Free Radical Biology and Medicine 151 (2020) 56–68

Contents lists available at ScienceDirect

Free Radical Biology and Medicine

journal homepage: www.elsevier.com/locate/freeradbiomed

Air pollution and its effects on the immune system T

a,b a,b b a,∗,1
Drew A. Glencross , Tzer-Ren Ho , Nuria Camiña , Catherine M. Hawrylowicz ,
Paul E. Pfefferc,1
a
Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, London, SE1 9RT, UK
b
MRC Centre for Environment and Health, King's College London, Franklin Wilkins Building, London, SE1 9NH, UK
c
Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK

ARTICLE INFO ABSTRACT

Keywords: A well-functioning immune system is vital for a healthy body. Inadequate and excessive immune responses
Particulate matter underlie diverse pathologies such as serious infections, metastatic malignancies and auto-immune conditions.
Oxidative stress Therefore, understanding the effects of ambient pollutants on the immune system is vital to understanding how
Lymphocyte pollution causes disease, and how that pathology could be abrogated.
Dendritic cell
The immune system itself consists of multiple types of immune cell that act together to generate (or fail to
Macrophage
generate) immune responses and in this article we review evidence of how air pollutants can affect different
Respiratory virus
Asthma immune cell types such as particle-clearing macrophages, inflammatory neutrophils, dendritic cells that or-
COPD chestrate adaptive immune responses and lymphocytes that enact those responses. Common themes that emerge
are of the capacity of air pollutants to stimulate pro-inflammatory immune responses across multiple classes of
immune cell. Air pollution can enhance T helper lymphocyte type 2 (Th2) and T helper lymphocyte type 17
(Th17) adaptive immune responses, as seen in allergy and asthma, and dysregulate anti-viral immune responses.
The clinical effects of air pollution, in particular the known association between elevated ambient pollution and
exacerbations of asthma and chronic obstructive pulmonary disease (COPD), are consistent with these identified
immunological mechanisms. Further to this, as inhaled air pollution deposits primarily on the respiratory mu-
cosa this review focuses on mechanisms of respiratory disease. However, as discussed in the article, air pollution
also affects the wider immune system for example in the neonate and gastrointestinal tract. Whilst the many
identified actions of air pollution on the immune system are notably diverse, immunological research does
suggest potential strategies to ameliorate such effects, for example with vitamin D supplementation. An in-depth
understanding of the immunological effects of ambient pollutants should hopefully yield new ideas on how to
reduce the adverse health effects of air pollution.

1. Introduction multicellular immune responses, but first will examine those in-
tracellular signalling pathways that air pollution can trigger starting the
The primary site of exposure to air pollution is the respiratory tract cascade of immune dysfunction that leads to pollution-induced pa-
following inhalation. The respiratory tract, from nasal passages down thology.
through the airways to alveolar gas exchange units in the lungs re-
presents the prime interface between the immune system and the air- 1.1. Toxicity of particulate versus gaseous components of air pollution
borne environment. Inhaled particulates and gases interact with epi-
thelial cells lining the airways and professional immune cells within the Ambient urban air pollution consists of gaseous components and
airways. These cells sense and can be ‘stimulated’ by air pollution as particulate matter (PM). The former includes ozone (O3), volatile or-
pollution constituents trigger cellular signalling pathways. Stimulated ganic compounds (VOCs), carbon monoxide (CO) and nitrogen oxides
cells act as part of multicellular immune responses and perturbation of (NOx), and these are well-established as inflammatory stimuli on the
these can cause disease. In this review we will therefore examine the respiratory tract although the inflammatory effects of PM have been
effects of air pollution on individual cell types, and then effects on studied to a greater extent.

∗
Corresponding author. Asthma UK Centre in Allergic Mechanisms of Asthma, 5th Floor Tower Wing, Guy's Hospital, King's College London, London, SE1 9RT, UK.
E-mail address: [email protected] (C.M. Hawrylowicz).
1
joint senior authors.

https://doi.org/10.1016/j.freeradbiomed.2020.01.179
Received 31 October 2019; Received in revised form 21 January 2020; Accepted 22 January 2020
Available online 30 January 2020
0891-5849/ © 2020 Elsevier Inc. All rights reserved.
D.A. Glencross, et al. Free Radical Biology and Medicine 151 (2020) 56–68

Fig. 1. Immune cells at the respiratory epithe-

lium. The respiratory epithelium lies in close
proximity to various immune cells, including
alveolar macrophages, dendritic cells, T cells,
innate lymphoid cells and granulocytes. Under
homeostasis these cells in combination provide
defence against infection, whilst limiting tissue
damage and promoting a tolerogenic environ-
ment. However, PM has been reported to induce
a proinflammatory phenotype in these cells. The
respiratory epithelium, as a primary point of
contact as PM enters the airways, is proposed to
play a central role in these events. The proin-
flammatory effects of PM (represented by red
arrows) can be both through direct PM-cell
contact and also through indirect mediator re-
lease that can signal to adjacent cells. (For in-
terpretation of the references to colour in this
figure legend, the reader is referred to the Web
version of this article.)

PM itself can be divided into fractions dependent on particle size, 1.2. Lung immunology at the interface
known as the aerodynamic equivalent diameter (AED), for example
PM10, PM2.5 and Ultra-Fine Particulate Matter (UFPM). Particles larger The adult lung inhales approximately 11,000 L of air per day, po-
than 10 μm are unlikely to enter lower airways as they will mostly be sitioning the respiratory epithelium for exposure to high volumes of
filtered by the nose and upper airways, whilst PM10, PM2.5 and UFPM pathogenic and environmental insults. The respiratory mucosa is
reach the lower airways [1]. Particles with a smaller AED are thought to therefore well adapted to both facilitate gaseous exchange and respond
penetrate and deposit into the deeper airways such as the terminal to such insults efficiently, with minimal damage to host tissue. The
bronchioles and alveoli, whilst the larger particles (PM10) will deposit respiratory mucosa consists of respiratory tract lining fluids; bronchial
in the more proximal conducting airways [2]. Primary particulate and alveolar epithelial cells; tissue resident immune cells such as al-
matter is generated by fuel combustion (importantly including diesel veolar macrophages (AM), dendritic cells, innate lymphoid cells and
exhaust particles (DEP)), wear on road-surface and brakes, re-sus- granulocytes; as well as adaptive memory T and B lymphocytes. Under
pended crustal matter (dust from the earth's crust) and organic matter homeostasis these cells cooperate with commensal bacteria and one
such as pollen. Secondary PM is formed by photo-chemical reactions of another via cytokine and cell-cell signalling to maintain a tolerogenic
PM in the atmosphere, with the nucleation of pollutant gases such as environment, as represented in Fig. 1. A growing body of evidence,
ammonium nitrate and sulphur dioxide. PM has a complex composition discussed in this review, suggests that this homeostasis can be disrupted
– it contains metals, elemental carbon and organic carbon (both in by air pollution. AMs and human bronchial epithelial cells (HBECs) are
hydrocarbons and peptides), sulphates and nitrates, as well as other ideally situated as the first cells to encounter air pollution. Literature
constituents [3,4]. Importantly the composition of ambient PM varies reviewed here suggests that pollutants can also activate the underlying
both geographically and temporally being dependent on the mix of immune cells and this can be both indirect, through HBEC/AM acti-
sources at any location at any given time. vation and subsequent mediator release, as well as direct.
Historically it has been the particulate component of air pollution
that was thought to be most important in causing disease and the ma-
1.3. Pollution and mechanisms of immune cell stimulation
jority of laboratory immunotoxicology studies of air pollution (in-
cluding the majority discussed below) have investigated reference
Pollution constituents stimulate cells through a variety of cellular
urban PM. This theory has been challenged recently, for example
sensing mechanisms including Toll-Like Receptors (TLRs), reactive
Wooding et al. have shown that particulate-depleted diesel exhaust
oxygen species (ROS) sensing pathways and poly-aromatic hydrocarbon
(DE) is still capable of providing an immunological adjuvant effect
(PAH) sensing pathways such as the aryl hydrocarbon receptor. These
despite the absence of PM itself [5,6]. Surprisingly, particulate deple-
in turn activate pro-inflammatory intracellular signalling cascades such
tion (via filtration) led to an increase in NO2.
as NFkB and MAPK pathways [9].
Nitrogen dioxide (NO2) is a particularly relevant component of
TLRs are a type of cellular receptor designed to sense pathogen-
ambient air pollution considering that it is the ambient pollutant tar-
associated molecular patterns (PAMPs) of potentially infectious micro-
geted in many national environmental health policies. NO2 is a tracer of
organisms and also other similar noxious stimuli, and it is notable that
traffic-related air pollution but is toxic itself and can combine with high
pollution can trigger these receptors. The ability of urban PM to sti-
O3 levels and VOCs in the atmosphere, producing highly promiscuous
mulate cells through TLRs is thought to be due to the particles con-
oxidants such as hydroxyl radicals (•OH), peroxyl radicals (HOO•) and
taining microbial molecules such as lipopolysaccharide (LPS) and
singlet oxygen (1O2) [7]. The tropospheric O3 in this reaction is another
fungal spores, that are natural ligands for TLRs, and also particles in-
highly oxidative agent, produced as a photochemical product of am-
ducing production of host-derived molecules that can act as alternative
bient air pollution with well-documented effects on the bronchial epi-
agonists for TLRs, such as oxidised phospholipids and nucleic acids
thelium. The atmospheric presence of NO2 and O3 becomes particularly
(from cellular damage). LPS stimulates cells through Toll-Like Receptor
pertinent when considering the depletion of respiratory tract lining
4 (TLR4) and PM has been shown to stimulate cells through the TLR4
fluid (RTLF) antioxidant defences that is evident in the airways of
pathway [10]. However, PM can also stimulate airway epithelial cells
susceptible individuals, such as those with asthma [8].
through TLR2 [11] and the proportion of PM induced cell stimulation

57
D.A. Glencross, et al. Free Radical Biology and Medicine 151 (2020) 56–68

that is through different TLRs may differ between different cell types considering the recent discoveries regarding endogenous AhR ligands,
and different types of PM. Shoenfelt et al. investigated the dependency in the form of tryptophan metabolites, and a newfound role of the AhR
upon different TLRs of PM stimulated macrophage responses induced in barrier immunity [22,23]. This gives the AhR the capacity to evoke
by PM10 and PM2.5 [10]. TLR4 knock-out mice had diminished re- either protective or harmful effects in a ligand-dependant manner.
sponses to PM10 while no difference was seen between wild-type con- Furthermore, the AhR is capable of cross talk with various in-
trols and TLR2 knock-out mice. The opposite pattern of TLR de- flammatory and antioxidant transcription factors, such as RORγt,
pendency was seen with the PM2.5. STAT1, Nrf2 and NFκB [19]. PAHs within air pollution may be able to
PM can generate free-radical oxidants (reactive oxygen species) in disrupt this transcription factor and barrier homeostasis through AhR-
both cellular and acellular experimental systems, and ambient parti- ligand competition and dysregulation.
culate matter is well known to cause oxidative stress and reduction of
endogenous antioxidants [4]. The induction of oxidative stress by PM is 1.4. Limitations of pollution toxicology in vitro cell culture studies
thought to be caused by both the heavy metal and organic compound
components of PM. Organic compounds present in PM, or formed by Although in vitro experiments are important for understanding the
cellular metabolism of PM, can donate electrons to O2 molecules to potential toxicology of air pollution, important issues concerning pol-
form superoxide free-radicals. Transition metals can similarly donate lution exposure in cell culture experiments and animal models may
electrons to form superoxide and hydrogen peroxide, and can directly limit the messages that can be drawn from these experiments. PM
deplete endogenous thiol antioxidants. Oxidative stress can induce concentrations of 5 μg/ml to 100 μg/ml are typically used in cell culture
NFκB and AP-1 signaling, as well as transcription of genes containing experiments [24], and depending on culture dish diameter, PM per cm2
the antioxidant-responsive element (ARE) promoter [12], however the surface deposition can vary considerably. These concentrations show
exact mechanisms are not fully elucidated. significant effects but whether they are representative of the density of
Nrf2 is the major transcription factor acting on ARE promoter se- PM deposited in the airway is questionable. In particular the con-
quences to enhance expression of antioxidant genes. Nrf2 action is centrations used in vitro may correspond to much higher deposition
regulated by the protein Keap1, which binds intra-cytoplasmic Nrf2 and than that seen in vivo. Li et al. have attempted to reconcile theoretical
inhibits its translocation to the nucleus to act on ARE sequences. Keap1 and experimental deposition, postulating increased deposition at
has a high cysteine content and one possible sensing mechanism for airway bifurcation points with uneven air flow in airways disease [25].
oxidative stress is that reactive oxygen species directly modify these However, cross-talk between airway macrophages and epithelial cells
cysteine residues, reducing binding of Keap1 to Nrf2, allowing trans- may also increase the sensitivity of the airways to lower, more realistic,
location of Nrf2 to the nucleus [13]. As well as enhancing expression of concentrations of inhaled particulate matter [26,27]. Similar issues
antioxidant pathways, Nrf2 also interacts with the NFκB and MAPK exist for pollutant exposure dosing in animal models.
signalling pathways. There is also evidence that reactive oxygen species PM is naturally inhaled as a particulate suspension in the air, itself
can directly affect cellular calcium channels and thereby perturb in- also containing pollutant gases, that deposits in the airway, passing
tracellular ion signalling [14]. Intracellular Ca2+ is an important through respiratory tract lining fluid (RTLF) before interacting with
second messenger signalling system and for example can affect the airway cells. The collection of PM on filters and re-suspension in a li-
NFκB pathway, as well as airway smooth muscle contraction. Brown quid is problematic and may not fully capture the toxicity of inhaled
et al. have shown that calcium antagonists can decrease PM10 stimu- PM. Lichtveld et al. compared the effect on IL8 and PTGS2 (encoding
lated production of TNFα by human monocytes, and the ability of COX-2) expression by A549 pulmonary epithelial cells of diesel emis-
conditioned medium from the monocyte cultures to stimulate CXCL8 sion particulate matter from an outdoor smog chamber that was either
chemokine production by A549 pulmonary epithelial cells [15]. Fur- applied directly to the cell cultures (using the Electrostatic Aerosol in
thermore, Yarova et al. indicate that extracellular calcium increases can Vitro Exposure System, EAVES) or that was collected on filters, re-
facilitate airway smooth muscle contraction and hyper-responsiveness suspended in medium containing bovine serum albumin and then ap-
in mice, in a calcium sensing receptor (CaSR) dependent manner [16]. plied to cell cultures [28]. They found direct PM exposure (using
PM may be a source of such elevated Ca2+ in the airways, particularly EAVES) at 2.65 μg/cm2 induced significantly increased expression of
considering the often high concentrations within PM. IL8 and PTGS2 whereas re-suspended PM at 2.65 μg/cm2 did not induce
As well as activating pro-inflammatory pathways, reactive oxygen increased expression of either gene. Re-suspended PM at much higher
species can cause toxicity by directly damaging cellular proteins and concentration did induce increased IL8 but not PTGS2 expression, po-
DNA. Oxidative stress generates intracellular danger signals that can tentially reflecting a dosing issue or qualitative differences in deposited
induce inflammasome responses – for example Hirota et al. have shown PM. Additionally, the protein composition of cell culture medium,
that PM can induce NLRP3 inflammasome responses in epithelial cells, compared to RTLF, is likely to strongly influence the effects of PM in
including production of IL-1β [17]. cell culture as the particles are coated by a bioactive protein corona
PM contains complex organic poly-aromatic hydrocarbon (PAH) formed from the medium/RTLF. The protein corona of particles in
molecules and these can induce oxidative stress. Cells have specific different media is profoundly different [29].
mechanisms for sensing PAHs, namely the aryl hydrocarbon receptor Given these limitations it is important to consider whether clinical
(AhR) which is a cytosolic environmentally sensing receptor, first dis- data support the mechanistic data, and this is considered in the next
covered as a ligand for dioxin and extensively reviewed by Stockinger section.
et al. [18,19]. Binding of PAH ligands triggers nuclear translocation and
induction of xenobiotic metabolising enzymes such as CYP1A1 and 2. Effects of air pollution and oxidative stress on different cell
CYP1B1 and these, in turn, produce more cytotoxic/genotoxic products. types of the immune system
The toxicity of PAHs is supported by research from den Hartigh et al. in
which they have shown that addition of an AhR antagonist, a-naph- The immune system is comprised of multiple types of dedicated
thoflavone, to monocyte cultures can decrease PM stimulated TNFα, immune cell. These have different roles in immunity and work co-
indicating that this PM-stimulated pro-inflammatory cytokine release is operatively with each other and also other (non-professional) cells in
somewhat regulated by AhR signalling [20]. Indeed, it is PAHs speci- the body such as barrier-lining epithelial cells. The ‘first responder’
fically within DEPs that have been argued as the predominant causal immune cells in the lungs are innate immune cells in the airways, such
factor in genotoxicity, indicating that DNA damage is dictated by PAH as alveolar macrophages and neutrophils, that can respond rapidly to
levels above other factors such as metal-derived ROS [21]. This re- inhaled pathogens. Dendritic cells underlie the epithelial lining cells
sponse becomes much more important in air pollution pathogenesis and can sample the airway lumen, triggering complex adaptive immune

58
D.A. Glencross, et al. Free Radical Biology and Medicine 151 (2020) 56–68

Fig. 2. The effects of air pollution on cell types of the immune system.

responses when they encounter pathogens. All these cell types have levels of air pollution, or a consequence of their disease pathology that
been shown to also respond to air pollutants (Fig. 2). leaves them particularly susceptible to pollutant oxidative damage.
Upon inhalation PM is likely coated in the RTLF in a protein corona
that will affect its immunological actions. One study, which in-
2.1. Respiratory tract lining fluid vestigated particle protein coronas upon healthy human RTLF incuba-
tion with either silica or poly(vinyl) acetate nanoparticles, found that
The first line of defence against airborne particulates and pathogens surfactant and complement proteins were amongst the most abundant
within the respiratory tract is the respiratory tract lining fluid (RTLF). particle-associated proteins and both of these types of protein have
RTLF contains a variety of secretions from lung epithelial and immune immunological actions [37]. Further to this, nanoparticle surfactant
cells, as well as plasma derived factors. These include low-molecular- interaction has previously been reported to significantly affect in vitro
weight antioxidants (ascorbate, α-tocopherol, urate, GSH); antioxidant alveolar cell infection by influenza A with particles potentially reducing
enzymes (superoxide dismutase, catalase, glutathione peroxidase, metal the capacity of surfactant to neutralise infection [38].
binding proteins); and substances that can opsonise foreign particles
(mucins, complement, surfactant, immunoglobulins) aiding their
clearance from the airways [30]. Collectively these protect the under- 2.2. Epithelial and parenchymal cells
lying airways and parenchyma. The respiratory tract is coated
throughout with RTLF, although the composition between the upper The bronchial airways are lined by epithelial cells. They have sev-
and lower airways differs significantly – importantly the amount of eral functions - they form a physical barrier facing the airway lumen,
antioxidant GSH present in the bronchoalveolar region is significantly produce a mucous lining of respiratory tract lining fluid, sense dan-
higher when compared with the upper respiratory tract [30]. Exposure gerous biological and anthropogenic particles depositing on the airway
to various components of air pollution leads to significant reductions in wall and by ciliary action help to clear particles from the airway.
RTLF antioxidant status. Ozone exposure decreases ascorbate and GSH Importantly, in response to sensing dangerous particles they produce
levels in RTLF from healthy individuals, though antioxidant status is many key cytokines, chemokines and other signalling molecules, in-
recovered 6-h post-exposure [31]. Antioxidant treatment can also pre- cluding IL-6, CXCL8 and GM-CSF which promote airway inflammation.
vent ozone-stimulated FEV1 impairment, though not concurrent neu- GM-CSF is notably important in the submucosa. It facilitates the ma-
trophilia [32]. Furthermore, NO2 is able to deplete ascorbate and urate turation of myeloid DCs, promotes monocyte differentiation into
in human RTLF samples ex vivo [33]. Nasal lavage fluid of healthy in- monocyte-derived DCs and is necessary for granulocyte survival, whilst
dividuals exposed to ambient pollution at underground train sites dis- its role in foetal alveolar macrophage development is indispensable
played significantly increased levels of the iron binding protein, lacto- [39]. Numerous in vitro cell culture studies have shown that human
ferrin, when compared with those individuals exposed to traffic sites – bronchial epithelial cells (HBECs) stimulated with pollutant extracts
likely as a result of the high metal composition [34]. Considering this, produce increased amounts of pro-inflammatory cytokines, including
individuals with respiratory conditions such as asthma, cystic fibrosis IL-1α, IL-1β, IL-6, IL-8 and GM-CSF [24].
and COPD display compromised antioxidant statuses within their RTLF These pollution-induced cytokine responses are clinically relevant.
[8,35,36]. However, it is currently unclear if the decline in antioxidant For example, in vivo PM exposure increases both local and systemic IL-6
status amongst patients with respiratory disease is caused by increased concentrations, and in murine models Kido et al. have shown elevation

59
D.A. Glencross, et al. Free Radical Biology and Medicine 151 (2020) 56–68

of bronchoalveolar lavage levels of IL-6 as early as 4 h after PM ex- can stimulate pro-inflammatory cytokine production by macrophages
posure [40]. This is accompanied by elevated levels of IL-6 in the sys- [24]. Cytokines, particularly TNFα and IL-1β, produced by macro-
temic circulation, most likely ‘spill-over’ from the lungs. Thompson phages can also stimulate epithelial cells and prime them for enhanced
et al. have shown systemic IL-6 levels in human volunteers positively responses to stimulation. Fujii et al. (2002) [26] and Ishii et al. (2005)
correlate with preceding pollution levels [41]. However, the patholo- [27] have both shown that co-cultures of PM-stimulated epithelial cells
gical contribution of epithelial-derived IL-6, as opposed to alveolar and AMs produce much higher levels of pro-inflammatory cytokines
macrophage-derived IL-6, in response to PM is uncertain. Regardless of such as IL-6 and GM-CSF than single cell type cultures - the effect is
cell-type responsible for pollution-induced IL-6, it has important im- more than additive suggesting a synergistic pro-inflammatory re-
munological actions. It stimulates pro-inflammatory responses and as lationship between AMs and epithelial cells.
discussed further below can inhibit regulatory responses. Kido et al. Macrophages are not a single class of cell – they show considerable
have further shown PM exposure in wild-type mice to be associated heterogeneity and tissue specific differentiation, for example Kupffer
with vascular dysfunction (impaired abdominal aorta relaxation re- cells in the liver and alveolar macrophages in the lungs [57]. They can
sponses to acetylcholine) but not in IL-6 knock-out mice [40]. Mutlu be subdivided, for example in to M1 and M2 macrophages, although the
et al. have reported pathologically increased blood coagulation in a nomenclature of macrophage subtypes is inconsistent and still debated
murine model of the cardiovascular effects of PM exposure, and simi- [58]. There is a paucity of research on whether air pollution may in-
larly reported that this was dependent on IL-6 production [42]. fluence macrophage subtype differentiation in the lungs.
More recently, Weng et al. have revealed that upon DEP exposure,
ex vivo cultured bronchial biopsies from asthmatics exhibited increased 2.4. Dendritic cells and lymphocytes – response to oxidative stress
epithelial-derived cytokine secretion including thymic stromal lym-
phopoietin (TSLP), IL-33 and IL-25 in an AhR-dependent manner [43]. Lymphocytes, both T and B cells, within the adaptive arm of the
These alarmin cytokines are strongly associated with airway hyper-re- immune system show immunological memory for specific antigens and
sponsiveness, allergic airway disease progression and submucosal in- can ‘learn’ to either tolerate new benign antigens, to generate highly-
flammatory infiltrate. Further to this, De Grove et al. discovered that effective immune responses to new pathological stimuli or, on occasion,
prophylactic treatment of mice with the recombinant, soluble IL-33 to cause inappropriate immune activation leading to pathology, for
decoy receptor (ST2) was able to impair the capacity of DEP to ex- example to allergens. All of those immune responses vary in character
acerbate allergic airway inflammation – strongly implicating IL-33 in (often termed the Th1/Tc1, Th2/Tc2 and Th17/Tc17 arms of the
the progression of DEP-induced respiratory exacerbations [44]. adaptive immune response) and are tailored to be optimally effective to
When investigating the gaseous component of air pollution, Devalia fight each specific pathological stimulus. For example, generating a
et al. found through in vitro studies that 6-h exposure of 400 ppb NO2, to Th1/Tc1 immune response to intracellular viral infections, rather than
primary human bronchial epithelial cells (HBECs) led to significant a Th2-predominant response that would be less effective in this situa-
production of GM-CSF, CXCL8 and tumour necrosis factor alpha (TNF- tion.
α) [45]. This supports previous reports of NO2 causing bronchocon- Dendritic cells form a link between the innate and the adaptive arm
striction and hyper-responsiveness in healthy and asthmatic airways; as of the immune system, recognising antigens through the expression of
well as generating a pro-allergic, Th2 inflammatory environment in innate receptors such as TLR, and then processing and presenting
healthy airways following repeated exposure [46]. Moreover, NO2 in- fragments of these antigens bound to major histocompatibility proteins
creases Th2 associated cytokines in healthy bronchial epithelium, (MHC antigen complexes) on their cell surface to T lymphocytes that
whilst increasing ICAM-1 expression and stimulating persistent neu- then deliver an effector response. Dendritic cells also express a range of
trophilia [46]. Changes in ICAM-1 expression could exacerbate re- costimulatory molecules and secrete soluble mediators. It is the manner
spiratory infections as it is a major receptor for both rhinovirus and or context in which dendritic cells present antigen to T lymphocytes -
respiratory syncytial virus [47,48]. Furthermore, NO2 increased HBEC the amount of peptide, the profile of costimulatory molecules and cy-
production of leukotriene C4 (LTC4) and arachidonic acid in vitro – lipid tokines that they express - that in major part determines the character
mediators which are well established in asthma pathogenesis and of the lymphocyte response and whether that is tolerogenic (reg-
airway hyper-responsiveness [49]. Findings such as these situate NO2 as ulatory), Th1 or Th2 for example. Given this close partnership we
a significant contributor towards pollution induced asthmatic exacer- consider these cell types together.
bations, particularly as NO2 lung deposition within primates largely There is an established scientific literature on the effects of oxida-
occurs within the conducting airways in which asthma pathology pre- tive stress itself on T lymphocyte responses (reviewed by Elahi and
sents [50]. Similarly, ozone can also stimulate production of pro-in- Metata, 2008 [59]). Oxidative stress and redox status have been shown
flammatory cytokines such as CXCL8, GM-CSF, and TNF-α, by epithelial to significantly influence antigen presenting cell (APC)-stimulated T cell
cells [51]. responses. For example, Kim et al. have shown that glutathione de-
pletion (which increases oxidative stress) decreases co-stimulatory
2.3. Macrophages molecule and IL-12 expression by lipopolysacharide (LPS) stimulated
DCs, and T cell proliferation [60]. Similarly, Peterson et al. found GSH
Alveolar macrophages (AMs) are a major population of immune (reduced glutathione) depletion to decrease antigen-stimulated IFNγ
cells in the airways in health and disease. One of their major functions production in mice without any decrease in IL-4 production [61].
is to phagocytose particulates and certain types of microbes in the Fraternale et al. studied the effect of glutathione state on T lym-
lungs, an initial step in their removal from the lungs. AMs can also phocyte responses in ovalbumin-sensitised mice [62]. In vivo treatment
phagocytose carbonaceous particles and this has therefore been sug- of the mice with pro-GSH molecules (decreasing oxidative stress) in-
gested as a possible biomarker for pollution exposure [52,53]. PM laden duced skewing of the T lymphocyte response towards a Th1 response
AMs are known to display decreased motility and mucociliary clear- (as indicated by levels of different anti-ovalbumin IgG isotypes and
ance, particularly in the case of chronic dust inhalation studies [54]. proportion of splenocytes producing IFNγ).
Overladen macrophages have impaired function. The extent of airway In summary these studies suggest that oxidative stress, acting on
macrophage carbon loading has also been inversely associated with both APCs and T cells, affects T1/T2 balance, favouring T2 responses.
lung function measures in healthy children and positively associated
with adverse cardiovascular outcomes, such as increases in oxidised 2.5. Dendritic cells and lymphocytes – response to air pollution
low-density lipoproteins [55,56].
Similar to epithelial cells there is a wealth of research showing PM PM is proposed to act on antigen-presenting cells (APCs), such as

60
D.A. Glencross, et al. Free Radical Biology and Medicine 151 (2020) 56–68

dendritic cells (DCs), as an adjuvant increasing the immunogenicity of production in murine splenocyte cultures [74].
antigens. Multiple studies have shown PM-stimulation of dendritic cells In addition to PM, NO2 exposure has been found to exacerbate
to increase DC maturation (for example expression of CD80 and MHC- airway inflammation in rats, particularly through the induction of a
II) and pro-inflammatory cytokine release [63,64]. PM stimulation also Th1/Th2 imbalance in favour of the latter [75]. Ji et al. reported that
promotes DC expression of CCR7 which directs lymph-node homing IFNγ and T-bet expression was decreased in rat lungs, whilst GATA-3
[65]. and IL-4 were increased following NO2 exposure, skewing towards an
Enhanced DC maturation, leads to enhanced T lymphocyte re- allergic airway phenotype [75].
sponses as has been reported by several research groups. For example, Poly-aromatic hydrocarbon (PAH) molecules within air pollution
Porter et al. found DEP treatment of DCs to result in enhanced T cell may be able to stimulate the AhR, as suggested by Weng et al. [43]. The
cytokine production in DC/CD4 lymphocyte allogeneic co-cultures AhR has an emerging fundamental role in the maintenance and function
[63]. Similarly, Bleck et al. showed TSLP and GM-CSF produced by of Th17/type 3 innate lymphoid cell (ILC3) responses at epithelial sites,
DEP–stimulated epithelial cells acts on DCs to promote maturation and particularly in response to infection and wound healing under home-
their ability to prime a T cell response [66,67]. In particular, these ostasis [76,77]. Together, this places the AhR as a potentially key factor
HBEC derived cytokines promoted DCs to prime a Th2 response. shaping the immune response to air pollution and may be particularly
However, other cell culture studies have highlighted that the actions relevant in Th17-skewed severe steroid refractory asthmatics [78,79].
of PM on DCs and lymphocytes are more complex. In studies with naive Most mechanistic research into the effects of air pollutants on
T cells, Matthews et al. showed urban PM (UPM) treated GM-CSF-sti- adaptive immunology, as reviewed above, has focussed on T lympho-
mulated DCs enhanced naive CD4 T cell proliferation in a mixed leu- cytes. B lymphocytes are another cell type important in adaptive im-
cocyte reaction (MLR) but with a reduced proportion of IFNγ-producing mune responses and upon stimulation they mature into im-
effectors (Th1 cells) [64]. Follow-up research with naïve CD8 T cells in munoglobulin antibody secreting plasma cells. Immunoglobulins (Ig)
mixed leucocyte reactions showed PM-stimulated DCs to enhance the themselves can be divided into different classes termed IgA, IgD, IgE,
IFNγ-producing response by CD8 T cells [65], suggesting different im- IgG and IgM. IgA is particularly important in mucosal defence and there
munomodulatory effects of PM-exposed DC on CD4 and CD8 T cells. is emerging evidence that suggests air pollution may be associated with
Further research has also shown profound effects of PM on DC-sti- effects on immunoglobulin production. For example, Zhao and collea-
mulated memory CD4 T cell responses. In particular, Matthews and gues have investigated immunoglobulin levels in traffic policemen in
colleagues have shown PM-treated DCs to stimulate a memory CD4 Shanghai, exposed to high levels of PM2.5, and found PM2.5 exposure to
response characterised by IFNγ and IL-17A co-production [68], sug- be associated with a decrease in IgA and increases in IgM, IgG and IgE
gestive of a pathological Th17.1 response [69]. [80]. In a house dust mite (HDM) sensitised mouse model, Castañeda
Murine models of instillation of particulate matter, or DEP, into the et al. have reported higher relative IgE gene expression in the lungs of
lungs of mice confirm it can affect the adaptive immune response and mice exposed to PM in addition to HDM challenge, compared with mice
promote allergic lymphocyte responses. For example, Saunders et al. challenged with HDM alone [81]. Consistent with this, in a human
compared the effects of PM on airway responses in lymphocyte-defi- nasal challenge model Diaz-Sanchez et al. have shown exposure to DEP
cient Rag1−/− knock-out mice and wild-type mice [70]. Although in vivo is associated in a dose-dependent manner with increased con-
PM-induced recruitment of macrophages into the lungs was similar in centrations of IgE in nasal wash fluid 4 days after challenge [82].
both groups of mice, PM-induced airways hyper-responsiveness (AHR)
and mucus cell hyperplasia were significantly decreased in Rag1−/− 2.6. Granulocytes
mice, implying it to be lymphocyte dependent. Brandt and colleagues
have examined T cell subset responses in a DEP challenge murine model Granulocytes such as neutrophils and eosinophils, are innate im-
and found DEP-exposure to stimulate a Th17 response [71]. DEP and mune cells that can detect foreign matter and pathogens via pattern
allergen co-exposure produced a mixed Th2 and Th17 response. Ad- recognition receptors (PRRs) such as TLRs. They contain granules of
ditionally, they found an association between high serum IL-17A con- enzymes such as proteases and oxidases that enable them to kill pa-
centrations and higher DEP exposure in a cohort of children with thogens but can also degrade connective tissue. This functionality
asthma. however positions them as significant threat to healthy tissue.
Moreover, Gour et al. determined that inhalation of urban PM from Neutrophils are a particularly important granulocyte when con-
both New York City and Baltimore could stimulate Th2 and Th17 in- sidering air pollution pathogenesis. They are the most abundant leu-
flammation in the airways of mice, with Baltimore PM evoking more kocytic cell in the blood and are rapidly recruited to inflammatory sites.
potent airway inflammation and hyper-responsiveness – potentially They express nicotinamide adenine dinucleotide phosphate (NADPH)
reflecting higher PM metal content [72]. This inflammation was con- oxidase and myeloperoxidase enzymes, capable of producing oxidant
comitant with airway hyper-responsiveness, inflammatory infiltrate superoxide anions (O2•-) and hypochlorous acid (HOCl), respectively
and cytokine release (IL-5, IL-13, IFNγ and IL-17A), whilst reference [83]. The presence of these oxidants upon neutrophil activation mean
particulates such as carbon black, DEP and coal fly ash were not capable that any transition metals present, such as those within PM, can cata-
of such inflammatory outcomes. Findings such as these emphasise the lyse further redox cycling and therefore oxidative damage within bio-
importance of utilising real-world urban PM when investigating adverse logical systems. Iron is one major constituent of PM and can also cat-
health effects of air pollution, whilst demonstrating that atmospheric alyse the Fenton reaction in which hydrogen peroxide, generated by
modifications may render PM more toxic. dismutation of NADPH generated O2•-, is converted into •OH – a reac-
Despite the importance of these findings there is relatively little tion which becomes particularly crucial when considering the disparity
research on the effect of PM directly on T cells. Sasaki et al. have re- in iron content of underground railway PM with ambient PM [84,85].
ported that DEP can directly affect intracellular signalling pathways The evidence of neutrophilic activation upon pollution exposure is well
and expression of transcription factors in T lymphocytes [73]. These documented, although studies investigating direct mechanistic effects
changes were associated with reduced expression of the genes for IFNγ of air pollution and PM upon neutrophil function are lacking.
and IL-10 but no significant suppression of the genes for Th2 cytokines, Human exposure studies have revealed an increase in the produc-
perturbing the Th1/Th2 balance. The addition of the antioxidant N- tion of IL-8 and CXCL1 (neutrophil attracting chemokines) in healthy
acetylcysteine reduced the effect of DEP, indicating an important role airways following diesel exhaust exposure [86,87]. This response was
for oxidative stress in these experiments. The effect of PM/DEP on IL-17 concomitant with increased neutrophil and mast cell infiltrate into the
production by T cells has been somewhat overlooked in the literature, bronchial mucosa, whilst exposure to ozone also increases this neu-
although Nakamura et al. have shown DEP to increase IL-17A trophilic infiltrate [88]. McCreanor et al. have shown that ambient

61
D.A. Glencross, et al. Free Radical Biology and Medicine 151 (2020) 56–68

Table 1
Dysregulation of immune tolerance and antimicrobial responses by air pollution.
Dysregulation of Immune Tolerance Dysregulation of Antimicrobial
& Antiviral Immunity

Stimulation of production of pro-inflammatory cytokines and leucocyte-attracting chemokines by Overladen macrophages with diminished phagocytic capacity
epithelial cells and macrophages

Adjuvant action of PM increases APC maturation and antigen expression NO2 increases epithelial expression of ICAM-1 (receptor for respiratory
viruses)

Suppression by pro-inflammatory cytokines (such as IL-6) of regulatory T cell responses Dysregulated IFNγ production by T cells

Protein oxidation leading to formation of neo-antigens Development of a Th2 biased inflammatory environment inappropriate to
microbial airway infection

diesel traffic pollution in central London facilitated a significant in- manner and that AhR agonists, such as dioxin, can lead to exacerbated
crease in neutrophilic inflammation (sputum myeloperoxidase) in 31 MC activation [96]. It may be the case that PAHs within air pollution
mild and 29 moderate asthmatic adults, in comparison with the same are able to cause a similar dysregulation of MC homeostasis in humans.
measurements following lower level background pollution exposure in Overall these studies suggest that granulocytes are important in
Hyde Park [89]. Fitting with these observations, healthy individuals airway pathology following air pollution exposure however more re-
exposed to NO2, display significant neutrophilia in bronchial wash search is needed. Furthermore, there is increasing interest in how
samples alongside increased MPO – observations that were simulta- granulocytes can shape the adaptive immune environment, including
neous with decreased lung function (FEV1 and FVC) [90]. This was the ability to express MHC class II molecules in some cases, as well as
counteracted through the induction of an antioxidant response upon immunoregulatory roles [97] – this could make their responses to
repeated exposures – a possibly unattainable response in individuals components of air pollution much more influential in disease progres-
with compromised antioxidant status. Despite this battery of evidence sion than previously thought.
for neutrophil involvement in air pollution pathogenesis, it is unclear if
neutrophil dysfunction is causative or symptomatic, and more me- 3. Effects of air pollution of immune responses
chanistic studies are required.
Eosinophils are effector cells that are characteristic of a Th2 re- Whilst examining the effects of air pollution on individual immune
sponse. Despite being central to asthma pathogenesis, the effects of cell types can highlight potential mechanisms by which our environ-
pollution upon eosinophilic inflammation have not been extensively ment causes pathology, individual immune cell types do not function in
investigated. Nevertheless, there is suggestive evidence that pollution isolation. It is dysfunction of multicellular immune responses that
can lead to changes in eosinophil homeostasis. For example, Søyseth causes disease. In health the immune system must respond effectively to
et al. have reported exposure of atopic children to higher levels of infections and neoplastic cells, with a response tailored to the insult,
ambient SO2 and fluoride to be associated with increased bronchial but must tolerate (i.e. not respond harmfully to) the healthy body and
hyper-responsiveness and decreased blood eosinophils [91]. The latter benign environmental influences. Diseases can result from inadequate
would be consistent with pollution triggering recruitment of eosino- responses to infectious microbes allowing fulminant infections, in-
phils from the blood to the respiratory tract. Similarly, Janssen et al. appropriate/excessive immune responses to microbes leading to more
have reported an association between increased serum eosinophilic (collateral) damage than the microbe itself, and inappropriate immune
cationic protein (ECP) and surrogate measures of truck traffic-related responses to self/environment. In the following sections we will discuss
air pollution exposure in children though no association with blood evidence that air pollution can cause disease by perturbing these multi-
eosinophil count [92]. The association was with truck traffic, implying cellular immune responses (Table 1). We will discuss these in the
that DEP exposure could be causative of the increased eosinophil acti- context of the airway diseases of asthma and COPD given that the
vation. Furthermore, recently, non-allergic eosinophilic nasal in- airway is a prime interface between the body and ambient environ-
flammation and disruption of epithelial homeostasis was reported by ment, and that both types of immune dysfunction contribute to these
Ramanathan et al. in mice exposed to PM2.5 over a period of 16 weeks, diseases.
indicating that prolonged PM2.5 exposure is capable of inducing eosi-
nophilic inflammation similar to that reported in asthmatics [93]. 3.1. Regulation and prevention of inappropriate immune responses
Mast cells (MCs) are another cell type similar to basophil granulo-
cytes and have an established and central role in immune responses to The ability of the immune system to distinguish between harmless
allergen and airway hyper-responsiveness. This is particularly true of self (including beneficial commensal microbes and harmless environ-
the tissue resident MCs in the immediate, acute phase of allergic airway mental antigens) and dangerous non-self (both infectious microbes and
disease. They express high levels of the IgE receptor, FceRI, and release neoplastic cells) is central to its function. It is vital for health that the
histamine, chymase, tryptase, eicosanoids and cytokines upon en- body only targets effector immune responses against harmful stimuli
counter of IgE-opsonised antigens [94]. Salvi et al. reported that there is and neither attacks itself nor innocuous, harmless antigens. The ma-
a significant increase in MC numbers in the bronchial submucosa 6 h jority of cases of asthma are characterised by reactions to inhaled aero-
following diesel exhaust challenge, although the source of this in- allergens such as pollens. Although many of these allergens do have
creased MC population is unclear [86]. Consistent with this Nemmar some proteolytic action they are generally in themselves harmless.
et al. have also reported that DEP exposure in hamsters led to sig- Pathological airways inflammation in asthma arises because the body
nificant histamine increases within broncho-alveolar lavage (BAL) and mounts a harmful Th2 immune response to these allergens rather than a
plasma potentially from basophils and mast cells – a response cir- healthy tolerogenic response to inhaled allergen – the immune response
cumvented with dexamethasone pre-treatment [95]. Interestingly the causes the pathology rather than the allergens themselves [98]. In
corticosteroid pre-treatment in this model also decreased DEP-induced COPD there is increasing evidence that the pathology, in part, may
experimental vascular thrombus formation. Zhou et al. propose that the result from an inappropriate immune response to self, in particular to
AhR controls murine MC homeostasis in a calcium and ROS-dependent matrix components such as elastin in the airways [99]. In both

62
D.A. Glencross, et al. Free Radical Biology and Medicine 151 (2020) 56–68

conditions there are inappropriate immune responses due to a failure to evidence that alarmin cytokine secretion by epithelial cells following
regulate immune responses to antigens that should be tolerated. The viral stimulation and promotion of Th2 responses (largely ineffective at
question therefore arises of whether air pollution can perturb reg- clearing viral infection) over effective Th1 immune responses, together
ulatory immune pathways to cause disease? Below we discuss evidence underlie the inflammatory exacerbations [115,116]. It is therefore
that air pollution can cause disease through such a mechanism. Failure concerning that pollutants have been shown capable of contributing to
of immune tolerance can result from either failure of regulatory path- these pathological mechanisms, as reviewed above.
ways, or the development of modified self-antigens that the immune This is consistent with clinical evidence from time-series studies of
system no longer recognises as self. There is suggestive evidence that associations between day-to-day ambient concentrations of air pollu-
pollutants could impair immune tolerance through both mechanisms. tants and exacerbations of asthma and COPD. Although the exact as-
A pro-inflammatory cytokine milieu in the lungs after inhalation of sociations reported vary from study-to-study, likely reflecting differ-
ambient pollution may be particularly important for perturbing im- ences in exacerbation definitions and pollutant mixes at different study
mune regulation. For example, IL-6 can block the capacity of regulatory sites, these studies do consistently show significant associations. For
T cells to suppress proliferation of stimulated T cells [100] and IL-6 has example meta-analyses have confirmed associations between elevated
also been shown to modulate lymphocyte responses in disease. There- ambient particulate matter and worsening of lung function in patients
fore, pollution-stimulated pro-inflammatory cytokines in concert with with COPD [117], between COPD exacerbations and both ambient
up-regulated presentation of antigens on pollution-stimulated DCs (as particulate matter and ambient pollutant gasses [118], and similarly for
discussed in preceding sections) may well act to block tolerogenic im- asthma exacerbations with elevated ambient pollutants [119,120]. The
mune responses, facilitating development of excessive immune re- epidemiologic evidence for associations between ambient pollution and
sponses, for example to inhaled allergens. Indeed Nadeau and collea- airways exacerbations is stronger than for associations with develop-
gues have reported an association between ambient air pollution, ment of chronic airways disease.
epigenetic changes in regulatory T cells and impaired regulatory However, exacerbations do not all have the same aetiology and
function [101]. different types of exacerbation can be characterised, such as those as-
The additional action of air pollution to potentially favour Th2 and sociated with infection and those not [121]. Pfeffer and colleagues re-
Th17 immune responses (as discussed above) is consistent with the cently studied the London COPD Cohort, comparing onset of char-
aberrant Th2 immune responses seen in allergic asthma and Th17 im- acterised exacerbations to ambient pollutants, and found the most
mune responses evident in subsets of patients with severe asthma and consistent association to be between ambient NOx and exacerbations
COPD [78,79,102]. characterised as of viral-type, supporting the mechanisms discussed
Post-translational modification of potential auto-antigens is a key above [122].
step in breaking self-tolerance in many autoimmune diseases and an-
tigen oxidation is one of the major post-translational modifications in 4. Examining the wider context
auto-immune disease [103,104]. Oxidative and nitrosative stress from
air pollutants can cause protein oxidation and other types of post- 4.1. Neonatal immunity
translational modifications to both self [105,106] and aero-allergen
peptides [107,108], enhancing their immunogenicity. Recognised environment related risks factors for the development
Therefore, these mechanisms identified in cell culture and animal and progression of asthma in early life are recurrent wheeze caused by
models are consistent with epidemiologic evidence of an association inappropriate responses to respiratory viral infection and early allergic
between exposure to air pollution and prevalence of asthma and auto- sensitization [123]. However, the risk for development of chronic
immune diseases. For example, meta-analysis of epidemiologic studies airway disease is increasingly thought to start in utero. Pregnancy and
provides evidence of significant associations between pollution ex- infancy may reflect a window of vulnerability for detrimental en-
posures and development of asthma [109]. Similarly an association vironmental effects, and recent evidence demonstrates the presence of
between ambient pollution and development of rheumatoid arthritis ambient particulates in the placenta and developing foetus [124]. An
has been reported although this association has not been consistently increasing body of evidence indicates that exposure to ambient air
evident across similar studies [110]. Evidence for associations between pollution in utero and early life is associated with asthma development
different autoimmune diseases and air pollution is an area of active in the child [125]. These effects have been reported globally, ranging
research. from studies using data from the Great Smog of London in 1952 [126]
to others including in the USA [127,128], Canada [129], and China
3.2. Antimicrobial immune responses [130]. These studies of traffic-related pollutants variously link NO,
NO2, CO, black carbon, PM2.5, PM10 and SO2 with elevated asthma risk.
Whilst the development of asthma and COPD may be due to failure Geographical location, associated with distinct pollutant compositions,
of immune tolerance and development of unwarranted immune re- are likely to deliver distinct exposure profiles and relative risks. At least
sponses in the airways, the majority of exacerbations of both allergic 2 studies indicate this risk is higher in male children [127,130]. The
asthma and COPD are precipitated by respiratory tract infections and a impact of gender on asthma risk in childhood is recognised, however
failure of the lungs to mount a warranted effective immune response. In the mechanisms for increased risk associated with ambient air pollution
particular in the lungs of patients with asthma and COPD upon re- are as yet unclear.
spiratory tract infection an immune response is mounted but one which Early life is characterised by increased susceptibility to infectious
is ineffective at clearing the pathogen and instead causes harm to the challenge and the requirement in utero to maintain maternal-foetal
patient [111], As discussed above there is significant mechanistic evi- tolerance [131]. Maternal exposure to air pollution has been shown to
dence that pollution may contribute to these aberrant antimicrobial affect the neonatal immune system. For example, Baïz and colleagues
immune responses. Inhaled NO2 enhances epithelial expression of CD54 have examined the effect of pollution exposure in pregnancy on neo-
(ICAM-1), which is required for adhesion of certain respiratory tract natal cord blood lymphocyte subpopulations and found a negative as-
viruses (e.g. rhinovirus, respiratory syncytial virus) to the epithelium sociation between PM10 exposure and the proportion of lymphocytes
[47,48,112]. Impaired macrophage function including impaired pha- found to be CD25 expressing CD4 T cells [132]. A similar association
gocytosis of airway pathogens is a particular feature of COPD and the was evident with ambient exposure to the VOC benzene [132]. In ad-
capacity of ambient particulate matter to contribute to that may be dition, it is likely that as in adults the capacity of ambient pollution to
important in the pathology [113]. In asthma macrophage dysfunction impair antimicrobial mechanisms required for pathogen clearance and
has also been reported [114]. However, in asthma there is increasing enhance Th2/IgE responses associated with allergic sensitization is

63
D.A. Glencross, et al. Free Radical Biology and Medicine 151 (2020) 56–68

important [133]. However, an effect of air pollution on the neonatal 4.3. Relation with the wider exposome
immune system is not the only mechanism by which early life pollution
exposure may lead to future asthma. Exposure to air pollution detri- It is important to consider the immunological effects of inhaled
mentally impacts lung development in children. For example, within ambient air pollution in the context of wider environmental factors
London's Low Emission Zone (LEZ), a smaller lung volume in children known to affect health. Tobacco smoking ‘pollutes’ the air inhaled by
was associated with higher annual air pollutant exposure [134], a smokers and those around them with a mixture of particulate and
finding that is mirrored by findings in other cities globally including gaseous components, and itself leads to lung pathology. Research has
across Europe [135] and the USA [136,137]. Impaired airway function shown non-redundant pathological effects of air pollution and smoking.
as early as shortly after birth predicts airflow limitation in early adult There is evidence at the level of transcriptomics of a biological effect of
life, which in turn is a strong predisposing factor for asthma and chronic air pollution over and above cigarette smoke [150,151]. Individuals
obstructive pulmonary disease in later life, highlighting the early ori- with smoking-related chronic obstructive lung disease (COPD) are also
gins of disease [138]. These data are further supported by exposure particularly vulnerable to adverse health effects of air pollution.
studies in mice demonstrating decreased number of alveoli and reduced Vitamin D is another environmental factor extensively investigated
lung function following pre- and post-natal exposure to PM2.5 [139]. in studies of airway immunopathology [152]. The combination of living
close to a major road and vitamin D deficiency has been shown to
particularly increase risk of asthma exacerbations [153]. There is evi-
4.2. Gastrointestinal tract & systemic effects dence of a mechanistic association between the two environmental
factors. For example, vitamin D can enhance epithelial antioxidant
Whilst the clear site of air pollution pathology is the respiratory pathways and decrease the pro-inflammatory effects of PM [154]. Vi-
tract and to a slightly lesser degree, the cardiovascular system, there are tamin D can also ameliorate the pathological effects of PM in experi-
other target organs whose immune homeostasis could be significantly mental dendritic cell stimulated T cell immune reactions [69]. Pro-
perturbed by air pollution. One example of this is the gastrointestinal spective studies of the capacity of vitamin D to decrease pollution-
(GI) tract. Mucociliary clearance within the conducting airways carries induced immunotoxicology have not yet to our knowledge been con-
out the effect of escalating mucous-bound pathogens and debris to pass ducted but interventions of this type may be future options to reduce
into the oesophagus, to then be excreted through the GI tract. Currently the harm from air pollution. It is important to note that although the
very few research groups have investigated the effect of PM upon the composition of polluted air has changed over the decades there is on-
human intestinal epithelium and immunological homeostasis. An as- going evidence of harm to health from current air pollution and that
sociation between increases in ambient air pollution and inflammatory this harm may well be worsening rather than decreasing [122].
bowel disease (IBD) hospitalisations has previously been reported by
Ananthakrishnan and colleagues [140]. However, another study found 5. Conclusions
no association between air pollution exposure as a whole, whilst ex-
posures to NO2 and SO2 may be associated with a risk of early onset IBD Ambient pollutants can directly trigger cellular signalling pathways,
[141]. Following such epidemiological studies, some research has been and both cell culture studies and animal models have shown profound
carried out in animal models. Mutlu et al. established that mice gavaged effects of air pollutants on every type of immune cell studied. In ad-
with a high dose of urban PM had increased gut permeability (with dition to the general pro-inflammatory nature of these effects, many of
decreased ZO-1 tight junction expression), alongside increases in IL-6 these studies suggest an action of air pollution to augment Th2 immune
expression and colonic epithelial cell apoptosis [142]. Further to this, responses and perturb anti-microbial immune responses. Consistent
mice gavaged with ambient PM10 for 7–14 days displayed significantly with these mechanistic immunological actions, elevated air pollution is
increased pro-inflammatory cytokine expression, with simultaneous associated with increased exacerbations of asthma – a disease char-
increased intestinal epithelial permeability [143]. Long-term treatment acterised by an underlying Th2 immuno-pathology in the airways with
(35 days) also altered intestinal microbiota and short chain fatty acid severe viral-induced exacerbations. Although the clinical effects are
homeostasis and these effects were significantly exacerbated in IL-10 consistent with the identified experimental immunological actions of
knockout mice [143]. Also, considering the pioneering studies carried air pollutants, the relative importance of specific immunological actions
out by the Stockinger group and subsequent work investigating the role and of different ambient pollutants to clinical pathology remains un-
of the AhR within intestinal barrier immunity, the GI tract becomes an certain. This is the next key question. Deeper understanding of these
inviting area of research with regards to PM-induced disruption of immunological actions in vivo may support new strategies to reduce the
barrier homeostasis [23,76,144]. PAHs within ambient pollution may harm to health from air pollution, for example potentially supple-
be able to significantly disrupt the balance between commensal bacteria menting susceptible individuals with vitamin D or anti-oxidants. Future
derived AhR ligands and the epithelial Th17/regulatory T cell equili- mechanistic studies will also assist in shaping governmental policies to
brium. reduce air pollution sources with particularly immunomodulatory
Inhaled ambient pollutants also have further systemic pro-in- characteristics.
flammatory actions, in addition to the organ-specific actions discussed
above. These systemic pro-inflammatory effects can result from several Funding
different mechanistic pathways. Pro-inflammatory cytokines produced
in the pollution-exposed lung can ‘spill-over’ into the systemic circu- The authors declare no competing interests and there was no spe-
lation resulting in increases in serum mediators such as IL-6, IL-1β, GM- cific funding for this review.
CSF; increased neutrophil and platelet numbers; as well as endothelial
dysfunction and arterial vasoconstriction [86,145,146]. Inhaled parti- Appendix A. Supplementary data
cles can also stimulate neurogenic pathways with potential systemic
effects [147]. There is also evidence that ultra-fine particulate matter Supplementary data to this article can be found online at https://
can translocate the alveolar membrane in to the systemic circulation, doi.org/10.1016/j.freeradbiomed.2020.01.179.
depositing in other parts of the body with local pro-inflammatory ef-
fects [148,149]. Inflammatory factors such as these are particularly References
thought to contribute to the association of air pollution with cardio-
vascular and cerebrovascular disease. [1] J.O. Anderson, J.G. Thundiyil, A. Stolbach, Clearing the air: a review of the effects
of particulate matter air pollution on human health, J. Med. Toxicol. 8 (2) (2012)

64
D.A. Glencross, et al. Free Radical Biology and Medicine 151 (2020) 56–68

166–175. marrow, Am. J. Respir. Cell Mol. Biol. 27 (2002) 34–41.

[2] G. Oberdorster, E. Oberdorster, J. Oberdorster, Nanotoxicology: an emerging [27] H. Ishii, S. Hayashi, J.C. Hogg, T. Fujii, Y. Goto, N. Sakamoto, H. Mukae,
discipline evolving from studies of ultrafine particles, Environ. Health Perspect. R. Vincent, S.F. van Eeden, Alveolar macrophage-epithelial cell interaction fol-
113 (7) (2005) 823–839. lowing exposure to atmospheric particles induces the release of mediators in-
[3] M.R. Heal, P. Kumar, R.M. Harrison, Particles, air quality, policy and health, volved in monocyte mobilization and recruitment, Respir. Res. 6 (2005) 87.
Chem. Soc. Rev. 41 (19) (2012) 6606–6630. [28] K.M. Lichtveld, S.M. Ebersviller, K.G. Sexton, W. Vizuete, I. Jaspers, H.E. Jeffries,
[4] A.J. Ghio, M.S. Carraway, M.C. Madden, Composition of air pollution particles and In vitro exposures in diesel exhaust atmospheres: resuspension of PM from filters
oxidative stress in cells, tissues, and living systems, J. Toxicol. Environ. Health B versus direct deposition of PM from air, Environ. Sci. Technol. 46 (16) (2012)
Crit. Rev. 15 (1) (2012) 1–21. 9062–9070.
[5] D.J. Wooding, M.H. Ryu, A. Huls, A.D. Lee, D.T.S. Lin, C.F. Rider, A.C.Y. Yuen, [29] A. Kumar, B. Forbes, I. Mudway, E.M. Bicer, L.A. Dailey, What are the biological
C. Carlsten, Particle depletion does not remediate acute effects of traffic-related air and therapeutic implications of biomolecule corona formation on the surface of
pollution and allergen. A randomized, double-blind crossover study, Am. J. Respir. inhaled nanomedicines? Nanomedicine (Lond.) 10 (3) (2015) 343–345.
Crit. Care Med. 200 (5) (2019) 565–574. [30] A. van der Vliet, C.A. O'Neill, C.E. Cross, J.M. Koostra, W.G. Volz, B. Halliwell,
[6] J.A. Bosson, I.S. Mudway, T. Sandstrom, Traffic-related air pollution, health, and S. Louie, Determination of low-molecular-mass antioxidant concentrations in
allergy: the role of nitrogen dioxide, Am. J. Respir. Crit. Care Med. 200 (5) (2019) human respiratory tract lining fluids, Am. J. Physiol. 276 (2) (1999) L289–L296.
523–524. [31] A.F. Behndig, A. Blomberg, R. Helleday, S.T. Duggan, F.J. Kelly, I.S. Mudway,
[7] P.L.H. Edgar, R. Stephens, Robert C. Doerr, William E. Scott, Reactions of nitrogen Antioxidant responses to acute ozone challenge in the healthy human airway,
dioxide and organic compounds in air, Ind. Eng. Chem. 48 (9) (1955) 1498–1504. Inhal. Toxicol. 21 (11) (2009) 933–942.
[8] F.J. Kelly, I. Mudway, A. Blomberg, A. Frew, T. Sandstrom, Altered lung anti- [32] J.M. Samet, G.E. Hatch, D. Horstman, S. Steck-Scott, L. Arab, P.A. Bromberg,
oxidant status in patients with mild asthma, Lancet 354 (9177) (1999) 482–483. M. Levine, W.F. McDonnell, R.B. Devlin, Effect of antioxidant supplementation on
[9] S. Muralidharan, P. Mandrekar, Cellular stress response and innate immune sig- ozone-induced lung injury in human subjects, Am. J. Respir. Crit. Care Med. 164
naling: integrating pathways in host defense and inflammation, J. Leukoc. Biol. 94 (5) (2001) 819–825.
(6) (2013) 1167–1184. [33] F.J. Kelly, T.D. Tetley, Nitrogen dioxide depletes uric acid and ascorbic acid but
[10] J. Shoenfelt, R.J. Mitkus, R. Zeisler, R.O. Spatz, J. Powell, M.J. Fenton, not glutathione from lung lining fluid, Biochem. J. 325 (Pt 1) (1997) 95–99.
K.A. Squibb, A.E. Medvedev, Involvement of TLR2 and TLR4 in inflammatory [34] M. Steenhof, I.S. Mudway, I. Gosens, G. Hoek, K.J. Godri, F.J. Kelly, R.M. Harrison,
immune responses induced by fine and coarse ambient air particulate matter, J. R.H. Pieters, F.R. Cassee, E. Lebret, B.A. Brunekreef, M. Strak, N.A. Janssen, Acute
Leukoc. Biol. 86 (2) (2009) 303–312. nasal pro-inflammatory response to air pollution depends on characteristics other
[11] S. Becker, L. Dailey, J.M. Soukup, R. Silbajoris, R.B. Devlin, TLR-2 is involved in than particle mass concentration or oxidative potential: the RAPTES project,
airway epithelial cell response to air pollution particles, Toxicol. Appl. Pharmacol. Occup. Environ. Med. 70 (5) (2013) 341–348.
203 (1) (2005) 45–52. [35] I. Rahman, W. MacNee, Lung glutathione and oxidative stress: implications in
[12] J.G. Scandalios, Oxidative stress: molecular perception and transduction of signals cigarette smoke-induced airway disease, Am. J. Physiol. 277 (6) (1999)
triggering antioxidant gene defenses, Braz. J. Med. Biol. Res. 38 (2005) 995–1014. L1067–L1088.
[13] T.W. Kensler, N. Wakabayashi, S. Biswal, Cell survival responses to environmental [36] R.K. Brown, H. Wyatt, J.F. Price, F.J. Kelly, Pulmonary dysfunction in cystic fi-
stresses via the Keap1-Nrf2-ARE pathway, Annu. Rev. Pharmacol. Toxicol. 47 brosis is associated with oxidative stress, Eur. Respir. J. 9 (2) (1996) 334–339.
(2007) 89–116. [37] A. Kumar, E.M. Bicer, A.B. Morgan, P.E. Pfeffer, M. Monopoli, K.A. Dawson,
[14] J.I. Kourie, Interaction of reactive oxygen species with ion transport mechanisms, J. Eriksson, K. Edwards, S. Lynham, M. Arno, A.F. Behndig, A. Blomberg,
Am. J. Physiol. 275 (1998) C1–C24. G. Somers, D. Hassall, L.A. Dailey, B. Forbes, I.S. Mudway, Enrichment of im-
[15] D.M. Brown, L. Hutchison, K. Donaldson, V. Stone, The effects of PM10 particles munoregulatory proteins in the biomolecular corona of nanoparticles within
and oxidative stress on macrophages and lung epithelial cells: modulating effects human respiratory tract lining fluid, Nanomedicine 12 (4) (2016) 1033–1043.
of calcium-signaling antagonists, Am. J. Physiol. Lung Cell Mol. Physiol. 292 (6) [38] Z. McKenzie, M. Kendall, R.M. Mackay, T.D. Tetley, C. Morgan, M. Griffiths,
(2007) L1444–L1451. H.W. Clark, J. Madsen, Nanoparticles modulate surfactant protein A and D
[16] P.L. Yarova, A.L. Stewart, V. Sathish, R.D. Britt Jr., M.A. Thompson, P.L. AP, mediated protection against influenza A infection in vitro, Philos. Trans. R. Soc.
M. Freeman, B. Aravamudan, H. Kita, S.C. Brennan, M. Schepelmann, T. Davies, Lond. B Biol. Sci. 370 (1661) (2015) 20140049.
S. Yung, Z. Cholisoh, E.J. Kidd, W.R. Ford, K.J. Broadley, K. Rietdorf, W. Chang, [39] B. Becher, S. Tugues, M. Greter, GM-CSF: From growth factor to central mediator
M.E. Bin Khayat, D.T. Ward, C.J. Corrigan, T.W. JP, P.J. Kemp, C.M. Pabelick, of tissue inflammation, Immunity 45 (5) (2016) 963–973.
Y.S. Prakash, D. Riccardi, Calcium-sensing receptor antagonists abrogate airway [40] T. Kido, E. Tamagawa, N. Bai, K. Suda, H.H. Yang, Y. Li, G. Chiang, K. Yatera,
hyperresponsiveness and inflammation in allergic asthma, Sci. Transl. Med. 7 H. Mukae, D.D. Sin, S.F. Van Eeden, Particulate matter induces translocation of IL-
(284) (2015) 284ra60. 6 from the lung to the systemic circulation, Am. J. Respir. Cell Mol. Biol. 44 (2)
[17] J.A. Hirota, S.A. Hirota, S.M. Warner, D. Stefanowicz, F. Shaheen, P.L. Beck, (2011) 197–204.
J.A. Macdonald, T.L. Hackett, D.D. Sin, S. Van Eeden, D.A. Knight, The airway [41] A.M. Thompson, A. Zanobetti, F. Silverman, J. Schwartz, B. Coull, B. Urch,
epithelium nucleotide-binding domain and leucine-rich repeat protein 3 in- M. Speck, J.R. Brook, M. Manno, D.R. Gold, Baseline repeated measures from
flammasome is activated by urban particulate matter, J. Allergy Clin. Immunol. controlled human exposure studies: associations between ambient air pollution
129 (4) (2012) 1116–11125 e6. exposure and the systemic inflammatory biomarkers IL-6 and fibrinogen, Environ.
[18] P.A. Bertazzi, D. Consonni, S. Bachetti, M. Rubagotti, A. Baccarelli, C. Zocchetti, Health Perspect. 118 (1) (2010) 120–124.
A.C. Pesatori, Health effects of dioxin exposure: a 20-year mortality study, Am. J. [42] G.M. Mutlu, D. Green, A. Bellmeyer, C.M. Baker, Z. Burgess, N. Rajamannan,
Epidemiol. 153 (11) (2001) 1031–1044. J.W. Christman, N. Foiles, D.W. Kamp, A.J. Ghio, N.S. Chandel, D.A. Dean,
[19] B. Stockinger, P. Di Meglio, M. Gialitakis, J.H. Duarte, The aryl hydrocarbon re- J.I. Sznajder, G.R. Budinger, Ambient particulate matter accelerates coagulation
ceptor: multitasking in the immune system, Annu. Rev. Immunol. 32 (2014) via an IL-6-dependent pathway, J. Clin. Invest. 117 (10) (2007) 2952–2961.
403–432. [43] C.M. Weng, C.H. Wang, M.J. Lee, J.R. He, H.Y. Huang, M.W. Chao, K.F. Chung,
[20] L.J. den Hartigh, M.W. Lame, W. Ham, M.J. Kleeman, F. Tablin, D.W. Wilson, H.P. Kuo, Aryl hydrocarbon receptor activation by diesel exhaust particles med-
Endotoxin and polycyclic aromatic hydrocarbons in ambient fine particulate iates epithelium-derived cytokines expression in severe allergic asthma, Allergy 73
matter from Fresno, California initiate human monocyte inflammatory responses (11) (2018) 2192–2204.
mediated by reactive oxygen species, Toxicol. Vitro : Int. J. Publ. Assoc. BIBRA 24 [44] K.C. De Grove, S. Provoost, H. Braun, E.E. Blomme, A.R. Teufelberger, O. Krysko,
(7) (2010) 1993–2002. R. Beyaert, G.G. Brusselle, G.F. Joos, T. Maes, IL-33 signalling contributes to
[21] M. Kowalska, A. Wegierek-Ciuk, K. Brzoska, M. Wojewodzka, S. Meczynska- pollutant-induced allergic airway inflammation, Clin. Exp. Allergy 48 (12) (2018)
Wielgosz, J. Gromadzka-Ostrowska, R. Mruk, J. Ovrevik, M. Kruszewski, 1665–1675.
A. Lankoff, Genotoxic potential of diesel exhaust particles from the combustion of [45] J.L. Devalia, A.M. Campbell, R.J. Sapsford, C. Rusznak, D. Quint, P. Godard,
first- and second-generation biodiesel fuels-the FuelHealth project, Environ. Sci. J. Bousquet, R.J. Davies, Effect of nitrogen dioxide on synthesis of inflammatory
Pollut. Res. Int. 24 (31) (2017) 24223–24234. cytokines expressed by human bronchial epithelial cells in vitro, Am. J. Respir.
[22] T. Zelante, R.G. Iannitti, C. Cunha, A. De Luca, G. Giovannini, G. Pieraccini, Cell Mol. Biol. 9 (3) (1993) 271–278.
R. Zecchi, C. D'Angelo, C. Massi-Benedetti, F. Fallarino, A. Carvalho, P. Puccetti, [46] S. Pathmanathan, M.T. Krishna, A. Blomberg, R. Helleday, F.J. Kelly,
L. Romani, Tryptophan catabolites from microbiota engage aryl hydrocarbon re- T. Sandstrom, S.T. Holgate, S.J. Wilson, A.J. Frew, Repeated daily exposure to 2
ceptor and balance mucosal reactivity via interleukin-22, Immunity 39 (2) (2013) ppm nitrogen dioxide upregulates the expression of IL-5, IL-10, IL-13, and ICAM-1
372–385. in the bronchial epithelium of healthy human airways, Occup. Environ. Med. 60
[23] F.J. Quintana, A.S. Basso, A.H. Iglesias, T. Korn, M.F. Farez, E. Bettelli, (11) (2002) 892–896.
M. Caccamo, M. Oukka, H.L. Weiner, Control of T(reg) and T(H)17 cell differ- [47] J.M. Greve, G. Davis, A.M. Meyer, C.P. Forte, S.C. Yost, C.W. Marlor,
entiation by the aryl hydrocarbon receptor, Nature 453 (7191) (2008) 65–71. M.E. Kamarck, A. McClelland, The major human rhinovirus receptor is ICAM-1,
[24] S. Mitschik, R. Schierl, D. Nowak, R.A. Jorres, Effects of particulate matter on Cell 56 (5) (1989) 839–847.
cytokine production in vitro: a comparative analysis of published studies, Inhal. [48] Z. Matsuzaki, Y. Okamoto, N. Sarashina, E. Ito, K. Togawa, I. Saito, Induction of
Toxicol. 20 (4) (2008) 399–414. intercellular adhesion molecule-1 in human nasal epithelial cells during re-
[25] N. Li, M. Hao, R.F. Phalen, W.C. Hinds, A.E. Nel, Particulate air pollutants and spiratory syncytial virus infection, Immunology 88 (4) (1996) 565–568.
asthma - a paradigm for the role of oxidative stress in PM-induced adverse health [49] J.L. Devalia, R.J. Sapsford, D.R. Cundell, C. Rusznak, A.M. Campbell, R.J. Davies,
effects, Clin. Immunol. 109 (2003) 250–265. Human bronchial epithelial cell dysfunction following in vitro exposure to ni-
[26] T. Fujii, S. Hayashi, J.C. Hogg, H. Mukae, T. Suwa, Y. Goto, R. Vincent, S.F. van trogen dioxide, Eur. Respir. J. 6 (9) (1993) 1308–1316.
Eeden, Interaction of alveolar macrophages and airway epithelial cells following [50] E. Goldstein, N.F. Peek, N.J. Parks, H.H. Hines, E.P. Steffey, B. Tarkington, Fate
exposure to particulate matter produces mediators that stimulate the bone and distribution of inhaled nitrogen dioxide in rhesus monkeys, Am. Rev. Respir.

65
D.A. Glencross, et al. Free Radical Biology and Medicine 151 (2020) 56–68

Dis. 115 (3) (1977) 403–412. C. Schiering, B. Stockinger, The environmental sensor AHR protects from in-
[51] C. Rusznak, J.L. Devalia, R.J. Sapsford, R.J. Davies, Ozone-induced mediator re- flammatory damage by maintaining intestinal stem cell homeostasis and barrier
lease from human bronchial epithelial cells in vitro and the influence of nedo- integrity, Immunity 49 (2) (2018) 353–362 e5.
cromil sodium, Eur. Respir. J. 9 (11) (1996) 2298–2305. [77] S. Li, J.W. Bostick, J. Ye, J. Qiu, B. Zhang, J.F. Urban Jr., D. Avram, L. Zhou, Aryl
[52] T. Terashima, B. Wiggs, D. English, J.C. Hogg, S.F. van Eeden, Phagocytosis of hydrocarbon receptor signaling cell intrinsically inhibits intestinal group 2 innate
small carbon particles (PM10) by alveolar macrophages stimulates the release of lymphoid cell function, Immunity 49 (5) (2018) 915–928 e5.
polymorphonuclear leukocytes from bone marrow, Am. J. Respir. Crit. Care Med. [78] D.F. Choy, K.M. Hart, L.A. Borthwick, A. Shikotra, D.R. Nagarkar, S. Siddiqui,
155 (4) (1997) 1441–1447. G. Jia, C.M. Ohri, E. Doran, K.M. Vannella, C.A. Butler, B. Hargadon, J.C. Sciurba,
[53] Y. Bai, R.E. Brugha, L. Jacobs, J. Grigg, T.S. Nawrot, B. Nemery, Carbon loading in R.L. Gieseck, R.W. Thompson, S. White, A.R. Abbas, J. Jackman, L.C. Wu,
airway macrophages as a biomarker for individual exposure to particulate matter J.G. Egen, L.G. Heaney, T.R. Ramalingam, J.R. Arron, T.A. Wynn, P. Bradding,
air pollution - a critical review, Environ. Int. 74 (2015) 32–41. TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma, Sci.
[54] P.E. Morrow, Possible mechanisms to explain dust overloading of the lungs, Fund. Transl. Med. 7 (301) (2015) 301RA129.
Appl. Toxicol. 10 (3) (1988) 369–384. [79] E.S. Chambers, A.M. Nanzer, P.E. Pfeffer, D.F. Richards, P.M. Timms,
[55] L. Jacobs, J. Emmerechts, M.F. Hoylaerts, C. Mathieu, P.H. Hoet, B. Nemery, A.R. Martineau, C.J. Griffiths, C.J. Corrigan, C.M. Hawrylowicz, Distinct en-
T.S. Nawrot, Traffic air pollution and oxidized LDL, PloS One 6 (1) (2011) e16200. dotypes of steroid-resistant asthma characterized by IL-17A and IFN-gamma im-
[56] N. Kulkarni, N. Pierse, L. Rushton, J. Grigg, Carbon in airway macrophages and munophenotypes: potential benefits of calcitriol, J. Allergy Clin. Immunol. 136 (3)
lung function in children, N. Engl. J. Med. 355 (1) (2006) 21–30. (2015) 628–637 e4.
[57] S. Gordon, P.R. Taylor, Monocyte and macrophage heterogeneity, Nat. Rev. [80] J. Zhao, Z. Gao, Z. Tian, Y. Xie, F. Xin, R. Jiang, H. Kan, W. Song, The biological
Immunol. 5 (12) (2005) 953–964. effects of individual-level PM(2.5) exposure on systemic immunity and in-
[58] P.J. Murray, J.E. Allen, S.K. Biswas, E.A. Fisher, D.W. Gilroy, S. Goerdt, S. Gordon, flammatory response in traffic policemen, Occup. Environ. Med. 70 (6) (2013)
J.A. Hamilton, L.B. Ivashkiv, T. Lawrence, M. Locati, A. Mantovani, F.O. Martinez, 426–431.
J.L. Mege, D.M. Mosser, G. Natoli, J.P. Saeij, J.L. Schultze, K.A. Shirey, A. Sica, [81] A.R. Castaneda, C.F.A. Vogel, K.J. Bein, H.K. Hughes, S. Smiley-Jewell,
J. Suttles, I. Udalova, J.A. van Ginderachter, S.N. Vogel, T.A. Wynn, Macrophage K.E. Pinkerton, Ambient particulate matter enhances the pulmonary allergic im-
activation and polarization: nomenclature and experimental guidelines, Immunity mune response to house dust mite in a BALB/c mouse model by augmenting Th2-
41 (1) (2014) 14–20. and Th17-immune responses, Phys. Rep. 6 (18) (2018) e13827.
[59] M.M. Elahi, B.M. Matata, Functional adaptation to oxidative stress by memory T [82] D. Diaz-Sanchez, A.R. Dotson, H. Takenaka, A. Saxon, Diesel exhaust particles
cells: an analysis of the role in the cardiovascular disease process, Biochem. induce local IgE production in vivo and alter the pattern of IgE messenger RNA
Biophys. Res. Commun. 376 (3) (2008) 445–447. isoforms, J. Clin. Invest. 94 (1994) 1417–1425.
[60] H.J. Kim, B. Barajas, R.C. Chan, A.E. Nel, Glutathione depletion inhibits dendritic [83] J.M. Robinson, Phagocytic leukocytes and reactive oxygen species, Histochem.
cell maturation and delayed-type hypersensitivity: implications for systemic dis- Cell Biol. 131 (4) (2009) 465–469.
ease and immunosenescence, J. Allergy Clin. Immunol. 119 (5) (2007) [84] A. Seaton, J. Cherrie, M. Dennekamp, K. Donaldson, J.F. Hurley, C.L. Tran, The
1225–1233. London Underground: dust and hazards to health, Occup. Environ. Med. 62 (6)
[61] J.D. Peterson, L.A. Herzenberg, K. Vasquez, C. Waltenbaugh, Glutathione levels in (2005) 355–362.
antigen-presenting cells modulate Th1 versus Th2 response patterns, Proc. Natl. [85] F. Kelly, J. Fussel, Size, source and chemical composition as determinants of
Acad. Sci. U. S. A 95 (1998) 3071–3076. toxicity attributable to ambient particulate matter, Atmos. Environ. 60 (2012)
[62] A. Fraternale, M.F. Paoletti, S. Dominici, A. Caputo, A. Castaldello, E. Millo, 504–526.
E. Brocca-Cofano, M. Smietana, P. Clayette, J. Oiry, U. Benatti, M. Magnani, The [86] S. Salvi, A. Blomberg, B. Rudell, F. Kelly, T. Sandstrom, S.T. Holgate, A. Frew,
increase in intra-macrophage thiols induced by new pro-GSH molecules directs the Acute inflammatory responses in the airways and peripheral blood after short-
Th1 skewing in ovalbumin immunized mice, Vaccine 28 (48) (2010) 7676–7682. term exposure to diesel exhaust in healthy human volunteers, Am. J. Respir. Crit.
[63] M. Porter, M. Karp, S. Killedar, S.M. Bauer, J. Guo, D. Williams, P. Breysse, Care Med. 159 (3) (1999) 702–709.
S.N. Georas, M.A. Williams, Diesel-enriched particulate matter functionally acti- [87] S.S. Salvi, C. Nordenhall, A. Blomberg, B. Rudell, J. Pourazar, F.J. Kelly, S. Wilson,
vates human dendritic cells, Am. J. Respir. Cell Mol. Biol. 37 (6) (2007) 706–719. T. Sandstrom, S.T. Holgate, A.J. Frew, Acute exposure to diesel exhaust increases
[64] N.C. Matthews, A. Faith, P.E. Pfeffer, H. Lu, F.J. Kelly, C.M. Hawrylowicz, Urban IL-8 and GRO-alpha production in healthy human airways, Am. J. Respir. Crit.
particulate matter suppresses priming of Th1 cells by GM-CSF-activated human Care Med. 161 (2 Pt 1) (2000) 550–557.
dendritic cells, Am. J. Respir. Cell Mol. Biol. 50 (2) (2014) 281–291. [88] J. Bosson, J. Pourazar, B. Forsberg, E. Adelroth, T. Sandstrom, A. Blomberg, Ozone
[65] P.E. Pfeffer, T.R. Ho, E.H. Mann, F.J. Kelly, M. Sehlstedt, J. Pourazar, R.E. Dove, enhances the airway inflammation initiated by diesel exhaust, Respir. Med. 101
T. Sandstrom, I.S. Mudway, C.M. Hawrylowicz, Urban particulate matter stimu- (6) (2007) 1140–1146.
lation of human dendritic cells enhances priming of naive CD8 T lymphocytes, [89] J. McCreanor, P. Cullinan, M.J. Nieuwenhuijsen, J. Stewart-Evans, E. Malliarou,
Immunology 153 (4) (2017) 502–512. L. Jarup, R. Harrington, M. Svartengren, I.K. Han, P. Ohman-Strickland,
[66] B. Bleck, D.B. Tse, I. Jaspers, M.A. Curotto de Lafaille, J. Reibman, Diesel exhaust K.F. Chung, J. Zhang, Respiratory effects of exposure to diesel traffic in persons
particle-exposed human bronchial epithelial cells induce dendritic cell maturation, with asthma, N. Engl. J. Med. 357 (23) (2007) 2348–2358.
J. Immunol. 176 (2006) 7431–7437. [90] A. Blomberg, M.T. Krishna, R. Helleday, M. Soderberg, M.C. Ledin, F.J. Kelly,
[67] B. Bleck, D.B. Tse, M.A. Curotto de Lafaille, F. Zhang, J. Reibman, Diesel exhaust A.J. Frew, S.T. Holgate, T. Sandstrom, Persistent airway inflammation but ac-
particle-exposed human bronchial epithelial cells induce dendritic cell maturation commodated antioxidant and lung function responses after repeated daily ex-
and polarization via thymic stromal lymphopoietin, J. Clin. Immunol. 28 (2) posure to nitrogen dioxide, Am. J. Respir. Crit. Care Med. 159 (2) (1999) 536–543.
(2008) 147–156. [91] V. Soyseth, J. Kongerud, P. Broen, P. Lilleng, J. Boe, Bronchial responsiveness,
[68] N.C. Matthews, P.E. Pfeffer, E.H. Mann, F.J. Kelly, C.J. Corrigan, eosinophilia, and short term exposure to air pollution, Arch. Dis. Child. 73 (5)
C.M. Hawrylowicz, T.H. Lee, Urban particulate matter-activated human dendritic (1995) 418–422.
cells induce the expansion of potent inflammatory Th1, Th2 and Th17 effector [92] N. Janssen, G. de Meer, B. Brunekreef, Exposure to air pollution from heavy traffic
cells, Am. J. Respir. Cell Mol. Biol. 54 (2) (2015) 250–262. is associated with increased eosinophilic activation in Dutch schoolchildren,
[69] E.H. Mann, T.R. Ho, P.E. Pfeffer, N.C. Matthews, E. Chevretton, I. Mudway, Epidemiology 15 (4) (2004) S55–S66.
F.J. Kelly, C.M. Hawrylowicz, Vitamin D counteracts an IL-23-dependent IL-17a [93] M. Ramanathan Jr., N.R. London Jr., A. Tharakan, N. Surya, T.E. Sussan, X. Rao,
(+)IFN-gamma(+) response driven by urban particulate matter, Am. J. Respir. S.Y. Lin, E. Toskala, S. Rajagopalan, S. Biswal, Airborne particulate matter induces
Cell Mol. Biol. 57 (3) (2017) 355–366. nonallergic eosinophilic sinonasal inflammation in mice, Am. J. Respir. Cell Mol.
[70] V. Saunders, P. Breysse, J. Clark, A. Sproles, M. Davila, M. Wills-Karp, Particulate Biol. 57 (1) (2017) 59–65.
matter-induced airway hyperresponsiveness is lymphocyte dependent, Environ. [94] K. Amin, The role of mast cells in allergic inflammation, Respir. Med. 106 (1)
Health Perspect. 118 (5) (2010) 640–646. (2012) 9–14.
[71] E.B. Brandt, M.B. Kovacic, G.B. Lee, A.M. Gibson, T.H. Acciani, T.D. Le Cras, [95] A. Nemmar, P.H. Hoet, J. Vermylen, B. Nemery, M.F. Hoylaerts, Pharmacological
P.H. Ryan, A.L. Budelsky, G.K. Khurana Hershey, Diesel exhaust particle induction stabilization of mast cells abrogates late thrombotic events induced by diesel ex-
of IL-17A contributes to severe asthma, J. Allergy Clin. Immunol. 132 (5) (2013) haust particles in hamsters, Circulation 110 (12) (2004) 1670–1677.
1194–1204 e2. [96] Y. Zhou, H.Y. Tung, Y.M. Tsai, S.C. Hsu, H.W. Chang, H. Kawasaki, H.C. Tseng,
[72] N. Gour, K. Sudini, S.M. Khalil, A.M. Rule, P. Lees, E. Gabrielson, J.D. Groopman, B. Plunkett, P. Gao, C.H. Hung, B.M. Vonakis, S.K. Huang, Aryl hydrocarbon re-
S. Lajoie, A. Singh, Unique pulmonary immunotoxicological effects of urban PM ceptor controls murine mast cell homeostasis, Blood 121 (16) (2013) 3195–3204.
are not recapitulated solely by carbon black, diesel exhaust or coal fly ash, [97] A. Lin, K. Lore, Granulocytes: new members of the antigen-presenting cell family,
Environ. Res. 161 (2018) 304–313. Front. Immunol. 8 (2017) 1781.
[73] Y. Sasaki, T. Ohtani, Y. Ito, M. Mizuashi, S. Nakagawa, T. Furukawa, A. Horii, [98] S.R. Durham, S.J. Till, C.J. Corrigan, T lymphocytes in asthma: bronchial versus
S. Aiba, Molecular events in human T cells treated with diesel exhaust particles or peripheral responses, J. Allergy Clin. Immunol. 106 (5) (2000) S221–S226.
formaldehyde that underlie their diminished interferon-gamma and interleukin-10 [99] E. Mortaz, P.J. Barnes, H. Heidarnazhad, I.M. Adcock, M.R. Masjedi,
production, Int. Arch. Allergy Immunol. 148 (3) (2009) 239–250. Immunological features of chronic obstructive pulmonary disease (COPD) induced
[74] R. Nakamura, K. Inoue, Y. Fujitani, M. Kiyono, S. Hirano, H. Takano, Effects of by indoor pollution and cigarette smoke, Tanaffos 11 (4) (2012) 6–17.
nanoparticle-rich diesel exhaust particles on IL-17 production in vitro, J. [100] C. Pasare, R. Medzhitov, Toll pathway–dependent blockade of CD4+CD25+ T
Immunot. 9 (1) (2012) 72–76. cell–mediated suppression by dendritic cells, Science 299 (2003) 1033–1036.
[75] X. Ji, M. Han, Y. Yun, G. Li, N. Sang, Acute nitrogen dioxide (NO2) exposure [101] K. Nadeau, C. McDonald-Hyman, E.M. Noth, B. Pratt, S.K. Hammond, J. Balmes,
enhances airway inflammation via modulating Th1/Th2 differentiation and acti- I. Tager, Ambient air pollution impairs regulatory T-cell function in asthma, J.
vating JAK-STAT pathway, Chemosphere 120 (2015) 722–728. Allergy Clin. Immunol. 126 (4) (2010) 845–852 e10.
[76] A. Metidji, S. Omenetti, S. Crotta, Y. Li, E. Nye, E. Ross, V. Li, M.R. Maradana, [102] M.A. Ponce-Gallegos, A. Ramirez-Venegas, R. Falfan-Valencia, Th17 profile in

66
D.A. Glencross, et al. Free Radical Biology and Medicine 151 (2020) 56–68

COPD exacerbations, Int. J. Chronic Obstr. Pulm. Dis. 12 (2017) 1857–1865. R.J. Wright, Prenatal particulate air pollution and asthma onset in urban children.
[103] B.J. Ryan, A. Nissim, P.G. Winyard, Oxidative post-translational modifications and Identifying sensitive windows and sex differences, Am. J. Respir. Crit. Care Med.
their involvement in the pathogenesis of autoimmune diseases, Redox Biol. 2 192 (9) (2015) 1052–1059.
(2014) 715–724. [128] S. Bose, M.J. Rosa, Y.H. Mathilda Chiu, H.H. Leon Hsu, Q. Di, A. Lee, I. Kloog,
[104] P. Eggleton, A. Nissim, B.J. Ryan, M. Whiteman, P.G. Winyard, Detection and A. Wilson, J. Schwartz, R.O. Wright, W.J. Morgan, B.A. Coull, R.J. Wright,
isolation of human serum autoantibodies that recognize oxidatively modified Prenatal nitrate air pollution exposure and reduced child lung function: timing and
autoantigens, Free Radic. Biol. Med. 57 (2013) 79–91. fetal sex effects, Environ. Res. 167 (2018) 591–597.
[105] J.M. Hemming, B.R. Hughes, A.R. Rennie, S. Tomas, R.A. Campbell, A.V. Hughes, [129] N.A. Clark, P.A. Demers, C.J. Karr, M. Koehoorn, C. Lencar, L. Tamburic,
T. Arnold, S.W. Botchway, K.C. Thompson, Environmental pollutant ozone causes M. Brauer, Effect of early life exposure to air pollution on development of child-
damage to lung surfactant protein B (SP-B), Biochemistry 54 (33) (2015) hood asthma, Environ. Health Perspect. 118 (2) (2010) 284–290.
5185–5197. [130] Q. Deng, C. Lu, D. Norback, C.G. Bornehag, Y. Zhang, W. Liu, H. Yuan, J. Sundell,
[106] Y. Kumagai, Y. Abiko, Environmental electrophiles: protein adducts, modulation Early life exposure to ambient air pollution and childhood asthma in China,
of redox signaling, and interaction with persulfides/polysulfides, Chem. Res. Environ. Res. 143 (Pt A) (2015) 83–92.
Toxicol. 30 (1) (2017) 203–219. [131] X. Zhang, D. Zhivaki, R. Lo-Man, Unique aspects of the perinatal immune system,
[107] H. Ribeiro, C. Costa, I. Abreu, J.C.G. Esteves da Silva, Effect of O3 and NO2 at- Nat. Rev. Immunol. 17 (8) (2017) 495–507.
mospheric pollutants on Platanus x acerifolia pollen: immunochemical and spec- [132] N. Baiz, R. Slama, M.C. Bene, M.A. Charles, M.N. Kolopp-Sarda, A. Magnan,
troscopic analysis, Sci. Total Environ. 599–600 (2017) 291–297. O. Thiebaugeorges, G. Faure, I. Annesi-Maesano, Maternal exposure to air pollu-
[108] F. Zhao, A. Elkelish, J. Durner, C. Lindermayr, J.B. Winkler, R.F. Rusmall io, tion before and during pregnancy related to changes in newborn's cord blood
H. Behrendt, C. Traidl-Hoffmann, A. Holzinger, W. Kofler, P. Braun, C. von Toerne, lymphocyte subpopulations. The EDEN study cohort, BMC Pregnancy Childbirth
S.M. Hauck, D. Ernst, U. Frank, Common ragweed (Ambrosia artemisiifolia L.): 11 (2011) 87.
allergenicity and molecular characterization of pollen after plant exposure to [133] D. Kim, Z. Chen, L.F. Zhou, S.X. Huang, Air pollutants and early origins of re-
elevated NO2, Plant Cell Environ. 39 (1) (2016) 147–164. spiratory diseases, Chronic Dis. Transl. Med. 4 (2) (2018) 75–94.
[109] H. Khreis, C. Kelly, J. Tate, R. Parslow, K. Lucas, M. Nieuwenhuijsen, Exposure to [134] I.S. Mudway, I. Dundas, H.E. Wood, N. Marlin, J.B. Jamaludin, S.A. Bremner,
traffic-related air pollution and risk of development of childhood asthma: a sys- L. Cross, A. Grieve, A. Nanzer, B.M. Barratt, S. Beevers, D. Dajnak, G.W. Fuller,
tematic review and meta-analysis, Environ. Int. 100 (2017) 1–31. A. Font, G. Colligan, A. Sheikh, R. Walton, J. Grigg, F.J. Kelly, T.H. Lee,
[110] C.R. Jung, H.Y. Hsieh, B.F. Hwang, Air pollution as a potential determinant of C.J. Griffiths, Impact of London's low emission zone on air quality and children's
rheumatoid arthritis: a population-based cohort study in taiwan, Epidemiology 28 respiratory health: a sequential annual cross-sectional study, Lancet Public Health
(Suppl 1) (2017) S54–S59. 4 (1) (2019) e28–e40.
[111] W.W. Busse, R.F. Lemanske, J.E. Gern, Role of viral respiratory infections in [135] U. Gehring, O. Gruzieva, R.M. Agius, R. Beelen, A. Custovic, J. Cyrys, M. Eeftens,
asthma and asthma exacerbations, Lancet 376 (9743) (2010) 826–834. C. Flexeder, E. Fuertes, J. Heinrich, B. Hoffmann, J.C. de Jongste, M. Kerkhof,
[112] V.N. Ayyagari, A. Januszkiewicz, J. Nath, Effects of nitrogen dioxide on the ex- C. Klumper, M. Korek, A. Molter, E.S. Schultz, A. Simpson, D. Sugiri,
pression of intercellular adhesion molecule-1, neutrophil adhesion, and cytotoxi- M. Svartengren, A. von Berg, A.H. Wijga, G. Pershagen, B. Brunekreef, Air pollu-
city: studies in human bronchial epithelial cells, Inhal. Toxicol. 19 (2) (2007) tion exposure and lung function in children: the ESCAPE project, Environ. Health
181–194. Perspect. 121 (11–12) (2013) 1357–1364.
[113] A.E. Taylor, T.K. Finney-Hayward, J.K. Quint, C.M. Thomas, S.J. Tudhope, [136] W.J. Gauderman, G.F. Gilliland, H. Vora, E. Avol, D. Stram, R. McConnell,
J.A. Wedzicha, P.J. Barnes, L.E. Donnelly, Defective macrophage phagocytosis of D. Thomas, F. Lurmann, H.G. Margolis, E.B. Rappaport, K. Berhane, J.M. Peters,
bacteria in COPD, Eur. Respir. J. 35 (5) (2010) 1039–1047. Association between air pollution and lung function growth in southern California
[114] J. Balhara, A.S. Gounni, The alveolar macrophages in asthma: a double-edged children: results from a second cohort, Am. J. Respir. Crit. Care Med. 166 (1)
sword, Mucosal Immunol. 5 (6) (2012) 605–609. (2002) 76–84.
[115] M. Contoli, K. Ito, A. Padovani, D. Poletti, B. Marku, M.R. Edwards, L.A. Stanciu, [137] W.J. Gauderman, R. Urman, E. Avol, K. Berhane, R. McConnell, E. Rappaport,
G. Gnesini, A. Pastore, A. Spanevello, P. Morelli, S.L. Johnston, G. Caramori, R. Chang, F. Lurmann, F. Gilliland, Association of improved air quality with lung
A. Papi, Th2 cytokines impair innate immune responses to rhinovirus in re- development in children, N. Engl. J. Med. 372 (10) (2015) 905–913.
spiratory epithelial cells, Allergy 70 (8) (2015) 910–920. [138] F.D. Martinez, The origins of asthma and chronic obstructive pulmonary disease in
[116] D.J. Jackson, H. Makrinioti, B.M. Rana, B.W. Shamji, M.B. Trujillo-Torralbo, early life, Proc. Am. Thorac. Soc. 6 (3) (2009) 272–277.
J. Footitt, D.-R. Jerico, A.G. Telcian, A. Nikonova, J. Zhu, J. Aniscenko, [139] T. de Barros Mendes Lopes, E.E. Groth, M. Veras, T.K. Furuya, N. de Souza Xavier
L. Gogsadze, E. Bakhsoliani, S. Traub, J. Dhariwal, J. Porter, D. Hunt, T. Hunt, Costa, G. Ribeiro Junior, F.D. Lopes, F.M. de Almeida, W.V. Cardoso,
T. Hunt, L.A. Stanciu, M. Khaitov, N.W. Bartlett, M.R. Edwards, O.M. Kon, P.H.N. Saldiva, R. Chammas, T. Mauad, Pre- and postnatal exposure of mice to
P. Mallia, N.G. Papadopoulos, C.A. Akdis, J. Westwick, M.J. Edwards, concentrated urban PM2.5 decreases the number of alveoli and leads to altered
D.J. Cousins, R.P. Walton, S.L. Johnston, IL-33-dependent type 2 inflammation lung function at an early stage of life, Environ. Pollut. 241 (2018) 511–520.
during rhinovirus-induced asthma exacerbations in vivo, Am. J. Respir. Crit. Care [140] A.N. Ananthakrishnan, E.L. McGinley, D.G. Binion, K. Saeian, Ambient air pollu-
Med. 190 (12) (2014) 1373–1382. tion correlates with hospitalizations for inflammatory bowel disease: an ecologic
[117] L.D. Bloemsma, G. Hoek, L.A. Smit, Panel studies of air pollution in patients with analysis, Inflamm. Bowel Dis. 17 (5) (2011) 1138–1145.
COPD: systematic review and meta-analysis, Environ. Res. 151 (2016) 458–468. [141] G.G. Kaplan, J. Hubbard, J. Korzenik, B.E. Sands, R. Panaccione, S. Ghosh,
[118] J. Li, S. Sun, R. Tang, H. Qiu, Q. Huang, T.G. Mason, L. Tian, Major air pollutants A.J. Wheeler, P.J. Villeneuve, The inflammatory bowel diseases and ambient air
and risk of COPD exacerbations: a systematic review and meta-analysis, Int. J. pollution: a novel association, Am. J. Gastroenterol. 105 (11) (2010) 2412–2419.
Chronic Obstr. Pulm. Dis. 11 (2016) 3079–3091. [142] E.A. Mutlu, P.A. Engen, S. Soberanes, D. Urich, C.B. Forsyth, R. Nigdelioglu,
[119] P. Orellano, N. Quaranta, J. Reynoso, B. Balbi, J. Vasquez, Effect of outdoor air S.E. Chiarella, K.A. Radigan, A. Gonzalez, S. Jakate, A. Keshavarzian,
pollution on asthma exacerbations in children and adults: systematic review and G.R. Budinger, G.M. Mutlu, Particulate matter air pollution causes oxidant-medi-
multilevel meta-analysis, PloS One 12 (3) (2017) e0174050. ated increase in gut permeability in mice, Part. Fibre Toxicol. 8 (2011) 19.
[120] X.Y. Zheng, H. Ding, L.N. Jiang, S.W. Chen, J.P. Zheng, M. Qiu, Y.X. Zhou, [143] L. Kish, N. Hotte, G.G. Kaplan, R. Vincent, R. Tso, M. Ganzle, K.P. Rioux,
Q. Chen, W.J. Guan, Association between air pollutants and asthma emergency A. Thiesen, H.W. Barkema, E. Wine, K.L. Madsen, Environmental particulate
room visits and hospital admissions in time series studies: a systematic review and matter induces murine intestinal inflammatory responses and alters the gut mi-
meta-analysis, PloS One 10 (9) (2015) e0138146. crobiome, PloS One 8 (4) (2013) e62220.
[121] M. Bafadhel, S. McKenna, S. Terry, V. Mistry, C. Reid, P. Haldar, M. McCormick, [144] M. Veldhoen, K. Hirota, A.M. Westendorf, J. Buer, L. Dumoutier, J.C. Renauld,
K. Haldar, T. Kebadze, A. Duvoix, K. Lindblad, H. Patel, P. Rugman, P. Dodson, B. Stockinger, The aryl hydrocarbon receptor links TH17-cell-mediated auto-
M. Jenkins, M. Saunders, P. Newbold, R.H. Green, P. Venge, D.A. Lomas, immunity to environmental toxins, Nature 453 (7191) (2008) 106–109.
M.R. Barer, S.L. Johnston, I.D. Pavord, C.E. Brightling, Acute exacerbations of [145] S.F. van Eeden, W.C. Tan, T. Suwa, H. Mukae, T. Terashima, T. Fujii, D. Qui,
chronic obstructive pulmonary disease: identification of biologic clusters and their R. Vincent, J.C. Hogg, Cytokines involved in the systemic inflammatory response
biomarkers, Am. J. Respir. Crit. Care Med. 184 (6) (2011) 662–671. induced by exposure to particulate matter air pollutants (PM(10)), Am. J. Respir.
[122] P.E. Pfeffer, G.C. Donaldson, A.J. Mackay, J.A. Wedzicha, Increased chronic ob- Crit. Care Med. 164 (5) (2001) 826–830.
structive pulmonary disease exacerbations of likely viral etiology follow elevated [146] R.D. Brook, J.R. Brook, B. Urch, R. Vincent, S. Rajagopalan, F. Silverman,
ambient nitrogen oxides, Am. J. Respir. Crit. Care Med. 199 (5) (2019) 581–591. Inhalation of fine particulate air pollution and ozone causes acute arterial vaso-
[123] F.D. Martinez, Childhood asthma inception and progression: role of microbial constriction in healthy adults, Circulation 105 (13) (2002) 1534–1536.
exposures, susceptibility to viruses and early allergic sensitization, Immunol. [147] R.K. Robinson, M.A. Birrell, J.J. Adcock, M.A. Wortley, E.D. Dubuis, S. Chen,
Allergy Clin. 39 (2019) 141–150. C.M. McGilvery, S. Hu, M.S.P. Shaffer, S.J. Bonvini, S.A. Maher, I.S. Mudway,
[124] H. Bove, E. Bongaerts, E. Slenders, E.M. Bijnens, N.D. Saenen, W. Gyselaers, P. Van A.E. Porter, C. Carlsten, T.D. Tetley, M.G. Belvisi, Mechanistic link between diesel
Eyken, M. Plusquin, M.B.J. Roeffaers, M. Ameloot, T.S. Nawrot, Ambient black exhaust particles and respiratory reflexes, J. Allergy Clin. Immunol. 141 (3) (2018)
carbon particles reach the fetal side of human placenta, Nat. Commun. 10 (1) 1074–1084 e9.
(2019) 3866. [148] A. Gonzalez-Maciel, R. Reynoso-Robles, R. Torres-Jardon, P.S. Mukherjee,
[125] A.J. Burbank, A.K. Sood, M.J. Kesic, D.B. Peden, M.L. Hernandez, Environmental L. Calderon-Garciduenas, Combustion-derived nanoparticles in key brain target
determinants of allergy and asthma in early life, J. Allergy Clin. Immunol. 140 (1) cells and organelles in young urbanites: culprit hidden in plain sight in alzheimer's
(2017) 1–12. disease development, J. Alzheim. Dis. 59 (1) (2017) 189–208.
[126] P. Bharadwaj, J.G. Zivin, J.T. Mullins, M. Neidell, Early-life exposure to the Great [149] L. Calderon-Garciduenas, A. Gonzalez-Maciel, P.S. Mukherjee, R. Reynoso-Robles,
smog of 1952 and the development of asthma, Am. J. Respir. Crit. Care Med. 194 B. Perez-Guille, C. Gayosso-Chavez, R. Torres-Jardon, J.V. Cross, I.A.M. Ahmed,
(12) (2016) 1475–1482. V.V. Karloukovski, B.A. Maher, Combustion- and friction-derived magnetic air
[127] H.H. Hsu, Y.H. Chiu, B.A. Coull, I. Kloog, J. Schwartz, A. Lee, R.O. Wright, pollution nanoparticles in human hearts, Environ. Res. 176 (2019) 108567.

67
D.A. Glencross, et al. Free Radical Biology and Medicine 151 (2020) 56–68

[150] P.E. Pfeffer, I.S. Mudway, The impact of real-world particulate matter air pollution [153] F. Rosser, J.M. Brehm, E. Forno, E. Acosta-Perez, K. Kurland, G. Canino,
on the airways of susceptible individuals, Am. J. Respir. Crit. Care Med. 198 (11) J.C. Celedon, Proximity to a major road, vitamin D insufficiency, and severe
(2018) 1362–1363. asthma exacerbations in Puerto Rican children, Am. J. Respir. Crit. Care Med. 190
[151] S.L. O'Beirne, S.A. Shenoy, J. Salit, Y. Strulovici-Barel, R.J. Kaner, S. Visvanathan, (10) (2014) 1190–1192.
J.S. Fine, J.G. Mezey, R.G. Crystal, Ambient pollution-related reprogramming of [154] P.E. Pfeffer, H. Lu, E.H. Mann, Y.H. Chen, T.R. Ho, D.J. Cousins, C. Corrigan,
the human small airway epithelial transcriptome, Am. J. Respir. Crit. Care Med. F.J. Kelly, I.S. Mudway, C.M. Hawrylowicz, Effects of vitamin D on inflammatory
198 (11) (2018) 1413–1422. and oxidative stress responses of human bronchial epithelial cells exposed to
[152] P.E. Pfeffer, C.M. Hawrylowicz, Vitamin D in asthma: mechanisms of action and particulate matter, PloS One 13 (8) (2018) e0200040.
considerations for clinical trials, Chest 153 (5) (2017) 1229–1239.

68