International Journal of

Molecular Sciences

Review
Oxidative Stress and Air Pollution: Its Impact on Chronic
Respiratory Diseases
Martha Patricia Sierra-Vargas 1, *, Josaphat Miguel Montero-Vargas 2 , Yazmín Debray-García 1 ,
Juan Carlos Vizuet-de-Rueda 2 , Alejandra Loaeza-Román 1 and Luis M. Terán 2, *

1 Departmento de Investigación en Toxicología y Medicina Ambiental, Instituto Nacional de Enfermedades

Respiratorias Ismael Cosío Villegas (INER), Ciudad de México 14080, Mexico
2 Departmento de Investigación en Inmunogenética y Alergia, Instituto Nacional de Enfermedades
Respiratorias Ismael Cosío Villegas (INER), Ciudad de México 14080, Mexico
* Correspondence: pat_sierra@yahoo.com (M.P.S.-V.); teranjlm@gmail.com (L.M.T.)

Abstract: Redox regulation participates in the control of various aspects of metabolism. Reactive
oxygen and nitrogen species participate in many reactions under physiological conditions. When
these species overcome the antioxidant defense system, a distressed status emerges, increasing
biomolecular damage and leading to functional alterations. Air pollution is one of the exogenous
sources of reactive oxygen and nitrogen species. Ambient airborne particulate matter (PM) is impor-
tant because of its complex composition, which includes transition metals and organic compounds.
Once in contact with the lungs’ epithelium, PM components initiate the synthesis of inflammatory
mediators, macrophage activation, modulation of gene expression, and the activation of transcription
factors, which are all related to the physiopathology of chronic respiratory diseases, including cancer.
Even though the pathophysiological pathways that give rise to the development of distress and bio-
logical damage are not fully understood, scientific evidence indicates that redox-dependent signaling
pathways are involved. This article presents an overview of the redox interaction of air pollution
inside the human body and the courses related to chronic respiratory diseases.

Citation: Sierra-Vargas, M.P.;

Keywords: oxidative stress; respiratory diseases; air pollution
Montero-Vargas, J.M.; Debray-García,
Y.; Vizuet-de-Rueda, J.C.;
Loaeza-Román, A.; Terán, L.M.
Oxidative Stress and Air Pollution:
Its Impact on Chronic Respiratory 1. Introduction
Diseases. Int. J. Mol. Sci. 2023, 24, 853. In the cell’s metabolic process, reactive oxygen and nitrogen species (ROS/RNS) are
https://doi.org/10.3390/ produced, which have high reactivity; they are free radicals. Free radicals come from
ijms24010853 redox reactions, radiolysis, photolysis, and hemolytic fission, where chemical bonds break
Academic Editors: Stefania Marzocco and each newly created fragment preserves one of the bounded initial electrons [1]. Even
and Stefano Lorenzetti though they are reactive molecules, they also contribute to different cellular processes, such
as protein phosphorylation, secondary messengers, the activation of transcription factors,
Received: 15 October 2022 immune responses, and apoptosis. The cellular organelles that contribute to the endogen
Revised: 20 December 2022
generation of ROS/RNS are the mitochondria, through the electron transport chain that
Accepted: 22 December 2022
produces the primary ROS, the superoxide anion radical (O2 •− ), which can further interact
Published: 3 January 2023
with other molecules to generate secondary ROS such as hydrogen peroxide (H2 O2 ) and the
hydroxyl radical (HO• ). Peroxisomes produce H2 O2 under physiological conditions, and
nicotine adenine dinucleotide phosphate (NAD(P)H) oxidase in phagocytes generates O2 •−
Copyright: © 2023 by the authors.
through respiratory bursts to destroy bacteria [2]. In parallel, RNS are also mainly produced
Licensee MDPI, Basel, Switzerland. under hypoxic conditions that activate the nitric oxide synthases in the mitochondria and
This article is an open access article phagocytic cells during respiratory bursts. Moreover, Toll-like receptors (TLR) such as
distributed under the terms and TLR1, 2, and 4 can produce ROS by recruiting mitochondria to macrophage phagosomes [3].
conditions of the Creative Commons All those mechanisms are driven at the physiological level of ROS/RNS, known as
Attribution (CC BY) license (https:// oxidative eustress. Cellular antioxidant mechanisms maintain eustress, and when the
creativecommons.org/licenses/by/ formation of ROS/RNS overwhelms the cell’s antioxidant defense, molecular damage is
4.0/). produced, characterized as oxidative stress or distress [4]. Exogenous factors contributing

Int. J. Mol. Sci. 2023, 24, 853. https://doi.org/10.3390/ijms24010853 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 2 of 16

All those mechanisms are driven at the physiological level of ROS/RNS, known as
Int. J. Mol. Sci. 2023, 24, 853 oxidative eustress. Cellular antioxidant mechanisms maintain eustress, and when the2for- of 15
mation of ROS/RNS overwhelms the cell’s antioxidant defense, molecular damage is pro-
duced, characterized as oxidative stress or distress [4]. Exogenous factors contributing to
the generation of ROS/RNS include exposure to environmental pollutants, such as heavy
to the generation of ROS/RNS include exposure to environmental pollutants, such as
metals (Cd, Hg, Pb, Fe, and As), certain drugs (cyclosporine, tacrolimus, gentamycin, and
heavy metals (Cd, Hg, Pb, Fe, and As), certain drugs (cyclosporine, tacrolimus, gentamycin,
bleomycin), chemical solvents, cooking (smoked meat, used oil, and fat), cigarette smoke,
and bleomycin), chemical solvents, cooking (smoked meat, used oil, and fat), cigarette
vaping, alcohol, and radiation [5]. There is growing evidence that air pollution enhances
smoke, vaping, alcohol, and radiation [5]. There is growing evidence that air pollution
oxidative stress and contributes to several diseases, from airway illnesses to DNA damage
enhances oxidative stress and contributes to several diseases, from airway illnesses to
[6].
DNA Thisdamage
review focuses onreview
[6]. This the participation
focuses onofthe
oxidative stress inofthe
participation pathophysiology
oxidative of
stress in the
respiratory tract diseases (Figure 1).
pathophysiology of respiratory tract diseases (Figure 1).

Figure
Figure1.1.Oxidative
Oxidative stress activates the
stress activates thelungs’
lungs’epithelial
epithelialcells,
cells, generating
generating inflammatory
inflammatory mediators
mediators that
that participate
participate in the
in the macrophage
macrophage activation
activation andand
thethe modulation
modulation of gene
of gene expression
expression and
and transcrip-
transcription
tion factors.
factors. All All of them
of them are are implicated
implicated in numerous
in numerous respiratory
respiratory diseases.
diseases.

2.2.Chronic
ChronicRhinosinusitis
Rhinosinusitis(CRS)
(CRS)and
andNasal
NasalPolyps
Polyps(NP)
(NP)
Chronic
Chronicrhinosinusitis
rhinosinusitis(CRS)(CRS)is isa chronic
a chronic inflammation
inflammation of the nose
of the andand
nose paranasal
paranasal si-
sinuses,
nuses, withwith a wide
a wide rangerange of clinical
of clinical phenotypes.
phenotypes. This This heterogeneous
heterogeneous disease
disease has anhas an
inci-
incidence
dence of approximately
of approximately 5%,5%, significantly
significantly impacting
impacting thethe patients’
patients’ qualityofoflife
quality lifeand and
productivity. One-third
productivity. One-third of thethe world’s
world’spopulation
populationwith withCRS
CRShashasnasal
nasalpolyps
polyps (CRSwNP)
(CRSwNP) [7].
A Type
[7]. A Type2 inflammation
2 inflammation mediated by theby
mediated mast
thecells
mastiscells
present in CRS in
is present in response to increased
CRS in response to
oxidativeoxidative
increased stress. It stress.
has been suggested
It has that air pollution
been suggested causes an
that air pollution inflammatory
causes an inflammatorychange
in the respiratory epithelium associated with CRS. However, there
change in the respiratory epithelium associated with CRS. However, there are few studies are few studies on the
impact of air pollution and oxidative stress on the development
on the impact of air pollution and oxidative stress on the development of CRS. Recently,of CRS. Recently, Patel
and colleagues
Patel and colleagues studied the relationship
studied between
the relationship levels levels
between of particulate air pollution
of particulate (PM2.5 )
air pollution
and2.5the
(PM ) andpathogenesis
the pathogenesisof CRS.of They foundfound
CRS. They that exposure to ambient
that exposure air pollutants
to ambient air pollutants may
contribute
may contribute to the pathogenesis
to the pathogenesis of of
this
thisdisease.
disease.Ozone
Ozoneisis another air component
another air componentlinked linked
totohigher
highertissue
tissueinflammation,
inflammation,eosinophilic
eosinophilicaggregates,
aggregates,and andCharcot–Leyden
Charcot–Leydencrystals crystalsinin
CRSwNP patients evaluated in one study [8]. Another critical
CRSwNP patients evaluated in one study [8]. Another critical aspect investigated was aspect investigated was
whether socioeconomic status and exposure to airborne
whether socioeconomic status and exposure to airborne pollutants such as PM2.5pollutants such as PM , black
, black
2.5
carbon(BC),
carbon (BC),andandNONO 2 increased
2 increased thethe disease’s
disease’s severity.
severity. TheThe results
results showed
showed that that
lower lower
so-
socioeconomic status predicted higher exposure to air pollution
cioeconomic status predicted higher exposure to air pollution and increased disease se- and increased disease
severity
verity in patients
in patients withwithCRSCRS[9].[9].
A study evaluated occupational
A study evaluated occupational airborne airborneexposure
exposureand andthe
theseverity
severityof ofCRS
CRS[10].
[10].The The
impact of exposure to vapors, gases, dust, fumes, fibers, and mist
impact of exposure to vapors, gases, dust, fumes, fibers, and mist on 113 patients with on 113 patients with
CRSwNP, 96 with CRS without nasal polyps (CRSsNP), and 96 patients with aspirin-
CRSwNP, 96 with CRS without nasal polyps (CRSsNP), and 96 patients with aspirin-ex-
exacerbated respiratory disease (AERD) were evaluated. Patients exposed to these air
acerbated respiratory disease (AERD) were evaluated. Patients exposed to these air con-
contaminants required higher steroid doses than nonexposed patients. Contrary to other
taminants required higher steroid doses than nonexposed patients. Contrary to other re-
reports, this study found that PM2.5 and BC did not have a high impact on disease severity.
ports, this study found that PM2.5 and BC did not have a high impact on disease severity.
On the other hand, Zheng and colleagues (2020) studied the role of nicotinamide adenine
On the other hand, Zheng and colleagues (2020) studied the role of nicotinamide adenine
dinucleotide phosphate (NADPH) oxidase in CRSwNP. This oxidase has been associated
dinucleotide phosphate (NADPH) oxidase in CRSwNP. This oxidase has been associated
with the pathogenesis of CRSwNP. Zheng et al. found, by Western blotting and real-time
PCR, that this oxidase is increased in the nasal polyps of patients. These findings suggest
that oxidative stress plays a role in the pathogenesis of CRSwNP [11]. The expression level
of several oxidative stress and inflammation-related genes provided valuable information
on the impact of air pollution on the nasal mucosa and nasal polyps of patients with CRS.
Int. J. Mol. Sci. 2023, 24, 853 3 of 15

Recently, at the molecular level, the expression of oxidative stress- and inflammation-
related genes in nasal polyps from patients with CRSwNP was evaluated. A significantly
lower difference in the expression levels of transcription of antioxidant enzymes, including
superoxide dismutase (SOD) and peroxiredoxin-2 (PRDX2), was reported, independent
of age, sex, and smoking in patients with CRSwNP [12]. These results correspond to
reduced SOD capacity with the increase in oxidative stress. Additionally, an analysis of
the advanced oxidation protein products (AOPP) and SOD showed the opposite effect
in patients with NP. The level of AOPP from NP was higher than in the healthy control
group. However, SOD activity was lower, indicating that oxidative stress plays a vital role
in the development of nasal polyps [13]. Another mechanism of regulating oxidative stress
is mediated by the thioredoxin-interacting protein (TXNIP), which acts as a pro-oxidant
protein by suppressing the activity of thioredoxin (TRX) and its antioxidant function [14].
However, in nasal tissue samples from patients with CRSwNP, the protein and mRNA of
TXNIP and TRX were significantly increased and decreased, respectively, compared with
the control subjects [15].
The transcription factors (TFs) are the primary regulators of gene expression. In this
sense, essential TFs are related to oxidative stress, such as nuclear erythroid 2-related
factor 2 (Nrf2), which regulates several antioxidant genes. For example, Nrf2 was nec-
essary for an antioxidant pathway in a mouse model of rhinosinusitis. Knockout mice
showed enhanced severity of eosinophilic sinonasal inflammation from disruption of the
epithelial-specific Nrf2 pathway [16] and enhanced susceptibility to eosinophilic sinonasal
inflammation [17]. This transcription factor has also been related to the stability of the
sinonasal epithelial cell barrier function [18]. Scavenger receptors (SRs) are a broad family
of transmembrane receptors involved in a dysfunctional host–environment interaction
through a reaction with ROS production. Lectin-like oxidized LDL receptor-1 (LOX-1) is
one member of these transmembrane receptors. In 2020, Nishida and colleagues found a
significant increase in the mRNA expression levels of LOX-1 in CRSwNP patients [19].
Moreover, human sinuses are the primary source of NO in the airways. NO plays a
role in regulating airway inflammation through the expression of NO synthase isoforms.
Oxidative damage to the cellular components occurs when excessive amounts of NO
are produced. Therefore, measuring NO levels can help diagnose CRS and sinonasal
inflammation [20]. Additionally, dupilumab, an anti-IL-4 receptor alpha monoclonal
antibody, has been used recently in the treatment of CRSwNP. Patients with CRSwNP
treated with dupilumab were evaluated through extended nitric oxide analyses (exhaled,
FENO; bronchial, JawNO; alveolar, CalvNO components; nasal, nNO) where the results
showed that nitric oxide significantly improved after 15 days of treatment [21].
Some patients with CRSwNP suffer from bacterial airway infection and damage to
the respiratory epithelia. TAS2R38 is an essential receptor in epithelial cells; its stimulation
increases the production of NO, then the NO damages bacterial membranes, enzymes,
and DNA, and increases the ciliary beat frequency. The expression of TAS2R38 in the
cilia of human sinonasal epithelial cells is associated with susceptibility to CRS. Patients
with advanced CRSwNP showed reduced TAS2R38 receptor expression in the sinonasal
mucosa [22]. Similar results were found in Italian patients with CRSwNP [23]. Another
critical receptor in the epithelial cells of the human airway is the bitter taste receptor (T2Rs).
T2Rs can stimulate endothelial NO synthase (eNOS), whereby NO enhances mucociliary
clearance with antibacterial effects on ciliated epithelial cells [24]. This activation of T2Rs is
associated with CRSwNP status and has been proposed as a biomarker [25]. Oxidation can
activate the calcium-activated kinase (CaMKII); the role of this kinase has been reported
in several models of asthma, CRSwNP, cardiovascular disease, diabetes mellitus, and
cancer [26]. The expression of ox-CaMKII was measured in CRSwNP with other proteins
such as indoleamine 2,3-dioxygenase 1, tryptophan 2,3-dioxygenase, and kynurenine.
Oxidized CaMKII was increased in eosinophilic polyps [27].
Nasal polyps (NP) are a common inflammatory mass affecting from 0.2% to 5.6% of
the population [28]. The etiology of NP is unclear because the factors involved in its oc-
Int. J. Mol. Sci. 2023, 24, 853 4 of 15

currence include the genetic background, the immune system, anatomical differences, and
environmental conditions. However, NP are associated with other chronic inflammatory
respiratory diseases such as cystic fibrosis, AERD, respiratory allergies, and, as mentioned
above, CRSwNP [29]. Epidemiologically, there is an association between air pollution
and the increased prevalence of these respiratory diseases [30]. Exposure to air pollutants
enhances the symptoms’ severity, resulting in an imbalanced concentration of free radicals
and ROS such as NO• , HO• , O2 •− , and H2 O2 . In this regard, some studies have explored
the association of the development and pathogenesis of NP with oxidative stress and air
pollution, although information is limited.
Since the nasal epithelium is the first barrier of entry for inhaled particles such as
pollutants, it plays a crucial role in the formation of NP. Oxidative stress damages the
epithelium and causes mucosal edema due to impaired ion transport. The intracellular
Na+ increases, the Ca2+ moves into the cell, and intracellular K+ decreases [31]. Moreover,
chronic exposure to air contaminants affects the concentration of H2 O2 and IL-8 in the nasal
epithelium, a physiological defense mechanism [32]. The increase in the cells’ permeability
and the migration of inflammatory cells of the proliferative and secretory response is
yet, another innate immune response mechanism. The release of cytokines by effector
cells, and the activity of cyclooxygenase and lipoxygenase are also associated with the
pathophysiology of NP [33].
One of the most critical lines of defense against ROS are enzymes crucial for the activity
of antioxidant, such as SOD, catalase, glutathione peroxidase, and thiol reductase [13]. The
expression and activity of SOD, which catalyzes the dismutation of superoxide anions, is
lower in NP than in healthy mucosa, which is correlated with lower antioxidant blood
levels in NP patients [34–36]. Different molecules are related to oxidative stress, for exam-
ple, malondialdehyde (MDA) and free radicals are the products of lipid peroxidation of
polyunsaturated fatty acids in cell membranes. These oxidant products have higher NP
levels than control tissues [37,38]. Another compound is nitric oxide, which is released in
response to inflammation. Nitric oxide is involved in antiviral and bactericidal activity but
inhibits cell proliferation, DNA synthesis, and collagen production. In NP, NO• reacts with
oxygen, producing peroxynitrite, which is associated with progressive epithelial injury. In
patients with nasal polyposis, there is a lower concentration of NO• compared with healthy
patients, which is related to the downregulation of the nitric oxide metabolism, in which
dismutase is crucial for the modulation of its activity [37].
In the same way, SOD activity was decreased, and MDA increased in NP samples, as
mentioned above. Another approach to studying the role of oxidative stress in NP is to
examine how the apoptotic pathway is related. In 2021, Simsek and colleagues reported
deficient apoptosis through the MAPK/JNK pathway in NP tissues, which may have a role
in the pathogenesis and is consistent with previous reports [39].
To date, oxidative stress is increased in patients with CRSwNP. However, this condition
has a multifactorial etiology, and the role of air pollution is unclear. However, airborne
pollutants may contribute to the pathogenesis of these diseases through the expression of
several transcription factors and receptors in sinonasal epithelial cells. Some of them have
been proposed as biomarkers.

3. Asthma
Asthma is a complex condition that is heterogeneous and is characterized by the critical
role of chronic airway inflammation and oxidative stress. The eosinophils, lymphocytes,
neutrophils, and mast cells generate inflammatory mediators and ROS/RNS that negatively
affect the redox balance [40,41]. Furthermore, these are the basis for identifying the actual
Type 2 high and Type 2 low phenotypes [42]. In Type 2 asthma patients, environmental
factors favor the release of alarmins from the respiratory epithelium, which induces the
differentiation of naïve T cells into Th2 cells. Damaged cells release interleukins such as
IL−6, IL-1β, nitric oxide (NO• ), prostaglandin E2 (PGE2), and tumor necrosis factor α
(TNFα); the principal marker in these patients is the sputum eosinophilia [43]. T2-low
Int. J. Mol. Sci. 2023, 24, 853 5 of 15

asthma patients are characterized by sputum neutrophilia secondary to the activation

of the NLRP3 inflammasome and elevated IL-1β; the activation of Th1 and/or Th17
cells associated with the imbalance of Th17/Treg cells seems to play an essential role in
the pathology of asthma [44]. The response to the combination of Th1, Th2, and Th17
and genetic predisposition induce permanent structural changes in T2-high and T2-low
asthma patients [45,46]. The process of airway remodeling is driven by subepithelial
fibrosis, thickening of the sub-basement membrane, increased airway smooth muscle mass,
angiogenesis, and mucous gland hyperplasia [45].
An imbalance in the airway-reducing state is a determinant of the initiation and sever-
ity of asthma. The ability of an individual to ward off oxidative lung damage depends
partly on their endogenous antioxidant systems and exogenous antioxidant intake [27].
Several groups have shown that the levels of enzymatic antioxidants such as SOD, catalase,
and glutathione peroxidases, as well as heme oxygenase-1 (HO-1), thioredoxins, perox-
iredoxins, and glutaredoxins, are decreased in the bronchoalveolar lavage, sputum, and
serum of asthmatic patients [40,47,48].
Some factors increase the risk of the development of asthma. Among these, regular
exposure through inhalation to oxidants derived from outdoor and indoor ambient air
pollutants is on the list of factors that contributes to the progression of the disease [49–51].
Since the relationship between oxidative stress and the inflammatory response depends
on each other, and genetic predisposition could modify their balance, there is interest
in the role of the inflammatory process as an activator of oxidative stress [52]. Signal-
ing pathways involving the inflammatory process and the oxidative response associ-
ated with the development of asthma are a current matter of evaluation. For example,
the adenosine 5’ monophosphate-activated protein kinase (AMPK)/sirtuin 1 (Sirt1) and
Nrf2/HO-1 pathway [53] and the nitrogen-activated protein kinase (MAPK) pathway that
includes extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinase (JNK), and
p38 [54] have been evaluated. Nrf2 potentiates the activity of the antioxidant response
element (ARE) that synthesizes antioxidant proteins such as HO-1 [55]. Multiple phyto-
chemicals involved in the immune response activate the Nrf2/HO-1 signaling axis. In this
sense, the Nrf2/HO-1, NF-κB, and MAPK pathways are relevant therapeutic molecular
targets in asthma [56–60].
The methodologies used to identify the molecular biomarkers associated with respi-
ratory diseases are varied and range from the use of proteomics platforms to the use of
real-time PCR. In 2021, Suzuki et al. evaluated the plasma proteome using an aptamer-base
affinity proteomic platform (SOMAscan® ) in 34 subjects with stable COPD and 51 subjects
with asthma, detecting 1238 proteins within which stress markers were found, such as
myeloperoxidase (MPO), heme oxygenase 2 (HMOX2), superoxide dismutase (Cu-Zn)
(SOD1), peroxiredoxin-1 (PRDX1), and glutathione-S-transferase P1 (GSTP1) [61].
However, some markers are associated with oxidative stress-related cell damage, such
as MDA, which can be measured by colorimetric techniques, high-performance liquid
chromatography (HPLC), or LC/atmospheric pressure chemical ionization tandem mass
spectrometry (LC/APCI–MS/MS). In asthmatic patients, the sputum measurement of MDA
in the sputum discriminated between patients and controls with greater accuracy than the
levels found in plasma, where it might be more difficult to evidence the redox imbalance
due to comorbidities and lifestyle risk factors. In addition, 8-isoprostane and the oxidative
DNA damage marker 8-oxo-7,8-dihydro-29-deoxyguanosine (8-OHdG) were also increased
in the sputum from asthmatic patients compared with nonasthmatic controls in several
studies [62].
The mitochondria are the organelles that contributes the most to the generation of
reactive oxygen species, and its contribution to oxidative stress in asthma has also been eval-
uated. The mitochondria are also susceptible to oxidative stress; under such conditions, they
undergo an adaptive response through mitochondrial biogenesis. In 2021, Carpagnano et al.
determined that the mitochondrial DNA/nuclear DNA (mtDNA/nDNA) ratio was a
marker of mitochondrial oxidative stress in the exhaled breath condensate (EBC) of
Int. J. Mol. Sci. 2023, 24, 853 6 of 15

53 patients with severe asthma, 11 patients with mild to moderate asthma, and 12 healthy
subjects. They found higher levels of exhaled mtDNA/nDNA in severe asthmatic pa-
tients compared with the mild-moderate and healthy controls; this may be useful for
differentiating the asthma phenotypes [63].
It is crucial to take into account that the presence of oxidative stress is a factor that
triggers asthma symptoms and contributes to the severity of the disease. Moreover, oxida-
tive stress promotes corticosteroid insensitivity by disrupting glucocorticoid receptor (GR)
signaling, leading to the sustained activation of proinflammatory pathways in immune
cells and the airway’s structural cells [64,65].
As already described in this section, many methodological strategies and various
target molecules are related to oxidative stress. However, specific biomarkers with clinical
applications in asthma have not yet been found.

4. Chronic Obstructive Pulmonary Disease (COPD)

Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized
by an airflow limitation that is not fully reversible even with treatment [66]. Risk factors
associated with the development of COPD are exposure to inhaling noxious particles,
mainly tobacco and biomass smoke and outdoor pollutants [67]. Airborne particulate
matter, ozone, and sulfur dioxide are related to an increased risk of exacerbation and
mortality in those patients [68]. In the alveolar space, air pollutants prime the alveolar
macrophages and neutrophils that, through pro-inflammatory transcription factors such
as nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs), produce
cytokines and chemokines. Likewise, these cells are a source of reactive oxygen and
nitrogen species (ROS and RNS); the increased production of ROS/RNS affects phagocytosis
and activates NF-κB and p38 MAPK, which enhance the expression of pro-inflammatory
genes [69]. Oxidative stress plays a crucial role in the pathogenesis of COPD; the imbalance
between the production of oxidants and antioxidant defenses may also contribute to
the worsening of the disease during acute exacerbation [70]. Studies have measured
hydrogen peroxide (H2 O2 ) in the exhaled air condensate. They have found that this reactive
species is increases even more during the exacerbation of the disease, which worsens the
inflammatory response in COPD patients [71].
Exposure to nitrogen dioxide (NO2 ) and particulate matter (PM10 and PM2.5 ) impairs
lung function. Dorion et al. studied 303,887 individuals aged 40–69 years and found that
higher concentrations of PM2.5 (OR: 1.52, 95% CI: 1.42–1.62, per 5 µg·m−3 ), PM10 (OR: 1.08,
95% CI: 1.00–1.16, per 5 µg·m−3 ), and NO2 (OR: 1.12, 95% CI: 1.10–1.14, per 10 µg·m−3 )
were associated with an increase in the prevalence of COPD [72]. Serum biomarkers of
oxidative stress are related to COPD severity; for example, increased plasma MDA, a
product derived from polyunsaturated fatty acid oxidation, is associated with the impaired
recovery after incremental exercise observed in COPD patients [73]. In an experimental
model of COPD, Sokar et al. showed that rats treated with a combination of dexamethasone
(Dex) and losartan (Los) demonstrated inhibited disease progression, and the MDA levels
significantly decreased by 50.75% and the SOD levels increased by 45.22% [74].
As we indicated before, airborne particulate matter increases the risk of COPD. Ex-
posure to PM2.5 impairs mucociliary clearance. Chronic exposure to cigarette smoke can
induce cell death by activating the receptor interacting protein (RIP) kinases 1 and 3 that
initiate the stimuli of necroptosis stimuli associated with inflammation, airway remodeling,
and emphysema [75]. The antioxidant defense system includes nonenzymatic and enzy-
matic molecules that prevent the uncontrolled increase in ROS/RNS and neutralizes the
oxidants’ adverse effects [76,77]. García-Valero et al. found the decreased expression of
extracellular SOD in the alveolar, bronchial, and arteriolar walls of COPD patients com-
pared with the control group (0.59 ± 0.64 vs. 1.39 ± 0.63, respectively; p < 0.05). Moreover,
MDA was a better marker for identifying COPD patients [78]. SOD activity has also been
used to evaluate the functional exercise capacity in COPD patients through the six-minute
walking test (6MWT). In this study, SOD was an independent predictor of the functional
Int. J. Mol. Sci. 2023, 24, 853 7 of 15

capacity in COPD patients; its activity explained a significant percentage of the variability
in 6MWT-derived outcomes such as the 6 min walking distance (6MWD) (23%) and the
6 min walking work (6MWW) (27%) [79].
Furthermore, the genetic variants of SOD1 (rs2234694) in COPD patients were associ-
ated with the risk and severity of COPD (OR = 0.15, p = 0.04). Interestingly, patients with
the +35AC genotype also had a statistically significant increase in glutathione plasma levels
and a lower level of carbonyls (p = 0.03, p = 0.04, respectively) compared with the control
group [80]. These findings emphasize the role of antioxidant enzymes and the impact of
their genetic variants in oxidative biomolecular damage and the progression of COPD.
Glutathione is one of the primary antioxidant defenses of the respiratory system, and
enzymes participating in its biosynthesis are affected in COPD patients. For instance, the
activity of glutathione peroxidase (GPx) in the whole blood or red blood cells of COPD
patients was lower than in controls [81]. In contrast, studies assessing serum/plasma GPx
activity did not show a statistical significance between COPD patients and the control
group. These contrasting results suggest further impairment of the antioxidant defense
mechanisms in COPD [82].
Gamma-glutamyltransferase (GGT) has been considered a new marker of oxidative
stress. Sun et al. showed the increased activity of serum GGT in patients with acute
COPD exacerbation compared with stable COPD patients and control subjects. The authors
suggested that a level of 21.2 IU/L GGT could be associated with a diagnosis of COPD;
meanwhile, 26.5 IU/L could predict the exacerbation of COPD [83].
Damage to several biomolecules occurs during the process of oxidative stress, and
lipids are one of the first to be damaged. Paraoxonase 1 (PON1) has an essential role in
preventing lipid damage. Current results regarding the participation of PON1 in the patho-
genesis of COPD are inconclusive. A report about the activity and phenotype distribution
in COPD patients and healthy individuals showed that COPD patients exhibited higher
PON1 activity than the control group (199.1 vs. 129.2, p = 0.002) [84]. Several studies have
shown that COPD has extrapulmonary consequences, with an impact on functionality and
quality of life; these include a reduction in muscle mass and muscle weakness which are
proportional to the severity of COPD and antioxidant capacity [85]. In this context, various
thiol-based antioxidants can increase the thiol content in the lungs and, in association with
nitric oxide (NO• ), can produce stable S-nitrothiols (RS–NOs) [86]. There is a need for
further research into antioxidant therapy for better control of COPD [87].

5. Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial
pneumonia of unknown cause that is characterized by abnormal epithelialization, excessive
tissue remodeling, and advanced fibrosis within the alveolar wall. The most substantial
factor is aging [88]. However, alterations in the production and clearance of mucus, architec-
tural distortion, and increased cough reflex sensitivity intervene in the development of IPF,
suggesting a role for targeted therapies and multidisciplinary treatment [89]. IPF is charac-
terized by the irreversible scarring of the distal lungs due to the excessive accumulation of
the extracellular matrix (ECM), rendering the lung stiff and compromising its normal gas
exchange function [90]. In addition, IPF is associated with uncontrolled fibroproliferation
and the activation of alveolar epithelial cells (AECs), inflammation, and oxidative stress [91].
Alongside the fibrotic process and the proliferation of many cell types, oxidative stress
plays an essential role in the development and progression of IPF [92,93]. For instance,
inhibited NADPH oxidase activation in the macrophages and several profibrotic mediators
may explain the decreased in vivo oxidative stress and the preservation of lung function in
patients [94]. Another recent study showed an elevation in a mitochondrial anion carrier
protein, uncoupling protein-2 (UCP2). UCP2 is highly expressed in human IPF lung myofi-
broblasts and aged fibroblasts [95]. Oxidative stress arises from an imbalance between ROS
and RNS, which leads to cellular dysfunction and tissue damage but directly damages the
lungs’ epithelium, favoring the development of fibrosis [96]. During fibrosis, the expression
 profibrotic mediators may explain the decreased in vivo oxidative stress and the preser-
vation of lung function in patients [94]. Another recent study showed an elevation in a
mitochondrial anion carrier protein, uncoupling protein-2 (UCP2). UCP2 is highly ex-
pressed in human IPF lung myofibroblasts and aged fibroblasts [95]. Oxidative stress
arises from an imbalance between ROS and RNS, which leads to cellular dysfunction and
Int. J. Mol. Sci. 2023, 24, 853 8 of 15
tissue damage but directly damages the lungs’ epithelium, favoring the development of
fibrosis [96]. During fibrosis, the expression of thromboxane-prostanoid receptor
(TBXA2R) was upregulated in fibroblasts in the lungs of patients with IPF. TBXA2R links
of thromboxane-prostanoid
oxidative stress to fibroblast receptor (TBXA2R)
activation during was upregulated
lung in fibroblasts
fibrosis, and TBXA2R in the lungs
antagonists
of patients
have been with IPF. TBXA2R
proposed linkspulmonary
for treating oxidative stress to fibroblast
fibrosis [97]. Growth activation
factor βduring
(TGF-β) lung is
fibrosis, and TBXA2R antagonists have been proposed for treating pulmonary
known to be modulated by ROS. TGF-β stimulates the proliferation of fibroblasts and their fibrosis [97].
Growth factor βinto
differentiation (TGF-β) is known to
myofibroblasts be modulated
[98]. Pyruvate kinaseby ROS.
M2TGF-β
(PKM2) stimulates
promoted the prolif-
the pro-
eration of fibroblasts and their differentiation into myofibroblasts [98].
gression of fibrosis by directly interacting with Smad7 and reinforcing transforming Pyruvate kinase
M2 (PKM2)
growth promoted
factor-beta1 the progression
(TGF- β1) signaling of fibrosis by directly
[99]. Oxidants mayinteracting with Smad7
alter the nature of the and
sur-
reinforcing transforming growth factor-beta1 (TGF- β1) signaling [99].
rounding ECM. In the lungs, alveolar inflammatory cells, including lymphocytes, macro-Oxidants may alter
the nature
phages, andofneutrophils,
the surrounding ECM.
produce In the lungs,
ROS/RNS. In IPFalveolar
patients,inflammatory cells, including
these inflammatory cells pro-
lymphocytes, macrophages, and neutrophils, produce ROS/RNS.
duce high levels of ROS/RNS in response to cytokines and growth factors and In IPF patients, these
are involved
inflammatory cells produce high levels of ROS/RNS in response to cytokines
in the underlying mechanisms. Given the critical role of oxidative stress in IPF, using an- and growth
factors anddrugs
tioxidant are involved
may improvein the some
underlying
aspects mechanisms. Given
of the disease, suchtheas critical role of oxidative
3’5-dimaleamylbenzoic
stress in IPF, using antioxidant drugs may improve some aspects of the disease, such as
acid (3’5-DMBA), which has demonstrated pro-apoptotic, anti-inflammatory, and anti-
3’5-dimaleamylbenzoic acid (3’5-DMBA), which has demonstrated pro-apoptotic, anti-
cancer properties and has been used in IPF treatment. 3’5-DMBA significantly reduced
inflammatory, and anti-cancer properties and has been used in IPF treatment. 3’5-DMBA
the expression of the genes involved in fibrogenesis. In addition, 3’5-DMBA lowered the
significantly reduced the expression of the genes involved in fibrogenesis. In addition,
GSH/GSSG ratio without promoting lipid oxidation [99].
3’5-DMBA lowered the GSH/GSSG ratio without promoting lipid oxidation [99].
6. Lung
6. Lung Cancer
Cancer
Oxidativestress
Oxidative stress
cancan
targettarget biomolecules
biomolecules such assuch
lipids,asproteins,
lipids, and
proteins, and even
even DNA/RNA,
DNA/RNA,
altering theiraltering
structuretheir
andstructure
disrupting andcellular
disrupting cellular
functions functions
(Figure (Figure
2). Lung 2). Lung
cancer can-
is associ-
cer is associated with several risk factors, such as genetics and environmental
ated with several risk factors, such as genetics and environmental exposures to xenobiotics exposures
to xenobiotics
such such as
as air pollution andairnutrition
pollution and The
[100]. nutrition [100]. The
International International
Agency Agency
for Research for Re-
on Cancer
search on Cancer (IARC) estimates that 1 out of 5 people will develop cancer
(IARC) estimates that 1 out of 5 people will develop cancer once in their lives, and 1 out once in their
of
lives, and 1 out of 8 men and 1 out of 11 women will die as a consequence
8 men and 1 out of 11 women will die as a consequence of the disease [101]. The global of the disease
[101]. The
burden global has
of cancer burden of cancer
increased hasmillion
to 19.3 increased
new tocases,
19.3 million new cases,
contributing to 10 contributing
million deaths to
10 million
during 2020,deaths during
with lung 2020,
cancer withthe
being lung cancer
second most being the second
common most common type.
type. Epidemiological data
Epidemiological
estimate that 2.2 data estimate
million that 2.2
new cases and million new cases
1.8 million andrepresent
deaths 1.8 million1 deaths represent
in 10 diagnoses
1 in 10 diagnoses (11.4%) and
(11.4%) and 1 in 5 deaths (18%) [102].1 in 5 deaths (18%) [102].

Figure 2.2. Air

Figure Air contaminants
contaminants enter
enter the
the respiratory
respiratory tract.
tract. Once in
in contact
contact with
with the
the epithelium,
epithelium, they
they
increase the
increase the reactive
reactive oxygen
oxygen and
and nitrogen
nitrogen species,
species, which
which initiate
initiate aa cascade
cascade of
of redox
redox reactions
reactions that
that
ultimately damage
ultimately damagelipids,
lipids,proteins,
proteins,and
andDNA.
DNA.

The evaluation of oxidative stress derived from air contaminants and their participa-
tion in the pathogenesis of cancer is complex because there is no exact amount of ROS/RNS
related to cancer development. The regulation of several pathways by ROS/RNS, especially
from the fine fraction of particulate matter (PM2.5 ), is also linked to its pathophysiology.
Some of the organelles activated by noxious gases and particles are involved in redox
pathways and are also associated with the development of cancer. The mitochondria and
Int. J. Mol. Sci. 2023, 24, 853 9 of 15

NADPH oxidase are both implicated in the generation of ROS/RNS; mitogen-activated

protein kinase, phosphoinositide 3-kinase, and protein tyrosine phosphatase all participate
in signal transduction cascades of covalent modifications. Nrf2, NF-κB, hypoxia-inducible
factor (HIF), tumor protein p53 (p53), and activator protein 1 (AP-1) participate in tran-
scription factors [103]. Among the environmental factors implicated in the pathogenesis
of lung cancer, cigarette smoking contributes to more than 85% of the cases. Cigarette
smoke contains over 5000 chemicals and at least 100 toxicants linked to many serious
diseases, including cancer [104]. The relative risk of lung cancer in smokers varies from
10- to 30-fold compared with non-smokers; the risk increases depending on the smoking
index. Several studies and meta-analyses have pointed out the participation of air pollu-
tion in the physiopathology of cancer. The scientific community recognizes that for every
10 micrograms per cubic meter (µg/m3 ) of increased exposure to PM2.5 , the risk of dying
from lung cancer rises by 36%. In Asia, the exposure to biomass fuels showed an odds ratio
of 4.93 (95% CI: 3.73–6.52) [105].
The mitochondria are the major contributors to ROS; oxidative phosphorylation pro-
duces almost 90% of ROS. It is well-known that cancer cells obtain their energy through
the glycolysis cycle, which is enhanced in these cells. Oxidative phosphorylation increases
the production of O2 •− , which gives rise to H2 O2 and HO• [106]. Mitochondrial DNA
(mtDNA) has a high risk of ROS damage due to its proximity to the electron transport
chain. The oxidative damage of DNA leads to the formation of carbon-centered radicals.
Moreover, H2 O2 generates HO• via the Fenton reaction. Radical HO• is considered t be
the most reactive among all the oxygen species, and it can directly damage DNA and cause
mutations. MDA and 4-hydroxynonenal (4-HNE) are reactive aldehydes derived from lipid
peroxidation that react with an amino group of proteins and DNA bases, giving rise to
mutagenic lesions [107]. Ye et al. performed a Kyoto Encyclopedia of Genes and Genomes
analysis and found that mutations of mitochondrial energy metabolism pathway-related
genes are essential for lung cancer. For example, the differential expression and mutation
of some proteins such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH), acyl-CoA
synthetase bubblegum family member 1 (ACSBG1), cytochrome P450 family 4 subfamily
A member 11 (CYP4A11), acyl-CoA oxidase 3 (ACOX3), and pristanoyl were related to
poor prognosis [108]. The increased expression of Bcl-2/adenovirus E1B 19kDa-interacting
protein 3 (BNIP3), a stress sensor protein, is associated with autophagy, dissemination, and
poor prognosis in the early stages of non-small-cell lung cancer (NSCLC). Additionally, the
decreased expression of sirtuin 3 (SIRT3) in lung cancer tissues and serum samples could
be a promising biomarker for diagnosis with a sensitivity of 86.4%, a specificity of 94%, and
a cutoff value of 3.12 [109,110].
Mammalian nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX)
have been implicated in the tumorigenesis of lung cancer. The ubiquitous isoform NOX4
produces H2 O2 continuously to regulate the physiological redox homeostasis. A hypoxic
environment activates NOX4, via mRNA transcription and initiating protein translation, in-
creasing its presence in multiple cancers [111]. NOX4 activates metabolic pathways related
to tumor development; it regulates the ROS production of cancer cells [112]. Furthermore,
the ROS produced by NOX4 stabilizes Nrf2 by inhibiting proteasomal degradation. It could
also enhance tumor-associated macrophage infiltration and the pro-tumor function in some
types of lung cancer by increasing the production of cytokines [113].
Moreover, NOX4 contributes to the inactivation of protein tyrosine phosphatase re-
ceptor Type J (PTPRJ or DEP-1) and negatively regulates the transformation of primary
cells. NOX4 is a mediator of TGFb-RHO-ROCK-stimulated c-Jun N-terminal kinase (JNK)
activation, which increases the expression of myofibroblast differentiation-related genes
implicated in cancer progression and survival [114]. The inhibition of NOX function or
mRNA expression slows tumor growth and promotes cancer cell death, hindering lung
cancer formation and invasion [111].
The Nrf2 signaling system is the master regulator of the redox response. It is expressed
at low concentrations by KEAP1 in the cytoplasm of all cell types due to its continuous
Int. J. Mol. Sci. 2023, 24, 853 10 of 15

proteasomal degradation in nonstressed circumstances. During oxidative stress, Nrf2

escapes from KEAP1 degradation, producing an increase in nuclear Nrf2 that allows
the activation of the expression of the cytoprotective genes [115]. There may be more
than 1000 cytoprotective genes regulated by Nrf2; the majority are related to detoxifying
enzymes associated with the redox metabolism; the maintenance of reduced glutathione is
an example [116]. The results of a meta-analysis performed by Wang et al. (2020) evidenced
that high expression levels of Nrf2 were predictive of a poor survival rate, with a hazard
ratio of 1.86 (95% CI: 1.44–2.41, p < 0.001) and were also a potential indicator of NSCLC
tumor s’ aggressiveness [117].
On the other hand, the results of an in vitro study of human lung cancer cells (A549/DDP,
a cisplatin-resistant A549, and H838 cell lines) demonstrated that treatment with metformin
combined with cisplatin produced the dephosphorylation of Nrf2, accelerating its pro-
teasomal degradation and overcoming chemoresistance in NSCLC [118]. There is still
controversy regarding role of oxidative stress in cancer cells and the tumor environment.
The participation of ROS/RNS in the pathophysiology of cancer seems to be cell-type-
and context-dependent. The exact point at which oxidative stress favors the development
and spread of such cells has been challenging to determine. More studies are needed to
elucidate these controversies. As Paracelsus said, the dose makes the poison.

7. Conclusions
It is well established that patients with chronic respiratory diseases are susceptible
to the damaging effects of air pollutants, which induce oxidative stress pathways and
transcription factors ranging from early protective adaptations to inflammation and cell
damage. Indeed, the large surface area for gas exchange makes the respiratory system
a target for redox reactions where the metabolites generated attack cellular components,
including protein structures, lipids, and DNA sequences, causing an imbalance between
oxidants and antioxidants (Figure 2). Even though scientific groups have reported evidence
related to air pollution and oxidative damage, there is still a long way to go. Studies are
underway to evaluate the modulation of the redox pathway by PM2.5 in human-derived
respiratory cells and its association with cellular damage. Finally, many antioxidant drugs
that accelerate the conversion and inactivation of free radicals have been proposed as a
treatment. However, to date, there are no highly effective therapies in the clinic, and further
research is needed.

Author Contributions: Conceptualization, M.P.S.-V. and L.M.T.; investigation, M.P.S.-V., J.M.M.-V.,

Y.D.-G., J.C.V.-d.-R., A.L.-R. and L.M.T.; writing—original draft preparation, M.P.S.-V., J.M.M.-V.,
Y.D.-G., J.C.V.-d.-R., A.L.-R. and L.M.T.; writing—review and editing, M.P.S.-V., J.M.M.-V. and
J.C.V.-d.-R.; supervision, M.P.S.-V. and L.M.T. All authors have read and agreed to the published
version of the manuscript.
Funding: This work was supported by the Instituto Nacional de Enfermedades Respiratorias Ismael
Cosío Villegas, Mexico City. This research did not receive any specific grant from funding agencies in
the public, commercial, or not-for-profit sectors.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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