activation of platelets and the coagulation cascade. Activation of platelets leads to increased aggregation, thrombosis, and vasoconstriction, which may increase the risk of acute cardiovascular events such as myocardial infarction and stroke (192, 193). tPA (anti-thrombotic) and PAI-1 (pro-thrombotic) are the main regulators of fibrinolysis, and an imbalance can alter fibrin clot formation. Alterations of tPA, PAI-1, and endothelin-1 were described previously in a study utilizing HUVECs(191). Other studies have shown that comorbid conditions, such as obesity, make individuals susceptible to PM-induced platelet activation and prothrombotic sequelae (192). This study in obese individuals was associated with increased pro-inflammatory cytokines (i.e., TNF-α, MIP-1α, IL-1β, IL-8, MPO, and fractalkine) and adipokines (leptin and PAI-1); these cytokines are associated with platelet activation (194). Interestingly, in this study, the association was noted in the obese group only (192). It is well established, via epidemiological studies, that inflammatory states are associated with platelet activation and thrombosis (195–197). The findings in obese individuals exposed to PM are likely due to PM-induced inflammation triggering platelet activation superimposed on obesity-related inflammation, exacerbating the effects of PM (197). Similarly, in vitro and animal studies support this mechanism of PM-induced inflammation and ROS leading to elevations of inflammatory cytokines (e.g., IL-6, IL-1β, and TNF-α) and the observation of downstream pro-thrombotic effects from these alterations (193, 198–202). Animal studies have shown that PM-exposure can result in elevated PAI-1 levels, decreased tPA expression, and increased thrombus formation as well as decreased thrombotic occlusion time (198, 199, 203–205).
PM can disrupt the autonomic nervous system, leading to sympathetic predominance and parasympathetic withdrawal, which can induce arrhythmias and increased blood pressure (BP) (206, 207). These alterations to hemodynamic stability result in increased peripheral vascular resistance and reduced cardiac output leading to hypertension, ischemia, and myocardial damage, especially in individuals with preexisting CVD. Epidemiological studies have demonstrated that increased concentrations PM2.5 are associated with increased BP, heart rate (HR), and decreased heart rate variability (HRV) (206, 207). Additionally, increased concentrations of elemental carbon, sulfate, ammonium, lead, and strontium within PM2.5 constituents were associated with higher elevations in BP and HR whereas increased concentrations of sulfate, ammonium, and strontium within PM2.5 constituents were associated with greater decreases in HRV (206, 208). PM-induced alterations to the autonomic nervous system are hypothesized to be the mechanism responsible for these hemodynamic changes, with some researchers suggesting that compounds within PM constituents, primarily sulfates, exacerbate these alterations. Further research into the pathophysiology of PM-induced autonomic dysfunction is needed to better understand these associations.
In summary particulate matter (PM) exposure contributes to cardiovascular dysfunction through various mechanisms. PM triggers inflammation, oxidative stress, and endothelial dysfunction, leading to atherosclerosis, impaired nitric oxide availability, and increased thrombosis. It also alters hemostasis and disrupts the autonomic nervous system, causing hypertension, arrhythmias, and other hemodynamic changes. These effects are particularly harmful to individuals with preexisting CVD. These changes underscore the need for further research to understand the full impact of PM on cardiovascular health.
Particulate matter, including that derived from wildfire smoke, initiates a temporally layered pathophysiologic cascade linking immune activation to vascular dysfunction and adverse cardiopulmonary outcomes. Within hours of exposure, inhaled PM deposits in the distal lung, activating alveolar macrophages and airway epithelial cells, triggering NF-κB–dependent cytokine release (e.g., IL-6, TNF-α) and oxidative stress (209). These mediators spill into the systemic circulation, promoting endothelial activation, reduced nitric oxide bioavailability, vasoconstriction, and heightened thrombogenicity, which are mechanisms that underlie acute increases in blood pressure, arrhythmogenesis, myocardial ischemia, and asthma exacerbations. Over days to weeks, sustained inflammatory signaling and autonomic imbalance reinforce endothelial dysfunction and impair vascular reactivity, amplifying susceptibility in individuals with preexisting cardiometabolic or pulmonary disease. Over time, repeated or chronic exposure drives persistent low-grade inflammation, vascular remodeling, arterial stiffness, and atherosclerotic plaque progression, thereby accelerating the trajectory toward heart failure, coronary artery disease, chronic obstructive pulmonary disease, and reduced lung function growth (140, 209, 210). Thus, immune activation serves as the mechanistic bridge connecting inhaled particles to vascular injury and cardiopulmonary morbidity across acute, subacute, and chronic time scales.
Exposure to PM and/or wildfire smoke-derived particles enriched with organic compounds, metals, and polycyclic aromatic hydrocarbons, can induce durable changes in immune function through epigenetic reprogramming. Inhaled particles generate oxidative stress and activate pattern-recognition receptors in airway epithelial cells and macrophages, initiating cytokine cascades that extend systemically. These inflammatory signals are accompanied by alterations in DNA methylation, histone modifications, and non-coding RNA expression in circulating immune cells and progenitor populations. Such epigenetic changes can shift transcriptional set points governing innate immune responsiveness, endothelial activation, and redox balance, effectively “training” or maladaptively priming the immune system toward heightened inflammatory reactivity. Over time, this persistent immune skewing may contribute to exaggerated responses to subsequent exposures, impaired resolution of inflammation, and sustained vascular dysfunction (140, 210).
During pregnancy, these processes intersect with fetal programming mechanisms. Maternal exposure to particulate matter can promote placental oxidative stress, altered nutrient transport, and inflammatory signaling that influence the developing fetal epigenome (211–213). The fetal immune and cardiovascular systems are particularly plastic, and epigenetic marks established in utero, such as differential methylation of genes regulating glucocorticoid signaling, cytokine production, or endothelial function, may persist postnatally. These molecular imprints can recalibrate baseline inflammatory tone, stress responsiveness, and metabolic regulation, thereby shaping long-term susceptibility to asthma, hypertension, and cardiometabolic disease. Importantly, the fetal period represents a window during which relatively modest environmental perturbations may have outsized and lifelong physiologic consequences.
Following early-life or repeated wildfire smoke exposure, persistent molecular alterations may extend beyond classical immune cells to include endothelial progenitors, hematopoietic stem cells, and even resident lung structural cells (214, 215). This broader reprogramming can sustain low-grade inflammation, impair vascular repair capacity, and alter lung growth trajectories. Epigenetic drift compounded by recurrent exposures across childhood and adulthood may reinforce maladaptive transcriptional networks, linking early immune programming to later-life cardiopulmonary pathology. Together, immune epigenetic programming and fetal programming provide a mechanistic framework for understanding how transient smoke events can translate into long-lasting molecular changes and cumulative disease risk across the life course.
Population vulnerability to air pollutants (in particular wildfire smoke) is shaped not only by acute exposure during fire events, but by the cumulative burden of repeated and chronic inhalation of fine particulate matter (PM2.5) and associated toxicants (216, 217). Children are particularly susceptible because of higher minute ventilation relative to body size, developing lungs and immune systems, and a longer lifetime horizon over which early inflammatory or epigenetic insults may exacerbate asthma, impaired lung growth, or cardiometabolic disease. Older adults face heightened risk due to age-related declines in pulmonary reserve, immunosenescence, and a greater prevalence of cardiovascular and metabolic comorbidities that amplify susceptibility to smoke-triggered ischemic events, arrhythmias, and heart failure exacerbations. Chronically exposed communities, including those in fire-prone regions, low-income areas with substandard housing, outdoor labor sectors, or regions already burdened by traffic-related air pollution, experience layered exposures that accumulate across seasons and years. This cumulative exposure burden interacts with social determinants of health, limited access to filtration or healthcare, and co-exposures such as heat and ozone, producing disproportionate respiratory and cardiovascular morbidity. A life-course and equity-focused framework is therefore essential to understand and mitigate the compounding health impacts of wildfire smoke across vulnerable populations.
As described above and in Figure 3, the impacts of PM and wildfire are vast and can affect many organ systems. While many have been greatly studied (including the impacts of PM and wildfire on the cardiovascular system), many others are not well described. The most common effect of both PM and wildfire exposure occurs through increased oxidative stress and inflammatory responses. These are mentioned in almost every organ system; however, the mechanism for how this impacts each organ system needs to be further studied. Nevertheless, much work has already been done to elucidate the mechanisms whereby these toxicants can impact various organ systems. With many similarities between PM and wildfire exposure effects, there is a concerning potential for a notable increase of these health effects as wildfires continue to become a large source of general PM.
Additional evidence is lacking regarding the effects of exposure to both PM and/or wildfire smoke during vulnerable periods of life, including during development (i.e. in utero exposure), in the elderly and during periods of compromised health. Much work has begun in these areas, but it remains only speculative on whether vulnerable individuals are further susceptible to disease upon exposure, and the potential mechanisms involved. In addition, many studies have not differentiated the sex-dependent effects of PM and/or wildfire smoke on the various organ systems, which compromises interpretation of the results. These studies are needed in order to truly understand the complex effects of PM and wildfire smoke on the human body in both males and females.
A key role in mitigating the effects of the air pollutants on health/disease is enacting strategies to reduce exposure. The recent COVID-19 pandemic has taught us that simple measures such as wearing a mask during everyday activities can limit the spread of viruses, but this measure can also protect from exposure to environmental toxicants. Further work must be done in order to reduce exposures to these toxicants through masks, reduced time in unfiltered areas, as well as the enforcement of policies to require exposure mitigation.