Immunopathological features of air pollution and its impact on inflammatory airway diseases (IAD)

Abstract

Air pollution causes significant morbidity and mortality in patients with inflammatory airway diseases (IAD) such as allergic rhinitis (AR), chronic rhinosinusitis (CRS), asthma, and chronic obstructive pulmonary disease (COPD). Oxidative stress in patients with IAD can induce eosinophilic inflammation in the airways, augment atopic allergic sensitization, and increase susceptibility to infection. We reviewed emerging data depicting the involvement of oxidative stress in IAD patients. We evaluated biomarkers, outcome measures and immunopathological alterations across the airway mucosal barrier following exposure, particularly when accentuated by an infectious insult.

Full text

Open Access
Immunopathological features of air pollution
and its impact on inflammatory airway
diseases (IAD)
Philip W. Rouadi
a
*, Samar A. Idriss
a
**, Robert M. Naclerio
b
, David B. Peden
c
, Ignacio J. Ansotegui
d
,
Giorgio Walter Canonica
e
, Sandra Nora Gonzalez-Diaz
f
, Nelson A. Rosario Filho
g
,
Juan Carlos Ivancevich
h
, Peter W. Hellings
i,j
, Margarita Murrieta-Aguttes
k
, Fares H. Zaitoun
l
,
Carla Irani
m
, Marilyn R. Karam
n
and Jean Bousquet
o,p,q
ABSTRACT
Air pollution causes significant morbidity and mortality in patients with inflammatory airway dis-
eases (IAD) such as allergic rhinitis (AR), chronic rhinosinusitis (CRS), asthma, and chronic
obstructive pulmonary disease (COPD). Oxidative stress in patients with IAD can induce eosino-
philic inflammation in the airways, augment atopic allergic sensitization, and increase susceptibility
to infection. We reviewed emerging data depicting the involvement of oxidative stress in IAD
patients. We evaluated biomarkers, outcome measures and immunopathological alterations
across the airway mucosal barrier following exposure, particularly when accentuated by an in-
fectious insult.
Keywords: Inflammatory airway disease, Air pollution, Oxidative stress biomarkers, Tobacco
smoke, Antioxidant
INTRODUCTION
The presence in the air of one or more natural or
anthropogenic substances at a concentration, or
location, for a duration, above their natural levels
with the potential to cause an adverse health effect
defines air pollution.
1
Indoor air pollution refers to
chemical, biological, and physical exposure of air
pollutants in homes, schools, and workplaces.
Similar to indoor air pollution, ambient (outdoor)
air pollution can result from chemical substances
or biologically derived contaminants modified by
climate change or human activity such as
bioaerosols and aeroallergens. Air quality
guidelines endorsed by the World Health
Organization (WHO) aim to provide clean air in
and around the home.
2
Air pollution reduced life
expectancy in 2017 by 1 year and 8 months on
average worldwide.
3
WHO has linked 4.3 million
deaths globally in 2012 to household cooking
using coal, wood and biomass stoves. Outdoor
air pollution in the same year caused an
estimated 3.7 million deaths.
4
In inflammatory
airway disease (IAD) patients an estimated 7–11%
increased risk in asthma-related mortality was
commensurate with a rise in ambient pollutant
concentrations such as NO2, PM2.5, or ozone
when computed few days prior to asthma death.
5
Similar but smaller increments in chronic
*Corresponding author. Department of Otolaryngology-Head and Neck
Surgery, Eye and Ear University Hospital, Beirut, Lebanon. E-mail:
rouadipws@gmail.com
**Corresponding author. Department of Otolaryngology-Head and Neck
Surgery, Eye and Ear University Hospital, Beirut, Lebanon E-mail: samar.a.
idriss@hotmail.com
Full list of author information is available at the end of the article
http://doi.org/10.1016/j.waojou.2020.100467
Received 11 May 2020; Received in revised from 31 August 2020; Accepted
11 September 2020
1939-4551/© 2020 The Authors. Published by Elsevier Inc. on behalf of
World Allergy Organization. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Rouadi et al. World Allergy Organization Journal (2020) 13:100467
http://doi.org/10.1016/j.waojou.2020.100467

obstructive pulmonary disease (COPD)-related
mortality were attributed to pollution and ranged
from 0.78% to 1.78%.
6
In the respiratory tract, air pollution can impact
wellness in healthy people and patients with IAD,
irrespective of their atopic status. Hence, the
airway mucosal barrier may be disrupted by
immunopathological mechanisms resulting from
effects of pollution and IAD. The co-occurrence of
IAD phenotypes (allergic rhinitis, and chronic rhi-
nosinusitis, COPD and asthma) within an individual
increases the likelihood of pollutant induced
exacerbation of disease or infection.
We reviewed the following IADs in relation to air
pollution. Allergic rhinitis (AR), is an IgE mediated
inflammatory disease generated by a spectrum of
outdoor aeroallergens like pollens or indoor aer-
oallergens such as dust mites, cockroaches, cat
allergens, or molds. CRS represents multiple
overlapping rhinosinusitis phenotypes with
different endotypes.
7
Asthma is characterized by
chronic atopic or non-atopic inflammation of the
airway with superimposed episodes of acute ex-
acerbations. The majority of exacerbations are
triggered by respiratory viral infections, most
commonly human rhinovirus.
8,9
Other triggers
include allergens and atmospheric
pollutants.
10,11
COPD, another chronic
inflammatory airway disease, is characterized by
airflow limitation and cough. Acute exacerbation
of COPD, like in the upper airway, can be
triggered by infection and inhalation of
irritants.
12,13
CHARACTERISTICS OF AIR POLLUTANTS
Chemical pollutants are health-damaging at-
mospheric aerosol and non-aerosol particles
originating from a variety of natural (eg, volcanic
eruptions) or anthropogenic sources (eg, biomass
burning, fossil fuel combustion, or traffic related
particles). Primary pollutants such as particulate
matter (PM) and volatile organic compounds are
aerosol particles directly emitted as solid or liquid
droplets in the air. In the atmosphere, natural gas-
to-particle conversion can culminate in secondary
chemical pollutant particles like are ozone and
PM.
14
Particular matter and nanoparticles
Particularte matter (PM) is a mixture of solid and
liquid particles suspended in indoor and outdoor
air. Their source, size, classification, and airway
distribution patterns are well described.
15–17
Various human indoor activities cause
resuspension and deposition of particles in
indoor air, a process governed primarily by the
effective size of the particle. This can range from
hours for PM
10
to several months for 2-
m
m
particulate pollutants.
18
PM
2.5
broadly represents
around 50% of the total mass of PM
10
and can
be inhaled more deeply into the lungs, with a
portion depositing in the alveoli and entering the
pulmonary and systemic circulation.
17
The
submicron PM family, ultrafine particles and
nanoparticles, due to their small size, have a
relatively large surface area allowing a greater
proportion of compounds to be displayed at the
surface such as metals and organic
compounds.
19,20
They cannot be taken by
macrophages and can escape phagocytosis.
When retained in the lungs, the ensuing
inflammation can result in asthma and lung
fibrosis;
20,21
yet they can allocate to distant
organs through systemic circulation resulting in
different toxicological phenotypes such as
diabetes and heart disease.
22–24
The adverse
health effects of PM are not uniform since PM is
not a single entity; rather its constituents and
their proportion in ambient air can change from
one geographical location to another depending
on the type of emissions inherent to each area.
25
Volatile organic compounds (VOCs) and
formaldehyde
VOCs are primary pollutants located mainly in-
doors and include benzene, toluene, xylenes, ter-
penes, and polycyclic aromatic hydrocarbons.
They produce a secondary pollutant, formalde-
hyde, by an indoor chemical reaction between
ozone or nitrogen oxide and terpene.
26
Formaldehyde appears to be associated with a
higher risk of nasopharyngeal carcinoma
27
and
leukemia.
28
The primary domestic,
29–31
microbial,
32
and socio-cultural sources of
VOCs
33,34
are well elaborated.
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Diesel exhaust particles (DEP)
Diesel exhaust represents the most important
local contributor to ambient air pollution and has
been classified by WHO as carcinogenic to
humans.
35
It is a complex mixture of chemicals and
metals stratified into 3 fractions: a solid fraction
(made of a soot of carbon core, metals, and their
oxides),
36
a gaseous fraction (made of nitrogen,
oxygen, and polycyclic aromatic hydrocarbons -
PAHs), and a liquid fraction
37
where PAHs can
adsorb into soot or water droplets.
38,39
Ultrafine
particles, nitrogen oxide, and PM (in the range of
2.5
m
m) can be produced also by internal
combustion of diesel engines. Metal elements
include Chromium, Magnesium, Zinc, and Lead
and are associated with engine emissions and
abrasion of tires and brake pads. Vanadium and
Nickel are tracers of long-range transport from
the use of heavy fuel oil.
40
The relatively large
surface area of diesel exhaust particles (DEPs)
permits many of these chemicals and metals to
attach to its core. Thus, most of the deleterious
effects of DEPs are due to chemicals that are
adsorbed onto their surface.
41
Ozone and nitrogen oxide (NOx)
To date, ozone is considered the most
damaging air pollutant in terms of adverse effects
on human health, vegetation, and crops.
42–47
It
produces short- and long-term effects on
cardiorespiratory function.
45
Recent evidence
suggests there is no threshold concentration
below which there are no effects on health.
Ground-level ozone is formed in the atmosphere
by a complex reaction of its precursors, nitrogen
oxide (NOx), carbon monoxide, and volatile
organic compounds in the presence of sunlight.
48
Background ozone concentrations are strongly
correlated with the increased global NOx
emissions derived from human-generated fossil
fuel combustion and biomass burning.
49
Tobacco smoke (TBS)
Tobaco smoke (TBS) emits a wide range of
gases, aerosolized liquids, and fine particulate
matter including VOC and formaldehyde, nitrogen
oxide, PM2.5, and nicotine.
50,51
TBS is estimated
to cause approximately 480,000 excess deaths
per year,
52
and it can contribute to 30% of all
cancer deaths.
53
Among other actions, TBS can
induce DNA damage,
51
change in sputum
(mucin) quality, and depressed antioxidant and
antimicrobial activity in smokers and among
COPD patients.
54,55
Household dust
Household dust represents a convenient means
to sample respiratory exposure to pollutants. In
one study, the respirable fraction of dust consti-
tuted less than 1% of the total weight of dust sur-
rounding us, and on scan electron microscopy
consisted of large flakes (>20
m
m diameter) to
which are adherent smaller particles.
56
The
median aerodynamic diameter of respirable dust
particles allows their deposition both in the nose
and lungs. The chemical composition of these
flakes suggests household dust might be an
important carrier vehicle of organic pollutants
into the airways in addition to its intrinsic risk of
oxidative stress.
56
TYPES AND AERODYNAMICS PROPERTIES
OF ALLERGENS
Allergens can pollute indoor and outdoor air
and exacerbate AR and asthma. Indoor allergenic
pollutants can be derived from skin scales of pets
(eg, cats, dogs), urine of rodents (eg, mice), molds,
or from fecal material of arthropods such as house
dust mites and cockroaches. Outdoor allergens
are aeroallergens originating from grasses, trees,
weeds, or molds. Outdoor pollen also modulates
indoor aeroallergen concentration. The concen-
tration of aeroallergens in the indoor environment
is governed by complex bioaerosol dynamics.
57
For example, airborne cat allergen (Fel d1) is
mostly associated with large particles (>9
m
m),
but around
1
/
4
of Fel d1 are carried on particles
less than 4 micra in diameter. Thus Fel d1 can be
deposited in the alveoli but most importantly
suspended for several days in the air favoring
distribution of the allergen in the environment.
58–
60
Also, the 33 groups of mite allergens listed in
the WHO nomenclature of allergens are
composed of particles ranging in diameter from
10 to 40
m
m.
61
Hence, they can become airborne
upon disturbance and can be carried on house
dust that becomes a vector for exposure. How
dust mite allergen particles can induce and
Volume 13, No. 10, October 2020 3

trigger asthma in lower airways remains to be
determined.
62
INFECTIOUS PARTICLES
The diversity and functioning of the normal
microbiome are crucial for maintaining the health
of the host. While the effects of PM on human
health are well established, the impact of infec-
tious particles on bacterial ecosystems has been
overlooked.
In vitro studies suggest black carbon, a major
component of PM, is strongly implicated in pre-
disposition to respiratory infectious diseases,
25,63
and induces structural and functional changes in
the biofilms of both Streptococcus pneumonia
and Staphylococcus aureus.
64
This is manifested
by increase in biofilm thickness and tolerance to
degradation by proteolytic enzymes, thereby
promoting colonization of the respiratory tract.
Similarly, evidence suggests indoor and outdoor
dust modifies microbial growth, virulence, and
biofilm formation of opportunistic pathogens. By
exposing 3 opportunistic bacteria (Pseudomonas
aeruginosa, Escherichia coli, and Enterococcus
faecalis) to progressively increasing
concentrations of indoor and outdoor dust, a
differential growth pattern of pathogens was
noted. This was commensurate with increased
biofilm formation and sensitivity to oxidative
stress following hydrogen peroxide challenge.
65
Consequently, the detrimental impact of
particulate pollutants on human health is not only
due to direct effects on the host but also may
involve the effect on bacterial behavior in the host.
COMPARATIVE ANALYSIS OF OXIDATIVE
STRESS-MEDIATED
IMMUNOPATHOLOGICAL ALTERATIONS
IN CLINICAL MODELS OF IAD
Oxidative stress is a disproportionate genera-
tion of free radicals beyond the body antioxidant
capacity. It translates into a non-IgE mediated Th2
airway inflammation following exposure to a
pollutant. In brief, reactive oxygen species (ROS),
generated naturally as by-product of cell growth
and metabolism, can be produced following
pollutant exposure.
66,67
ROS include oxygen
radicals (eg, superoxide, hydroxyl, hydroperoxyl)
and certain non-radicals (eg, H
2
O
2
, ozone, singlet
oxygen) that are easily converted into radicals.
68
ROS have a pivotal role in cell signaling in the
oxidation/reduction cascades following exposure
and ultimately generation of anti-oxidant mecha-
nisms thru nrf-2, activator protein 1, and nuclear
factor-kappa B.
69–72
Antioxidants are scavengers
of ROS and can be enzymatic or non-enzymatic
systems, constitutive or de novo synthesized by
activated gene expression, according to ROS load.
The inflammatory phase of oxidative stress in-
volves cytokines- and chemokines-mediated acti-
vation and recruitment of inflammatory cells
secondary to direct effect of pollutants on airway
epithelial cells.
67
This can propagate oxidative
stress further and augment the inflammatory
response and tissue damage.
73
Alternatively,
ROS can contribute directly to cell injury and
apoptosis by disrupting cellular and nuclear
membranes in the epithelial barrier wall and
altering the function of cellular enzymes.
74,75
A
different mechanism by which environmental
pollution can trigger disease in the nose is via a
neurogenic mechanism.
76
Another component of
oxidative pathway is the exposure-driven adju-
vant effect on atopy where environmental pollution
acts as an exacerbating factor for allergic airway
disease by enhancement of allergic airway hyper-
sensitivity in atopic individuals. The evidence
emerges from experimental protocols involving
inhalation of pollutants and allergen challenge
which show pollutants can act synergistically to
heighten the allergic response with increased
expression of Th2 inflammatory biomarkers.
76,77
This is in contrast to healthy individuals which
express either Th1 or a mixed Th1/Th2 profile in
controlled exposure studies.
78
Epidemiological studies suggest pollution
modulates AR,
79–85
rhinosinusitis,
86
and
asthma.
85,87
Other studies suggest a positive
association between exposure and prevalence of
AR and asthma
83,88–91
in children and adults
predominately in reports on short-term expo-
sure
88
and residential proximity studies to sources
of traffic pollution.
87,92
However, other long-term
exposure studies provided evidence to the con-
trary.
93–95
This could be due to differences in
study design, methods of exposure assessment,
and complex nature of studied
pollutants.
79,80,82,92
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Author
/year
Clinical
Model Group under study Outcome measure/
Biomarkers Clinical Findings
Elhini A,
2006
112
Human
In-vivo Perennial AR Inferior turbinate:
- HO-1 and HO-2
isoenzyme antioxidant
mRNA expression
Upregulated expression of
nasal cytoprotective stress
response markers, HO-1,
but not HO-2, in perennial
allergic diseases.
Gratziou C,
2008
106
Human
In-vivo SAR/Allergic
asthma Exhaled breath air and
condensate variation with
pollen season and INS
therapy
- eNO; Iso-8 (lipid
peroxidation marker),
LTB
4
; Nitrate/Nitrite
Compared to healthy
subjects, increased all OS
markers in (SAR) patients
during natural allergen
exposure irrespective of
asthma comorbidity;
compared to patients with
SAR only, eNO and nitrates
more pronounced in
patients with concomitant
asthma. Iso-8 and LTB
4
but
not nitrate/nitrite are
reduced with nasal steroids
suggesting a regulatory
role in OS response.
Moon J,
2009
113
Human
In-vivo AR or CRSwNP Inferior turbinate and
nasal polyps:
- NOX1 and NOX4
antioxidant levels and
mRNA expression
Increased NOX -1 and 4
levels and mRNA
expression in allergic nasal
mucosa and nasal polyps
mediated by ROS-
generating NADPH oxidase
suggest their role in
pathogenesis of AR and
CRSwNP.
Sadowska-
Woda I,
2010
114
Human
In-vivo Perennial AR in
children Blood erythrocytes
analysis with
desloratadine therapy:
- Catalase and
superoxide dismutase
(antioxidant enzymes),
malondialdehyde (lipid
peroxidation marker)
Reduction in antioxidant
enzyme (catalase and
superoxide dismutase)
activity and
malondialdehyde level and
reversal with desloratadine
suggest OS is implicated in
pathogenesis of PAR and
desloratadine can exert an
antioxidant effect
Sagdic A,
2011
107
Human
In-vivo Allergic and non-
allergic asthma, AR Blood erythrocyte
analysis:
- CuZnSOD and GSH-Px
antioxidant enzyme
activity;
malondialdehyde (lipid
peroxidation marker)
Decreased CuZnSOD
enzyme activity but not
GSH-Px and MDA in
allergic and non-allergic
asthma and AR suggest OS
mediates inflammation in
rhinitis and asthma,
irrespective of atopic status.
Celik M,
2012
111
Human
In-vivo Allergic asthma
and rhinitis in
children
Nasal and oral exhaled
breath condensate with
topical steroid therapy:
Decrease in GSH
antioxidant enzyme level
and increase in MDA
oxidative biomarker in both
(continued)
Volume 13, No. 10, October 2020 5

Author
/year
Clinical
Model Group under study Outcome measure/
Biomarkers Clinical Findings
- MDA (lipid
peroxidation marker)
and GSH (antioxidant)
enzyme level
allergic asthma and rhinitis,
separately or combined.
Also co-existence of
allergic asthma and rhinitis
does not augment OS, and
no apparent regulatory role
of topical steroid on OS
response.
Cho DY,
2012
96
Human
In-vivo CRSwNP and
CRSsNP Nasal polyp, tissue and
lavage:
- Cytokines (Eotaxin,
monokine-induced by
IFN-
g
-MIG, TNF-
a
, and
IL-8) and H
2
O
2
(released into mucosal
fluid layer); DUOX1 and
DUOX2 (NADPH
oxidase) mRNA
expression and protein
level
Increased level of DUOX1
and DUOX2 in nasal polyps
positively correlate with
cytokine levels of eotaxin,
MIG and TNF-
a
; also
increased level of DUOX2
but not DUOX1 in nasal
tissue of CRSsNP positively
correlate with H
2
O
2
.
Findings suggest OS can
differentially modulate
different CRS phenotypes
in terms of DUOX -1 and
2 antioxidant enzyme
level and expression.
Emin O,
2012
108
Human
In-vivo Perennial AR in
children Blood analysis:
- Plasma total oxidant
status (TOS); total
antioxidant status (TAS);
total serum IgE levels;
skin sensitization
Increased TOS and
decreased TAS is
independent of total IgE
levels and allergic
sensitization in children
with PAR.
Guibas G,
2013
126
Rat
In- vivo Ova-sensitized rats Sinonasal tissue and blood
with NAC and Ova
challenge:
- Tissue eosinophil and
mast cells; iNOS and
COX2 mucosal
expression; and serum
TNF-
a
Following Ova challenge,
upregulated count of
eosinophils and mast cells,
mucosal expression of
iNOS, COX-2, and TNF-
a
level and their
downregulation by NAC
(except for COX2
expression) suggest
important antioxidant
property of NAC in allergic
reactions and a diverse role
of COX2 in redox sensitive
reactions.
Ozkaya E,
2013
109
Human
In-vivo Perennial AR in
children Blood analysis:
- Plasma PON1
(antioxidant enzyme
activity) and TOS; total
serum IgE level; Nasal
symptoms score
Nasal symptom scores
correlate negatively with
serum PON1 and positively
with TOS levels and hence
serve as predictors of
disease severity in children
with AR, independently of
total IgE levels.
(continued)
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Author
/year
Clinical
Model Group under study Outcome measure/
Biomarkers Clinical Findings
Yu Z, 2015
97
Human
In-vivo Eosinophilic and
non-eosinophilic
CRS with nasal
polyps
Nasal Polyp (NP):
- HO-1 and HO-2
(antioxidant) enzymes
mRNA expression and
protein level.
Increased HO-1 and HO-2
expression in nasal polyps,
more so for HO-1
expression in non-ECRS
compared to ECRS; their
induction by cytokines and
inhibition by TGF-
b
1
suggest a differential role
of HO-1 in different
endotypes of nasal polyps.
Chan TK,
2016
75
Mice
and
human
In-vivo
Asthmatic HDM-
sensitized mice Mice BAL þ/or LT
following HDM challenge;
or BEAS or asthmatic
patients:
- Neutrophil, Eosinophil,
M4, Total T cell counts;
8-IP, 3- NT, 8-OG
(markers of oxidative
damage to lipids,
proteins and nucleic
acids, respectively);
g
H2AX [DNA DS breaks
marker-DSB] positive
cells, Rad51, Ku70,
PARP-1 and PAR (DNA
repair pathway marker);
NU7441 (DNA DSB
repair inhibitor); IL-4, IL-
5, IL-13, IL-33
production; Apoptosis
in situ and in vitro
HDM challenge triggered
an ROS-mediated induction
of DNA damage (
g
H2AX)
in healthy or asthmatic
humans and mice; in
challenged mice
recruitment of inflammatory
cells and upregulation of
markers involved in
oxidative damage to lipids,
proteins and nucleic acids
(8-IP, 3-NT, 8-OG); in all
three groups induction of
DNA repair proteins.
HDM challenge and
administration of DNA
repair inhibitor (NU7441)
induces DNA repair
markers (Rad51, Ku70,
PARP-1 and PAR) in
asthmatic patients and
HDM-challenged mice
concomitant with increased
cytokines (IL-4, IL-5, IL-13,
IL-33) and Annexin V/P
staining in BEAS; all
suggesting the importance
of DNA repair in protection
against HDM exposure-
induced cell apoptosis and
in suppressing airway
inflammation in-vitro.
Ulusoy S,
2016
110
Human
In-vivo SAR Blood analysis with pollen
season:
Thiol-SH (antioxidant
marker) level, disulfide-SS
(oxidative stress marker)
level, and total SH (TT)
level
Decreased levels of thiol-
SH and increased levels of
disulfide-SS during
exacerbations of SAR
compared to asymptomatic
period suggests natural
allergen exposure reverses
oxidative and anti-oxidative
status in SAR, which are not
completely abolished even
outside pollination season
(continued)
Volume 13, No. 10, October 2020 7

InIn- vivovivo studies in both human and animal
models suggest pollutant exposure induces in-
flammatory changes in normal, chronically
diseased and allergic nasal and sinonasal tissues
(Table 1). The cytokine profile of affected tissues
suggests activation of the oxidative inflammatory
pathways.
96–98
Moreover, there is compelling
evidence for involvement of oxidative stress
inflammatory pathways following pollutant
exposure in the pathogenesis of rhinitis, CRS,
and asthma irrespective of atopic status. This
stems from an abundance of literature on
oxidative stress biomarkers studied under natural
or experimental allergen exposure both in
seasonal and perennial AR described in Table 1.
In fact, dust mite or ragweed allergic patients
exposed to diesel exhaust particlesDEPs in
climate chamber expressed higher nasal
symptom scores following dust mite or ragweed
challenge, respectively, when compared to non-
exposed but allergen-challenged patients.
99,100
Also in the lower airways, short-term natural in-
crease in ambient air ozone was associated with
deteriorating lungh function tests in atopic asth-
matics despite use of proper asthma controller
therapy.
101
Similarly, an ozone exposure protocol
revealed atopic asthmatics expressed depressed
spirometry testing results compared to healthy
volunteers.
102
Along with this, climate chamber
studies revealed (ozone) exposure of healthy or
allergic asthmatics induces a neutrophilic
103
or a
mixed neutrophilic and eosinophilic
104
inflammatory profile in the lower airways,
respectively. Furthermore, gene expression
profiles of sputum cells recovered from healthy
volunteers and allergic asthmatic patients also
confirmed significant difference in inflammatory
response to ozone exposure.
105
Analysis of biomarkers activity greatly improved
our understanding of cascade and signal pathways
involved in atopic and non-atopic phenotypes of
airway disease following exposure. Although most
oxidative stress biomarkers require tissue spec-
imen collection, some studies suggest an analysis
of biomarkers can be determined non-invasively in
Author
/year
Clinical
Model Group under study Outcome measure/
Biomarkers Clinical Findings
Hong Z,
2016
98
Human
In-vitro PM2.5 NEC with pollutant
exposure and NAC
administration:
Cell viability, Reactive
oxygen species (ROS);
Antioxidant enzyme
activity of superoxide
dismutase (SOD), catalase
(CAT), and glutathione
peroxidase (GSH-Px);
nuclear translocation of
NF-E2-related factor-2
(Nrf2) (protector from
oxidative stress); Levels of
cytokines and respective
mRNA expression of GM-
CSF, TNF-
a
, IL-13, eotaxin,
IL-6 and IL-8
Pollutant exposure
decreased cell viability and
antioxidant enzymes levels
in parallel with increased
ROS levels, cytokines
expression and important
Nrf2 protective activity;
overall effect reversed by
NAC treatment.
Table 1. (Continued) Outcome findings in clinical exposure models of IAD with reference to biomarkers. 3-NT (3-Nitrotyrosine); 8-IP (8-
Isoprostane); 8-OG (8-Oxoguanine); AR (Allergic rhinitis); BEAS (human bronchial epithelial cell); CAT (Catalase); COX (cyclooxygenase); CRS (chronic
rhinosinusitis); CRSsNP (chronic rhinosinusitis without nasal polyps); CRSwNP (chronic rhinosinusitis with nasal polyps); DNA-DS (double stranded DNA); DSB
(Double-strand break); DUOX (Duol oxidase); ECRS (Eosinophilic chronic rhinosinusitis); eNO (exhaled nitric oxide); GM-CSF (Granulocyte Macrophage
Colony-Stimulating Factor); GSH (Glutathione); GSH-Px (Glutathione peroxidase); H2AX (histone family member X); HDM (house dust mite); HO (heme
oxygenase); IFN (interferon); IgE (immunoglobin); IL (interleukin); iNOS (inducible Nitric oxide oxygenase); INS (intranasal steroid); Iso-8 (8-iso-prostaglandin);
LTB4 (leukotriene B4); MDA (malondialdehyde); MIG (Monokine-induced by interferon
g
); mRNA (Messenger RNA); M4(Macrophages); NAC (N-
acetylcysteine); NADPH (Nicotinamide adenine dinucleotide phosphate); NEC (Nasal epithelial cell); NOX (nitrogen oxide); NP (nasal polyps); Nrf2 (Nuclear
factor erythroid 2-related factor 2); OS (oxidative stress); Ova (ovalbumine); PAR (perennial allergic rhinitis); PARP (poly ADP ribose polymerase); PM
(particulate matter); PON (paraoxonase); ROS (reactive oxygen species); SAR (seasonal allergic rhinitis); SOD (Superoxide dismutase); TAS (total antioxidant
stress); TGF (transforming growth factor); TNF (tumor necrosis factor); TOS (total oxidant status)
8Rouadi et al. World Allergy Organization Journal (2020) 13:100467
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exhaled breath condensates or blood.
106–111
Natural allergen exposure reverses oxidative and
antioxidative status compared to asymptomatic
period, with a persistent oxidative state outside
pollination season in allergic patients when
compared to healthy controls. AR and asthma
comorbidity in children does not seem to
augment oxidative stress markers compared to
AR alone,
111
although adult patients with
seasonal AR and asthma manifest an
exaggerated stress response during natural
allergen exposure compared to AR alone.
106
Clinically, oxidative stress correlates with nasal
symptom scores in children with perennial AR
and can predict AR severity independent of total
IgE.
109
Additionally, ROS status does not
correlate with atopic skin sensitization in children
with perennial AR.
108
Furthermore, dust mite
challenge in asthmatics or sensitized mice
resulted in oxidative damage to nucleic acids as
well as lipids and proteins and subsequently
triggered DNA repair pathways. Further blockage
of DNA repair proteins resulted in increased
production of DNA double-strand breaks and cell
apoptotic enzymes suggesting importance of DNA
repair in suppressing airway inflammation.
75
Endogenous antioxidant response in atopic res-
piratory diseases is complex and oxidative stress
response to anti-inflammatory drugs isare poorly
understood. Antioxidant enzymes mostly studied in
atopic respiratory diseases include heme oxygen-
ase 1 and 2,
112
, NADPH oxidases,
113
catalase,
98,114
superoxide dismutase,
98,107,114
dual oxidases 1 and 2 (in CRS patients),
96
paraoxonase,
109
and glutathione
peroxidase.
98,111
Antioxidant activity can also be
measured by serum thiol-SH and total antioxidant
status (Table 1). In this respect, evidence suggests
oxidative stress decreases antioxidant enzyme
activity or total antioxidant status in atopic
children
108,109,111
or in human in vitro controlled
exposure studies,
98
whereas other studies present
evidence to the contrary. For example, heme
oxygenase antioxidant (iso)enzyme-1 activity was
preferentially increased in a human in vitro model
of perennial AR,
112
and upregulated in a human
exposure model of COPD aggravated by
infection;
115
; also dual oxidase antioxidant (iso)
enzymes showed preferential upregulation in
different phenotypes and endotypes of CRS.
96,97
Contrary to this, antioxidant enzymes can be
downregulated in asthma and rhinitis irrespective
of atopic status,
107
and in vitro animal exposure
models challenged by an infectious insult.
72
Importantly, genetic polymorphism in antioxidant/
detoxifying genes like GSTM1 and GSTP1 can
alter oxidative stress response in patients with
COPD and those with AR following
exposure.
116,117
Exogenous (dietary) antioxidants are scavengers
of oxygen free radicals and can act on different
levels of defensive antioxidation pathways.
118,119
Epidemiologic,
120
in vivo
121,122
and in vitro
123
studies suggest a beneficial role of exogenous
antioxidants in patients with IAD or in controlled
exposure studies of healthy sinonasal epithelial
cells. However, lack of clinical trials data clearly
supporting their efficacy, in addition to their
potential role in skewing Th1/Th2 balance
towards a Th2-type immunity as suggested
in vitro,
124
renders their indication restricted to
special situations such as over exposure to
environmental pollutants, among others.
125
N-
acetylcysteine maintains a potent antioxidant
effect in in vitro studies
98
or in ovalbumin-
sensitized rats by downregulating tumor necrosis
factor-alpha in recruited inflammatory cells.
126
Along these lines, intranasal steroids can exhibit
an exogenous antioxidant regulatory role in
seasonal AR by decreasing exhaled breath
condensates of leukotriene B4 and 8-Isoprostane,
although no effect was seen on exhaled carbon
monoxide and nitrogen oxide.
106
In another study
involving children with AR and asthma, no effect of
topical nasal steroid therapy was noted on
measured lipid peroxidation oxidative stress
biomarkers and antioxidant enzymes.
111
Data on
potential antioxidant effect of inhaled steroids in
adult asthmatics is scarce. Epidemiological
studies suggested prior intake of oral
127
or
inhaled steroids
128
in adult asthmatic patients
had no effect on asthma control, as measured by
clinical symptoms and FEV1 testing, with PM and
ozone exposure. Other similar studies noted
increased consumption of asthma controller
therapy (bronchodilators, inhaled corticosteroids,
or both) with PM10
129
or NO
2
exposure
130
in
adults. Moreover, in children inhaled steroid
therapy downregulated induced expression of
heme oxygenase-1 in non-smoking patients with
Volume 13, No. 10, October 2020 9

bronchiectasis but had no effect on exhaled car-
bon monoxide.
131
Furthermore, desloratadine can
exert an antioxidant effect in children with
perennial AR by increasing antioxidant enzyme
activities (catalase and superoxide dismutase)
and decreasing lipid peroxidation marker
(malonaldehyde) although no effect was seen on
total antioxidant status.
114
When compared to
placebo, fexofenadine improved nasal symptom
scores in ragweed AR patients following ragweed
challenge and DEP controlled exposure.
100
The majority of controlled human exposure
studies to ambient pollutants have been conduct-
ed in climate chambers on healthy individuals.
132–
135
For example, relative to clean air, mixtures of
VOCs increased ratings of nasal irritation, odor
intensity
136
and cognitive symptoms (memory
loss, dizziness), and a two-fold increase in
polymorphonuclear cells in nasal lavage
immediately following exposure.
137
Similar
studies using different pollutants showed no
detectable effects on nasal symptom scores or
markers of nasal inflammation.
134,138
Additionally, healthy subjects exposed to room
air, nanoparticles, or O
3
/terpene showed no
significant changes in inflammatory biomarkers in
blood, sputum or nasal secretions and pulmonary
function tests. However, only nanoparticles
exposure increased significantly high frequency
variability in heart rate, thereby indicating a shift
in autonomic balance to a more parasympathetic
tone.
133
Low level ozone exposure in healthy
subjects resulted in increased sputum production
of airway inflammatory cells such as neutrophils,
monocytes, and dendritic cells, and modification
of cell surface phenotypes of antigen presenting
cells.
139
Using a similar protocol the reported
decrement in lung spirometry testing (FEV1) of
healthy subjects was associated with increased
neutrophilic airway inflammation following
exposure;
140
the latter likely being more
pronounced in healthy individuals with GSTM1
null genotype.
141
More importantly, comparing
healthy controls to atopic asthmatics, exposure to
high levels of ultrafine particles in a climate
chamber was associated with a small but
significant fall in arterial oxygen saturation, a fall
in forced expired volume over 1 s (FEV1) the
morning after exposure, and a transient slight
decrease in low frequency (sympathetic) power
during quiet rest.
142
These controversial results
can be related partly to the nature and
concentration of the investigated pollutant or its
experimental duration of exposure keeping in
mind brief exposure to a single pollutant in a
climate chamber does not reflect chronic
exposure to multiple pollutants in real life.
Controlled exposure studies in atopic patients
involving allergen challenge revealed more
consistent results. For example, dust mite allergic
patients reported worsening nasal symptom
scores following intranasal dust mite challenge
and DEP exposure commensurate with increased
histamine levels in nasal washes, all suggestive of
induced mast-cell degranulation.
143
Similarly,
controlled exposure studies in ragweed allergic
patients challenged with DEP and ragweed
outside their pollen season reported higher total
nasal symptoms scores
100
or increased levels of
specific IgE and expression of Th2 inflammatory
cytokines, when compared to ragweed
challenged alone.
77
Taken together, controlled airway exposure
studies to ambient pollutants in healthy individuals
show small but significant negative health effects
whereas exposure studies in allergic patients sup-
port the role of pollutants in increasing atopic
airway hypersensitivity. Large scale translational
studies are needed to correlate the bio-cellular
toxic effects of pollution with epidemiological
studies.
COMPARATIVE ANALYSIS OF
IMMUNOPATHOLOGICAL ALTERATIONS
IN CLINICAL EXPOSURE MODELS OF IAD
ACCENTUATED BY INFECTION
Signal and cascade pathways triggered across
the airway mucosal barrier at first encounter of
pollutants are complex (see Fig. 1). Airway
mucosal cells can recognize pollutants through
an epithelial toll-like receptors (TLR)-mediated
mechanism either directly or indirectly by the
intermediary of pattern recognition receptors (see
below). More precisely, pollutants such as PM,
cigarette smoke, and ozone can present them-
selves directly to subclasses of surface TLRs,
namely TLR2 and TLR4, which can serve as ligands
for these pollutants. Alternatively, pollutants can
be bound to pattern recognition receptors, a
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collective conglomerate of receptors which en-
compasses TLRs and normally can recognize
conserved molecular structures derived from mi-
crobial agents or released by damaged non-
microbial cells. Once triggered, pattern recogni-
tion receptors and TLRs attract antigen presenting
cells and leukocytes to the site of inflammation
resulting in priming of the airway to subsequent
mucosal infectious insults.
144
Afterwards, when
eventuated by an infectious challenge, alveolar
macrophages mount a heightened inflammatory
response aimed at containing and clearing
bacteria while producing minimal collateral tissue
damage.
145,146
The immunological “storm”
resulting from co-exposure and infection is stud-
ied in different clinical models of respiratory cells
and also in patients with IAD such as COPD
(Table 2). Another signal pathway is mediated by
submucosal innate lymphoid cells (ILCs) which
can differentiate into adaptive subsets. ILC1s
relates to immune reactions in CRS without nasal
polyps, COPD, and some viral and bacterial
infections; whereas ILC2s becomes important in
regulating type 2 immunity and some helminthic
and viral infections.
147,148
Other immunologic
and antimicrobial responses to pollutant
exposure modulate expression of host defense
peptides and antiviral mechanisms, impair mucus
production crucial for capturing pollutants or
weaken tight junctions essential for the epithelial
airway defense barrier.
149,150
Epidemiological studies suggest indoor and
outdoor air pollution increase the risk of respira-
tory tract infections in both pediatric
151–154
and
adult populations.
80,151,152,155
For example,
morbidity of the recent COVID-19 pandemic dis-
ease has been linked partly to air pollution.
156–159
Also, air pollution can aggravate the severity of
asthma caused by respiratory viral infections.
160
Moreover, in vitro studies suggest air pollution
may suppress innate and adaptive immunity and
increases susceptibility to bacterial and viral
respiratory infections in both human and animal
clinical models, following short- or long-term
exposure (see Table 2). For example, in the
upper airways diesel exhaust exposure increased
the number of human nasal epithelial cells
infected by Influenza A virus in vitro The
proposed mechanism was enhancement of virus
attachment and entry into respiratory cells
mediated by radical oxygen species, despite
increased antiviral interferon-dependent signaling
and interferon-stimulated gene expression by DEP
exposure.
161
Also, in vitro Rrhinovirus (RV) 16
infectivity following nitrogen oxide and ozone
exposure in human respiratory epithelial cells
Fig. 1 Immunopathological alterations in innate and adaptive immune system in patients with IAD following pollutant exposure
and infection. DAMP-R (Damage-associated molecular pattern receptor); ICAM-1 R (Intracellular adhesion molecule receptor); IL
(Interleukin); ILC (Innate lymphoid cell); NK (Natural killer); PAFR (Platelet-activating factor receptor); PAMP-R (Pathogen associated
molecular pattern receptor); PRR (Pattern recognition receptor); TLR (Toll like receptor); TSLP (Thymic stromal lymphopoietin); TTF1
(Thyroid transcription factor-1)
Volume 13, No. 10, October 2020 11

Author, year Clinical
Model
Sample
under
study
Pollutant Infectious
agent Outcome measure Clinical Findings
Yang H,
2001
168
Rats
In-vivo
&
In-vitro
LT & BALF DEP LM LT and BALF, M
f
following
exposure and infection:
- ROS formation; NO level;
CD4 and CD8, CD4
þ
/CD8
þ
T
cells & M
f
DEP exposure in rats increases
susceptibility to LM infection by
attenuating M
f
function (ROS
and NO production) and T cell
(CD4 and CD8) mediated
immunity.
Spannhake W,
2002
71
Human
In-vitro NEC &
BEC NO
2
&
O
3
RV16 BEC, following infection and
exposure:
- IL-8 release (neutrophil
chemotactic factor,
phagocytosis stimulant);
ICAM-1 (receptor for human
RV 16- Epithelial surface
inflammatory binding
protein) mRNA expression
Pollutant-induced exaggerated
RV16 infectivity manifested by
upregulation of ICAM-1 and
increased binding to airway
epithelial cells and mediated by
induction of proinflammatory IL-8
cytokines production and
oxidative stress pathway
Yin X, 2004
171
Rats
In-vivo LT & BALF DEP LM BALF and LT, following
exposure and infection:
- LPS-assisted AM IL-1
b
(acts
on NK cell), TNF-
a
(acts on NK
cell), IL-12 (initiator of cell
mediated immunity), IL-10
(immunosuppressive cytokine
and prolongs intracellular
pathogens survival- e.g. LM),
IL-2, IFN-
g
(released by NK),
and IL-6 (induction of
cytotoxic T lymphocyte
development from murine
thymocytes); Lung draining
lymph node CD4
þ
/CD8
þ
T
cells
LM-mediated suppression of
innate (i.e. M
f
, IL-1
b
, TNF-
a
, IL-
12, IL-2 and IFN-
g
) and adaptive
(i.e. CD4 and CD8 T cell) immune
response upon repeated low
dose DEP exposure and
downregulation of protective
bacteria-induced T cell cytokines
(IL-10 and IL-6) and upregulation
of macrophage bactericidal
cytokines
Jaspers I,
2005
161
Human
In-vitro NEC &
BEC DEas IVA NEC/BEC cells, following
exposure and infection:
- IVA m-RNA transcription
level, viral proteins; IVA-
induced IFN-
b
-mRNA level,
ISRE promoter reporter
activity (IFN-stimulated
Increased oxidative stress-
mediated (DCF-DA) susceptibility
to viral infections is manifested by
increase in IVA RNA transcription
activity and viral proteins in NEC
cells. Increased susceptibility is
likely unrelated to IFN-
b
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genes); DCF-DA (oxidative
marker); BEC-attached IVA
RNA level
production (IFN-
b
-mRNA level,
ISRE promoter reporter activity
not decreased) and expressed by
increasing number of infected
cells and enhancement of virus
attachment and entry into BEC
(measured by BEC-attached IVA
RNA level)
Harrod K,
2005
163
Mice
In-vivo BEC DEE PAE BEC, following exposure and
infection:
- Histopathology severity
scores; tissue bacterial count
of PAE
- Tissue
b
tubulin (BEC ciliary)
marker, epithelial SCGB1A1
(non-ciliated BEC cell marker
i.e. Clara cell) marker, and
tissue TTF-1 (lung-specific
host defense gene
expression/transcription
regulator)
Impaired bacterial clearance in
BEC following PAE infection and
short-term DEP exposure (1
week), partly by airway
remodeling as manifested by
decrease in ciliated (tissue
b
tubulin) and non-ciliated airway
epithelial cell markers
(SCGB1A1) and concordant with
decrease in lung-specific host
defense gene expression in Clara
cells (TTF-1)
HongweiZhou,
2007
179
Mice
In-vitro BALF PM <2.5
m
m SP BALF M
f
, following exposure
and infection:
- Tissue count of total SP
uptake, ingestion, and killing
Impairment of SP clearance and
phagocytosis following PM
exposure likely due to decreased
internalization but not decreased
killing rate nor increased binding
of bacteria to macrophages.
Sigaud S,
2007
174
Mice
In-vivo
&
In-vitro
BALF PM <2.5
m
m SP BALF M
f
and PMN, following
IFN-
g
priming and exposure:
- PMN count, DCF-DA (OS
marker); lung expressed pro-
inflammatory cytokine mRNA
BALF M
f
and PMN, following
IFN-
g
priming, exposure, and
infection:
- Remaining viable count of SP
in-vitro and in-vivo;
histopathology
PM <2.5
m
m exposure in
addition to viral infection
exemplified by IFN-
g
priming
trigger a neutrophilic
inflammation as suggested by
activation of genes encoding
PMN-recruiting chemokines or
their receptors. This can
predispose to an SP-induced
ROS-mediated severe
pneumonia in mice, likely
secondary to a neutrophilic (and
to a lesser extent M
f
-mediated)
impaired bacterial clearance and
phagocytosis.
(continued)
Volume 13, No. 10, October 2020 13

Author, year Clinical
Model
Sample
under
study
Pollutant Infectious
agent Outcome measure Clinical Findings
Mushtaq N,
2011
165
Human
In-vitro BEC PM <10
m
m SP BEC, following exposure and
infection:
- Adhesion of SP to PM-
exposed BEC in-vitro and in-
vivo; and glutathione
(oxidative stress marker) level
reversal by NAC
- PAFR (putative receptor for
PM-stimulated pneumococcal
adhesion to airway cells)
mRNA transcript level,
receptor expression, and
blocking
PM-enhanced vulnerability to
human SP infection in vitro,
manifested by increased
bacterial adhesion and
penetration into BEC, mediated
by oxidative stress and PAFR, and
reversed by NAC and PAFR
blockage
Chaudhuri N,
2012
177
Human
In-vitro Serum
MDM
f
DEP E-Coli (LPS
endotoxin) Serum MDM
f
, following
exposure:
- Cell count of DEP-
incorporating MDM
f
in
COPD and healthy
volunteers; MDM
f
mitochondrial membrane
electrical potential and
lysosomal fluorescence in
healthy volunteers
Serum MDM
f
, following
exposure, TLR agonist, and LPS
endotoxin:
- CXCL8 (M
f
produced IL-8)
cytokine responses following
TLR4, TLR7 agonists or heat
killed E. coli in both COPD
and healthy volunteers;
MDM
f
CD14 (co-receptor to
TLR4 for LPS recognition),
CD11b (M
f
differentiation
marker) surface marker
expression in healthy
volunteers
Loss of low-level DEP-exposed
MDM
f
along their differentiation
into macrophages likely due to
dysfunctional (loss of
mitochondrial membrane
electrical potential and lysosomal
function) and phenotypic (TLR-
mediated reduction in CD14 and
CD11 surface marker expression)
structural changes in MDM
f
of
healthy exposed individuals. This
can likely contribute to
inflammation in COPD by
decreased MDM
f
pro-
inflammatory cytokines (CXCL8)
production.
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Migliaccio C,
2013
170
Mice
In-vivo
&
In-vitro
AM &
BMdM WS derived
PM or IWS SP BALF, following high level IWS
and SP infection:
- Bacterial load; AM
Phagocytosis; IFN-
g
production; leucocytes class
II
þ
MHC (marker of MO
activation), AF (marker of
phagocytosis); RelB activation
and translocation (NF-
kb
pathway activity), Cyp1A1
activation (AhR pathway
activity)
Impaired antimicrobial defense
system with inhalation of high
level WS and infection with SP
secondary to decrease in IFN-
g
production and macrophage
number and activation
(leucocytes class II
þ
MHC) but not
in phagocytic activity (unchanged
AF marker), likely mediated via
NF-
kb
pathway activation and
AhR pathway. Unchanged
phagocytic activity and no
increase in neutrophils or TNF-
a
(data not shown).
Zhao H,
2014
167
Rats
In-vitro BALF PM 2.5
m
m SA BALF, following exposure:
- AM, neutrophils,
lymphocytes, and total cells;
IL-6 and TNF-
a
level
Following exposure and
infection:
- Histopathological scoring,
rats growth rate, bacterial
burden, response of natural
killer (NK) cells; and
phagocytosis index of SA by
AM
PM exposure triggers recruitment
of inflammatory cells, secretions
of key inflammatory cytokines (IL-
6, TNF-
a
) in BALF and increases
susceptibility to SA infection
through depressed phagocytosis
and abnormal NK cell response,
both restored by adoptive
transfer of NK cells.
Roos A, 2015
173
Mice
In-vitro BALF CS NTHi BALF, following CS exposure
and NTHi infection in IL-17
þ
and/or IL-17
–
(knock out) or IL-
1R1
–
mice:
- Neutrophils, total cells,
neutrophils count following
anti-IL-17A therapy; IL-17
(Th17 pathway) level, CXCL1,
and CXCL5
Following exposure and infection
in BALF of IL-17
þ
mice, an
increased cell counts of
neutrophils, total lymphocytes
and IL-17 noted; Important role
of IL-17 in inducing NTHi
exacerbated neutrophilia of
exposed mice stems from
attenuation of IL-17 and cell
counts in IL-17 “knock out”mice
or with suppression of
neutrophilia in NTHi infected
mice pre-treated with anti-IL-17A
antibody; Important role of IL-1
signaling in exacerbating IL-17A-
mediated neutrophilia stems
(continued)
Volume 13, No. 10, October 2020 15

Author, year Clinical
Model
Sample
under
study
Pollutant Infectious
agent Outcome measure Clinical Findings
from concomitant absence of
CXCL1 and CXCL5 induction with
decreased IL-17 level in IL-17
“knock out”mice, and from
decreased induction of IL-17A-
mediated airway neutrophilia in
IL-1R1
–
mice compared with wild-
type control animals.
Human
In-vivo Sputum &
Serum
Stable
COPD
&
NTHi-
AECOPD
Not applicable NTHi Sputum, before, during or after
NTHi AECOPD and stable
COPD:
- IL-17A, IL-17F, IL-8 (neutrophil
chemo attractant)
During NTHi-associated
AECOPD a concomitant
increased levels of sputum IL-8
and IL-17A noted, with IL-17
expression normalized after
resolution of the exacerbation,
but no correlation seen among
them during AECOPD caused by
other microorganisms
suggesting IL-17 is a critical
mediator of CS-exacerbated
pulmonary neutrophilia
associated with NTHi in AECOPD
Overall, there is an important role
of IL-17, and potentially anti-IL-17
therapy, in CS-exacerbated
pulmonary neutrophilia
mediated by IL-1 signaling and
associated with NTHi in AECOPD
Rylance J,
2015
169
Human
In-vivo
&
In-vitro
BALF
&
Serum
WS
PM <4
m
m
HAP
E-Coli (LPS
endotoxin) BALF, following natural
(household) or experimental
(WS) PM exposure or LPS
infection and glutathione
depletion:
- AM phagocytosis, proteolysis
(LDH), and oxidative burst;
Glutathione (antioxidant
marker) response to
buthionine sulfoximine (BSO-
Natural (chronic) PM exposure of
human BALF decreases AM
cytokine (CXCL8) release,
downregulates induced
phagosomal oxidative burst but
does not impair redox potential,
proteolysis or phagocytosis. LPS
priming following PM ex vivo
exposure increased all cytokine
(CXCL8, IL-6, TNF-
a
, CCL2)
levels; however, reduction of
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oxidant); Cytokines (CXCL8,
IL-6 and TNF-
a
, CCL2) release CCL2, but not CXCL8, response
to glutathione depletion upon
LPS stimulation and natural
exposure suggests CCL2 may
have a role in preventing
excessive inflammation
Buonfiglio L,
2017
162
Pig
&
Human
In-vitro
NEC, BEC
ASL/AMP
b
PM (CFA) SA Pig NEC, ASL/AMP and human
BEC, following exposure and
infection; and human lysozyme
following exposure:
- Live bacterial tissue count;
HBD-3 (human
b
defensin-3),
LL-37 (Cathelicidin), and
lysozyme (cationic) level (all 3
are components of ASL/
AMP); CFA adsorption to
Lysozyme; Zeta potential
(electrostatic interaction
between CFA and lysozyme)
In human and animal model PM-
induced impairment of airway
antimicrobial activity against SA
manifests as decreased levels of
HBD-3, LL-37, and free lysozyme
level, all components of epithelial
air surface liquid antimicrobial
proteins, and results from
adsorption and electrostatic
interactions between pollutants
(CFA) or bacteria with ASL AMPs,
leading to depletion of the latter
thereby increasing the chance of
bacterial proliferation.
Jaligama S,
2017
172
Neonatal
Mice
In-vivo
LT DCB
(combustion
derived PM
with EPFR)
IVA Neonatal LT and Treg following
exposure, or exposure and
infection, or Treg depletion, or
Treg adoptive transfer, or
recombinant IL10 (rIL-10)
treatment:
- IL-10; Treg; IL-10-anti CD25;
weight change and
pulmonary viral load.
Following IVA infection in
neonatal mice, a PM-induced
suppression of adaptive immune
system is mediated by increase in
Treg and IL-10, reversed by Treg
depletion and recapitulated by
Treg adoptive transfer or rIL-10
treatment
Ma J, 2017
178
Mouse
In-vivo BALF PM2.5 IVA BALF following exposure and
infection, in normal or in Kdm6a
(IFN-
b
and I L-6 gene expression
regulator through respective
activation by histone
demethylation) knockdown
mice:
- Mice survival rate; IFN-
b
and
IL-6 levels, OAS1 (IFN-
b
stimulating gene) expression;
M
f
Kdm6a
Short-term (1 day) exposure to
PM-inhalation followed by IVA
infection results in early phase
robust upregulation of IL-6 level
and IFN-
b
level and expression
(OAS1), whereas long-term
(starting day 3) exposure
downregulates innate immune
response to IVA infection, likely
mediated by macrophage
cytokine expression gene
regulator, Kdm6a.
(continued)
Volume 13, No. 10, October 2020 17

Author, year Clinical
Model
Sample
under
study
Pollutant Infectious
agent Outcome measure Clinical Findings
Zarcone M,
2017
115
Human
In-vitro PBEC DEP NTHi PBEC following exposure and
infection in healthy and COPD
patients:
- Epithelial barrier activity; LDH
(cytotoxicity) release;
Epithelial gene expression of
OS response markers (heme
oxygenase - HO), HSPA5
binding protein (endoplasmic
reticulum chaperone), CHOP
(marker for ER-stress induced
apoptosis)
DEP- and NTHi-mediated acute
attacks in COPD patients results
in no epithelial barrier
dysfunction nor cytotoxicity. It
can be induced by increased
expression of HO epithelial
antioxidant marker and by
alterations in epithelial innate
immunity undertaken at the level
of endoplasmic reticulum and
manifested by depressed gene
expression, but not apoptosis
(CHOP), of integrated stress
response markers HSPA5.
Bhat T, 2018
175
Mice
Ex-vivo BALF, LT,
&serum SHS NTHi LT, BALF, serum, bone marrow
and splenocytes following
exposure and infection, and/or
P6 vaccination:
- Lymphocytic inflammation
around broncho-alveolar
bundles; DC, neutrophils,
and M
f
; CD4
þ
CD8
þ
B and T
cells, ROR
g
tþTh17, IL-6, IL-
1
b
, and TNF-
a
; Anti-P6 (NTHi-
derived outer membrane
lipoprotein DNA binding
protein) total antibodies;
Antibodies subclasses IgG1,
IgG2a, IgG2b, IgA and
Antibody-secreting specificB
cells; P6-specific producing
Th17 cells, IL-4 and IFN-
g
producing T cells, IgG1 and
IgG2a subclasses of Anti P6 -
secreting B cells; IL-4 and
IFN-
g
secreting P6-specificT
cells; Bacterial clearance,
albumin level
SHS exposure and infection
impaired bacterial clearance
manifested as increase in
immune cell infiltrate
(Neutrophils, DC, B cells, T cells)
except for macrophages, and
impeded induction of a robust
adaptive immune response
manifested as decreased IFN-
g
despite increased IL-17, IL-6, IL-
1
b
, TNF-
a
and ROR
g
tþTh17;
also, prolonged depression in B
cell adaptive immune response
manifested as reduced total anti-
P6 antibodies and Antibody
subclasses (IgA, IgG1, IgG2a
IgG2b)
Following exposure and (P6-)
specific T cell stimulation
(vaccination), a decrease in IL-4
and IFN-
g
in lung and spleen,
both required for Antibody class
switching to IgG1 and IgG2a,
concomitant with decreased
frequency of anti-P6 Ig-secreting
B cells for both IgG1 and IgG2
18 Rouadi et al. World Allergy Organization Journal (2020) 13:100467
http://doi.org/10.1016/j.waojou.2020.100467

sub-classes suggest depressed T
cell adaptive immune system
essential for inducing robust
antibody responses to NTHi
infection.
P6 Immunization and SHS
exposure impaired induction of
robust T and B cell mediated
immune response when
compared to air exposure,
increased influx of neutrophils
but not bacterial clearance
thereby suggesting significant
impairment of neutrophils
phagocytic function.
Consequently, depressed B and
T cell adaptive immune response
can be mitigated by P6 antigen
vaccination
Chen X,
2018
164
Human
In-vitro BEC PM PAE BEC, following exposure and
infection:
- Invasion by PA; Oxidation-
sensitive fluorescent probe
(DCFH-DA) for ROS
formation; SA-
b
-gal
biomarker (cell senescence);
hBD-2 (epithelial
antimicrobial peptide) level;
mRNA expression of hBD-2,
lactoferrin, IL-8, and IL-13
PM followed by PAE infection
increases epithelial cell
senescence biomarker (SA-
b
-gal)
in an ROS-mediated and a
concentration-dependent
manner and interferes with innate
bactericidal response of airway
epithelium by suppressing
induction of hBD-2 level and
mRNA expression, but not
lactoferrin, IL-8, or IL-13
Gotts J, 2018
176
Mice
Ex-vivo LT, BALF,
blood
and
spleen
CS SP BALF, LT and blood following
exposure and infection, and/or
antibiotic therapy:
- Mice lung injury (survival rate,
lung weight loss,
hypothermia, arterial oxygen
saturation, excess extra-
vascular lung water) with brief
or severe CS exposure;
Neutrophils, lymphocytes,
M
f
and monocytes;
Chemokines for neutrophils
CS improved mice survival on
severe exposure but no other
parameters of bacterial
pneumonia; contributed to
confinement of the infection to
the lung manifested by a
decreased number of neutrophils,
increase in M
f
and monocytes
but no change in lymphocytes;
and caused a differential
elevation of neutrophils
antimicrobial peptides MPO, but
(continued)
Volume 13, No. 10, October 2020 19

Author, year Clinical
Model
Sample
under
study
Pollutant Infectious
agent Outcome measure Clinical Findings
(KC-murine homolog of IL-8),
lymphocytes (CXCL9), and
monocytes (MIP-1
a
); MPO
(antimicrobial enzyme in
neutrophilic granules), and
lymphocytes granzyme B
(serine protease contained in
the cytotoxic granules of
lymphocytes); IL-1
a
, IL-17,
TNF-
a
; SP-D and Ang-2
(alveolar and endothelial cell
injury markers, respectively)
notNEorgranzymeB.On
supplemental antibiotic therapy
benefit in survival rate was lost
manifested by increased
pulmonary edema concomitant
with increased numbers of BAL
monocytes, upregulated
neutrophil, lymphocyte, and
monocyte chemokines (KC,
CXCL9, and MIP-1
a
), induced
alveolar and endothelial cell
injury markers (SP-D Ang- 2), and
downregulated Th1 and Th17
inflammatory cytokines (IL-1
a
,IL-
17).
Wang W,
2018
72
Chicken
Ex-vivo LT H
2
S LPS Lung tissue following exposure
& infection:
- Histopathology; m-RNA level
of IL-4, IL-6 (secreted by Th₂),
TNF-
a
, IL-1
b
, IFN-
g
(secreted
by Th₁), and HO-1
(antioxidant enzyme); m-RNA
expression of oxidative stress
NF-
k
B pathway genes (I-
k
B
and I-
ka
), TNF-
a
, and PPAR-
g
(peroxisome proliferator
nuclear receptor)
H
2
S exposure aggravated LPS-
induced inflammatory changes in
the lungs through Th₁/Th₂
imbalance manifested by
increased mRNA expression of IL-
4, IL-6, IL-1
b
, and TNF-
a
expression and a concordant
decrease in IFN-
g
expression;
also by depressed antioxidant
mechanisms such as antioxidant
enzyme (HO-1) levels and PPAR-
g
expression, and by activation of
NF-
k
B pathway-related genes (I-
k
B and I-
ka
).
Table 2. (Continued) Outcome findings in IAD clinical models challenged by exposure and infection with reference to biomarkers. AECOPD (Acute exacerbation of chronic obstructive
pulmonary disease); AF (Autofluorescence); AhR (Aryl hydrocarbon receptor); AM (Alveolar macrophages); AMPS (Antimicrobial proteins and peptides); ASL (Airway surface liquid); BALF (Bronchoalveolar lavage
fluid); BEC (Bronchial epithelial cells); BMdM (Bone marrow derived Macrophages); BSO (Buthionine sulfoximine); CCL2 (Chemokine Ligand); CAP (Concentrated ambient particles);CD(Cluster of differentiation);
CFA (Coal fly ash); COPD (Chronic obstructive pulmonary disease); CS (Cigarette Smoke); CYP1A1 (Cytochrome P450 Family 1 Subfamily A Member 1); DC (Dendritic cells); DCB (Combustion derived PM with
chemisorbed EPFR); DCF-DA (Dichlorofluorescein diacetate); DEas (Aqueous-trapped solution of Diesel exhaust); DEE (Diesel engine emissions); DEP (Diesel exhaust particles); E. Coli (Escherichia coli);EPFR
(Environmentally persistent free radicals); H
2
S(Hydrogen sulfide); HAP (Household Air Pollution); HBD (Human
b
defensin); HO (Heme oxygenase); HSPA5 (Heat Shock Protein Family A (Hsp70) Member 5);
ICAM-1 (Intercellular adhesion molecule 1); IFN (Interferon); Ig (Immunoglobulin); IL (Interleukin); IL-1R (Interleukin 1 receptor); ISRE (Interferon specific element); IVA (Influenza A virus); IWS (Inhaled wood
smoke); LDH (Lactate dehydrogenase); LM (Listeria Monocytogenes); LPS (Lipopolysaccharide); LT (Lung tissue); MDM
f
(Monocyte-Derived Macrophages); MHC (Major histocompatibility complex); MIP-1alpha;
MO (monocytes); MPO (Myeloperoxidase); mRNA (messenger RNA); M
f
(Macrophages); NAC (N-acetylcysteine); NEC (Nasal epithelial cells); NF-
kb
(Nuclear factor kappa beta); NK (Natural killer); NO (Nitric
oxide); NO
2
(Nitrogen Dioxide); NTHi (Nontypeable Haemophilus influenzae); O
3
(Ozone); OAS (Oligoadenylate synthetase); OS (oxidative stress); P6 (Protein 6); PAE (Pseudomonas Aeruginosa); PAFR (Receptor
for platelet-activating factor); PBEC (Primary bronchial epithelial cells); PM (Particulate matter); PMN (Polymorphonuclear leukocyte); PPAR (Peroxisome proliferator-activated receptor); rIL-10 (Recombinant IL-
10); ROR-
g
(reactive oxygen radicals); ROS (Reactive oxygen species); RV16 (Rhinovirus 16); SA (Staphylococcus aureus); SA-
g
-gal (Senescence-associated
b
-galactosidase assay); SCGB1A1 (Secretoglobin); SHS
(Secondhand smoke); SP (Streptococcus Pneumonia); TLRs (Toll-like receptors); TNF (Tumour Necrosis Factor); Treg (Regulatory T cells); TTF1 (Thyroid transcription factor 1); WS (Wood smoke)
20 Rouadi et al. World Allergy Organization Journal (2020) 13:100467
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resulted in increased ICAM 1 receptor expression
(receptor for RV16) and pro-inflammatory IL-8
cytokine production.
71
In another combined
human and animal model, activated nasal airway
microbial proteins at the surface mucosal liquid,
which include lysozyme, human cathelicidin
antimicrobial peptide, and human
b
defensins,
were attenuated following (PM) exposure and
Staphylococcus aureus infection. The ensuing
impaired bacterial killing resulted from
adsorption and electrostatic interactions between
either pollutant or bacteria with activated
microbial proteins leading to the depletion of the
latter.
162
The literature on the lower airways exceeds that
on the upper airways. In this respect, susceptibility
to infections following exposure was examined at
several stages of immunological alterations trig-
gered in host cells.
Starting with the epithelial barrier level, an initial
in vivo PM exposure of bronchial epithelial cells in
mice followed by experimental infection with
Pseudomonas aeruginosa resulted in decreased
levels of an epithelial ciliary marker (
b
tubulin) and
a non-ciliary epithelial (Clara cells) marker, and
their gene expression/transcription regulator, all
suggesting airway remodeling is a contributing
factor to the impaired bacterial clearance.
163
Furthermore, an initial infection with
Pseudomonas aeruginosa induced an epithelial
antimicrobial peptide human beta defensin 2;
but as the model was pre-exposed to PM, induc-
tion of human beta defensin 2 was suppressed and
a cell senescence biomarker (SA-
b
-gal) was upre-
gulated in an ROS-dependent process.
164
Also, in
an in vitro human model, a PM-enhanced suscep-
tibility to Streptococcus pneumoniae infection was
heightened by increased bacterial adhesion and
penetration into bronchial epithelial cells. This was
mediated by a receptor for platelet-activating fac-
tor, a putative receptor for PM-stimulated pneu-
mococcal adhesion to airway cells.
165
On a submucosal level, macrophages and
monocytes play a central role in phagocytosis. The
study of immunopathological alterations in
phagocytosis has shown inconsistent results. For
example, in an exposure (PM)-infectious animal
model, impaired Streptococcus pneumoniae
clearance and phagocytosis resulted from
decreased macrophages internalization of bacte-
ria, although increased binding of microbe to
surface of macrophages was reported.
166
In a
similar model increased susceptibility to
Staphylococcus aureus infection resulted from
depressed phagocytosis index and abnormal
natural killer cell response.
167
Also, in another
animal exposure model increased infectivity to
Listeria monocytogenes resulted from decreased
ROS-induced nitric oxide production by alveolar
macrophages.
168
In contrast, natural (chronic) PM
exposure of human bronchoalveolar lavage fluid
decreased macrophage cytokine (CXCL8) release
and downregulated induced phagosomal
oxidative burst. Per contra, no impairment in
macrophage redox potential, proteolysis or
phagocytosis was observed likely due to the
experimental chronicity of exposure.
169
Additionally, in an analogous model using high
levels of the same pollutant (PM), the impaired
antimicrobial defense resulted from defective
macrophage activation of T cells by class II
þ
major histocompatibility complex and
subsequent decrease in interferon-
g
production,
but unaltered phagocytic activity.
170
Interestingly,
no increase of neutrophils and TNF-
a
levels was
observed in bronchoalveolar lavage following
exposure and infection suggesting acute
exposure to relatively high level of PM does not
trigger a classic or sustained inflammatory
response.
170
Besides suggesting interference with innate
immunity, exposure studies suggest further al-
terations in adaptive immunity as evidenced by
immunopathological relationships between anti-
gen presenting cell cytokines, the corresponding
sensitized T cells subsets, and recruited neutro-
phils (see Table 2). As such, a Listeria
monocytogenes-mediated suppression of
macrophages immune response upon low dose
DEP exposure manifested as “dysfunctional”
production of macrophages-derived cytokines.
This was associated with downregulation of
innate protective cytokines (e.g. IL-1
b
, tumor ne-
crosis factor-
a
,IL-12,IL-2andinterferon-
g
), sup-
pressionofadaptiveCD4andCD8Tcellimmune
response, and upregulation of macrophage
bactericidal anti-inflammatory cytokines (IL-10
and IL-6).
171
Other examples of altered cytokine
release include the pro-inflammatory
Volume 13, No. 10, October 2020 21

interleukin-8 (IL-8) synergistic release by respira-
torycellsinanexposure model challenged by
viral infection (rhinovirus 16);
71
also a decrease in
chemokine ligand 2 level in an experimental PM
exposure model involving lipopolysaccharide
priming, thereby suggesting an important role
of chemokine ligand 2 in preventing excessive
inflammation.
169
Besides the role of cytokines in
fine tuning extent of inflammation in these
models, T cell subsets like T cytotoxic (CD8
þ
)
and regulatory T cells (Treg) in addition to
neutrophils have been studied. DEP exposure in
rats increased susceptibility to Listeria
monocytogenes infection by attenuating T cell
mediated immunity, namely CD4
þ
Thelper
lymphocytes and CD8
þ
T cytotoxic cells;
168
PM
exposure in neonatal mice resulted in
depression of adaptive response to influenza
virus A infection and by an increased expression
in Treg cells and IL-10 in lung tissues. Interest-
ingly, the induced immunosuppressive effect was
reversed by Treg depletion and restored by
either Treg transfer or recombinant IL-10
treatment.
172
Furthermore, airway neutrophilia, which is
instrumental in bacterial clearance, has been
studied in inin- vitrovitro infectious exposure
model in relationship to Th1 and Th17 proin-
flammatory cytokine release. The concomitant in-
crease in bronchoalveolar lavage fluid IL-17 with
airway neutrophilia, and their attenuation in IL-17
“knock out”mice following exposure and infec-
tion suggested the importance of IL-17 in inducing
neutrophil-mediated airway inflammation. Also,
decreased induction of IL-17A-mediated airway
neutrophilia following exposure and infection in IL-
1R1
–
mice compared with wild-type controls also
suggests IL-1 signaling is required in IL-17A-
exacerbated neutrophilia.
173
Moreover, in an
in vivo exposure-infectious animal model
modulated by interferon-
g
priming to mimic viral
infection, an impaired PM-mediated bacterial
phagocytosis correlated with activation of genes
encoding neutrophil-recruiting chemokines and
increased histopathology suggestive of severe
pneumonia.
174
Still, in an animal in vivo model,
exposure followed by LPS infection induced
cytokine changes in the lung suggestive of a
Th1/Th2 imbalance and manifested by increased
expression of IL-4 among others, and a concor-
dant decrease in IFN-
g
expression.
72
The infectious-exposure model is an attractive
tool to explore immunopathological alterations in
COPD patients or in laboratory cells exposed to
secondhand smoking. In a mice model, 8 weeks
secondhand smoking pre-exposure was followed
by infection with non-typeable Haemophilus influ-
enza which is a pathogen commonly implicated in
acute exacerbation of COPD. The model revealed
increased number of immune cell infiltrates except
for macrophages, and a suppressed induction of a
robust adaptive immune response manifested as
decreased IFN-
g
. Also, a downregulated T cell
adaptive response manifested by decreased bac-
terial clearance and diminished efficiency of spe-
cific antibody subclass switching, both mitigated
by anti-viral vaccination.
175
In a similar animal
model examining the immunological effect of
antibiotic therapy, cigarette smoke exposure
followed by Streptococcus pneumoniae infection
resulted in recruitment of macrophages and
monocytes in lung tissue and alveolar fluid
reportedly to confine infection to the lung; also a
decreased number of neutrophils but a
differential increase in neutrophil-mediated anti-
microbial peptide, myeloperoxidase. Antibiotic
therapy had no effect on mice survival rate but
reduced lung injury and induced a differential
change of cytokine levels in bronchoalveolar
lavage fluid most importantly downregulation of
Th1 and Th17 inflammatory cytokines.
176
Human
in-vitro pre-exposure and infectious models are
designed to mimic acute exacerbations in stable
but exposed COPD patients. DEP exposure fol-
lowed by non-typeable Haemophilus influenza
infection did not compromise mucosal barrier
function in COPD or healthy patients. However,
epithelial endoplasmic reticulum activity was
markedly disrupted in COPD patients, manifested
by depressed gene expression of the integrated
stress response markers in an ROS-mediated pro-
cess.
115
In another model, macrophages
differentiating from locally recruited monocytes
in lungs of COPD patients were pre-exposed to
low level DEP and subsequently challenged with
TLR agonists or heat killed E.coli. This resulted in
structural and functional changes in innate and
adaptive immune system consisting of mitochon-
drial and lysosomal dysfunction in macrophages,
22 Rouadi et al. World Allergy Organization Journal (2020) 13:100467
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decreased expression of their surface recognition
markers, loss of macrophage differentiation, and
reduction in proinflammatory cytokine production
(e.g.IL-8).
177
The majority of exposure-infection human and
animal models have examined immunological al-
terations following long-term (weeks) and low-
dose pre-exposure periods which best mimics
real-life outdoor pollutant exposure or indoor
secondhand smoking relevant to COPD. Never-
theless, other models which studied brief and
short-term (hours to days) exposure periods have
yielded mixed results. For example, one-week
diesel exhaust pre-exposure of mice in vivo
decreased Pseudomonas aeruginosa clearance
from bronchial epithelial cells, whereas in the same
model a six-months pre-exposure did not.
163
Also,
in an in vivo model, mice were pre-exposed to PM
for 1 day (short term) or 2 weeks (long term), later
infection with Influenza virus A and survival rate
was assessed over the ensuing 10 days following
contamination. Short-term exposure improved
mice survival rate and triggered a robust immune
response whereas long-term exposure did not,
178
reportedly mediated by macrophage cytokine
gene expression regulator Kdm6a. To model
secondhand smoking exposure or for recent
initiation of active smoking, mice were exposed
to brief (2 h per day for 2 days) low dose of side
stream cigarette smoke or to prolonged (2.5
weeks) high dose cigarette smoke, respectively,
and later inoculated with Streptococcus
pneumonia. Surprisingly, brief exposure did not
show significant survival benefit whereas
prolonged exposure in mice did, reportedly due
to diminished propagation of bacteria into the
systemic circulation during chronic exposure.
176
Finally,in a mice model examining only chronic
secondhand smoking exposure and its impact on
non-typeable Haemophilus influenza antimicro-
bial response, 8 weeks secondhand smoking pre-
exposure, theoretically mimicking mainstream
smoking, compromised the ability of host T cell-
mediated adaptive immune system to mount an
effective response against non-typeable Haemo-
philus influenza infection.
175
Taken together, these models suggest exposure
impairs innate and adaptive immunity against
airway microbial infections. Limitations inherent to
the design of these models compel a careful
interpretation of results taking into consideration
the response to infectivity of animal host cells, the
duration and intensity
64,163,178,179
of pollutant
pre-exposure, and the nature of microbial agents
used for contamination.
SUMMARY
We reviewed evidence for the involvement of
oxidative stress pathways and their nature in healthy
individuals and patients with inflammatory airway
diseases following exposure to a spectrum of
important chemical, allergic and infectious air con-
taminants. When comparing exposure clinical
models in patients with AR, CRS, and allergic
asthma, the signal and cascade pathways can
generate important oxidative and anti-oxidative
markers and induce specific changes in adaptive
and innate immune system. Thus, exposure can
amplify the inflammatory process in patients with
AR,CRS,andallergicasthmasupportingevidence
that, at least in atopic individuals, exposure can in-
crease airway hypersensitivity. When accentuated by
an infectious insult, pre-exposure clinical models in
patients with inflammatory airway diseases show
specific immunopathological alterations at mucosal
and submucosal levels of the airway epithelial bar-
rier and ultimately in the adaptive immune system.
The resultant increased susceptibility to infection
can be due to either increased infectivity of micro-
bial agents or to a ROS-mediated direct effect of
pollutant on host immune defense cells.
FUTURE RESEARCH
The complex nature and composition of chem-
ical air pollutants and their aerodynamic proper-
ties is reflected in conflicting epidemiological and
experimental results on exposure and its impact on
health. Also, the oxidative stress-mediated immu-
nopathological changes have highlighted impor-
tant antioxidant markers, which can be
therapeutically bio-engineered. Since there is no
clear consensus on efficacy of natural or synthetic
antioxidants,
125,180,181
current research should
search for new therapeutic modalities and define
the role of currently available ones such as
antihistamines, intranasal or inhaled steroids,
antibiotics and anti-viral vaccination in patients
with inflammatory airway diseases challenged by
exposure and at times by an infectious process.
Volume 13, No. 10, October 2020 23

Abbreviations
AR: Allergic rhinitis; COPD: Chronic obstructive pulmonary
disease; CRS: Chronic rhinosinusitis; DEP: Diesel exhaust
particles; IAD:Inflammatory airway diseases; IL: Inter-
leukin; ILC: Innate lymphoid cells; NOx: Nitrogen oxides;
PAH: Polycyclic aromatic hydrocarbons; PM: Particulate
matter; ROS: Reactive oxygen species; TBS: Tobacco
smoke; TLR: Toll-like receptors; Treg: Regulatory T cell;
VOCs: Volatile organic compounds
DECLARATIONS
Funding source
Not applicable.
Human and animal research
Not applicable.
Registration of clinical trials
Not applicable.
Availability of data and materials
Not applicable.
Author contributions
We attest that all authors contributed significantly to the
creation of this manuscript.
-Philip Rouadi and Samar Idriss initiated the work, contrib-
uted substantially to the conception and design of the
study, the acquisition, analysis, and interpretation of data.
-Philip Rouadi, Samar Idriss, Robert Naclerio, David
Peden, and Ignacio Ansotegui wrote the draft and did a
critical review of the article and provided final approval of
the version to publish.
-Giorgio Walter Canonica, Sandra N. Gonzalez Diaz,
Nelson A. Rosario Filho, Juan Carlos Ivancevich, Peter W.
Hellings, Margarita Murrieta-Aguttes, Fares H. Zaitoun,
Carla Irani, Marilyn R. Karam, and Jean Bousquet
reviewed the manuscript and agreed to be accountable
for all aspects of the work in ensuring that questions
related to the accuracy or integrity of any part of the work
are appropriately investigated and resolved.
-Philip Rouadi supervised the manuscript.
Ethics committee approval
Not applicable.
Publication consent
All authors agreed to the publication of this work.
Declaration of competing interest
The authors have nothing to declare relative to this paper.
Acknowledgements
This project was initiated by the Rhinitis and Sinusitis
Committee of the World Allergy Organization (2018–2019
term).
Author details
a
Department of Otolaryngology-Head and Neck Surgery,
Eye and Ear University Hospital, Beirut, Lebanon.
b
Johns
Hopkins University Department of Otolaryngology - Head
and Neck Surgery, Baltimore, MD, USA.
c
UNC Center for
Environmental Medicine, Asthma, and Lung Biology,
Division of Allergy, Immunology and Rheumatology,
Department of Pediatrics UNS School of Medicine, USA.
d
Department of Allergy and Immunology, Hospital
Quironsalud Bizkaia, Bilbao, Spain.
e
Asthma & Allergy
Clinic,Humanitas University & Research Hospital IRCCS,
Milano, Italy.
f
University Autonoma de Nuevo Leon
Facultad de Medicina y Hospital Universitario U.A.N.L,
Monterrey, NL, c.p. 64460, México.
g
Federal University of
Parana, Brazil.
h
Faculty of Medicine, Universidad del
Salvador, Buenos Aires, Argentina and Head of Allergy and
Immunology at the Santa Isabel Clinic, Buenos Aires,
Argentina.
i
Department of Otorhinolaryngology, University
Hospitals Leuven, Leuven, Belgium.
j
Department of
Otorhinolaryngology, Academic Medical Center
Amsterdam, The Netherlands - Department
Otorhinolaryngology, University Hospital Ghent, Belgium.
k
8 Rue Pierre Poli, Issy Les Moulineaux, 92130, France.
l
LAUMC Rizk Hospital, Otolaryngology-Allergy
Department, Beirut, Lebanon.
m
Department of Internal
Medicine and Infectious Diseases, St Joseph University,
Hotel Dieu de France Hospital, Beirut, Lebanon.
n
Division
of Rheumatology, Allergy and Clinical Immunology,
Department of Internal Medicine, American University of
Beirut, Beirut, Lebanon.
o
INSERM U 1168, VIMA: Ageing
and Chronic Diseases Epidemiological and Public Health
Approaches, Villejuif, France.
p
University Versailles St-
Quentin-en-Yvelines, France.
q
Allergy-Centre-Charité,
Charité–Universitätsmedizin Berlin, Berlin, Germany.
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