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Biological Mechanisms of Respiratory Effects of Particulate Matter andits Interaction with COVID-19
Akiko HONDA1* and Tomoya SAGAWA2, 3
1

Department of Environmental Engineering, Graduate School of Engineering, Kyoto University
C Cluster, Kyoto-Daigaku-Katsura, Nishikyo-ku, Kyoto, 615-8540, Japan
2
Graduate School of Global Environmental Studies, Kyoto University
3
Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine*E-mail: akko@health.env.kyoto-u.ac.jp

Abstract
Particulate matter (PM) is an aggregate of particles and chemical/biological components. Some of thesecomponents include harmful substances, and fine PM easily reaches the bronchioli and alveoli when inhaled,causing health challenges in the respiratory and immune systems. Exacerbation of respiratory diseases, such asbronchitis and bronchial asthma, is one of the representative cases. There is also concern that PM exacerbates
coronavirus disease 2019 (COVID-19). Here, we introduce the health effects of PM and its components and theunderlying mechanisms, focusing on the respiratory and immune systems from the perspective of anexperimental approach.
Key words: acquired immune system, allergy, bronchitis, COVID-19, epithelial barrier, innate immune system

1. Effects of PM on the Epithelial Barrier andInnate and Acquired Immune Systems
Air pollutants in the atmosphere surrounding usaffect our respiratory and immune systems adversely.
Particulate matter (PM) in the atmosphere, especiallyPM2.5 (particulate matter with aerodynamic diameters≤2.5 µm), reaches deep into the lungs (Heyder et al.,1986). PM2.5 is generated by human activities(combustion, industrial production, etc.) and naturalactivities (sand dust, volcanic activity, etc.) and containshydrocarbons, metals, ions, endotoxins and β -glucan(Chowdhury et al., 2018). Compared to large particles,
PM2.5 easily reaches the bronchioli and alveoli when
inhaled, and some of these various components containharmful substances; therefore, PM2.5 can contribute torespiratory and immune diseases such as bronchitis andbronchial asthma (Ko and Kyung, 2022).
Airway epithelial cells are constantly exposed toenvironmental contaminants and are the firstphysicochemical contact point between xenobiotics andthe respiratory system. These cells physically remove
xenobiotics by mucociliary transport (Fig. 1). The
respiratory mucosa also contains antimicrobial peptides
and proteins, contributing to bacterial eradication
Global Environmental Research
27/2023 21-26
printed in Japan(Beentjes et al., 2022). When PM and its components
induce damage and inflammation in airway epithelial cells,
xenobiotics can easily enter the airway. Phagocytes,
including neutrophils and macrophages, and group 2
innate lymphoid cells (ILC2) are activated in innate
immunity, while dendritic cells/macrophages that haveantigen-presenting abilities and phagocytic functions,
lymphocytes including T cells and B cells, along witheosinophils and mast cells are involved in acquired
immunity.
Diesel exhaust particles (DEP), representative of
PM2.5, and H2O2 produced from the photolysis of ozone
or ambient PM2.5, have been reported to reduce airway
mucociliary motility (Bayram et al., 1998; Honda et al.,2014) and weaken epithelial tight junctions (Smyth et al.,2020; He et al., 2021). These are associated with
dysfunction of the epithelial barrier. PM2.5 collected from
Asian countries, such as Japan, Bangkok, Taiwan andSingapore, induces the release of pro-inflammatory
molecules such as interleukin (IL)-6 or IL-8 from airway
epithelial cells (Chowdhury et al., 2019, Honda et al.,2022). IL-6 and IL-8 play important roles in inflammationof the respiratory system by inducing neutrophil
recruitment, up-regulating mucin secretion and stimulating
lymphocytes (Bautista et al., 2009; Chen et al., 2003;
Levine et al., 1993; Thacker, 2006). PM2.5 also©2023 AIRIES22

A. HONDA and T. SAGAWA

Fig. 1

Effects of particulate matters on respiratory and immune systems.

suppresses the expression of the antibacterial peptides
β-defensin2 and β-defensin3 in airway epithelial cells as afactor in increased susceptibility to respiratory infections(Rivas-Santiago et al., 2015). Regarding the effects on
innate immunity, in vivo studies have shown that PM2.5
increases the number of inflammatory cells, especiallyneutrophils and macrophages, and cytokines, such as IL-6,
IL-1β, TNF-α, and KC (an IL-8 homolog) in bronchiallavage fluid (BALF) and lung tissues (Honda et al., 2021).
These molecules activate acute inflammation (Zhang &An 2007). PM2.5 suppresses macrophage phagocytic
activity and nitric oxide production during pneumococcal
infection, enhancing pneumococcal infectivity andaggravating pulmonary pathogenesis (Chen et al., 2020).
In an in vitro study, PM2.5 induced IL-6, IL-1β, andTNF-α in bone marrow-derived antigen-presenting cells(Honda et al., 2021). Interestingly, the inflammatory
response induced by PM2.5 in antigen-presenting cells
was drastically suppressed when the particles were
removed as an extract (Honda et al., 2021); therefore, theshape of xenobiotics is important in triggering an immune

response. In addition, the recognition receptors for PM
have also been elucidated. SRB-1 and Siglec-14 on
antigen-presenting cells recognize silica and multi-walledcarbon nanotubes, respectively, leading to the productionof inflammatory cytokines, such as IL-1β, and theenhancement of phagocytosis (Tsugita et al., 2017;
Yamaguchi et al., 2023). ILC2 is a new player in the
innate immune system and expressed in the lungs,
mesentery, skin, etc. ILC2 produces IL-5 and IL-13 inresponse to epithelial-derived cytokines, such as IL-33,
IL-25 and thymic stromal lymphopoietin (TSLP), andinduces a Th2-type immune response. IL-5 facilitateseosinophil production and maturation, and IL-13
stimulates epithelial cells to secret mucins (Habib et al.,2022). Previous studies have reported that multi-walledcarbon nanotubes, O3, diesel exhaust particles andcigarette smoke activate pulmonary or BALF ILC2 in thepresence or absence of allergens (Estrella et al., 2019; Leeet al., 2019).
Regarding the effect on acquired immunity, in thepresence of allergens, PM2.5 has increased the number ofMechanisms by which PM worsens respiratory disease

eosinophils, lymphocytes, neutrophils and macrophages in
BALF and accelerated eosinophilic inflammation,
antibody production and mucus production via IL-5,
eotaxin, antigen-specific IgG and IgE, IL-13, muc5AC
and TSLP (He et al., 2015; He et al., 2017; Liu et al.,
2017: Liu et al., 2022). As underlying mechanisms,
PM2.5 can activate the TLR2/TLR4/MyD88 signaling
pathway (He et al., 2017), JAK-STAT6 signaling pathway(Yang et al., 2020) and notch signaling pathway (Liuet al., 2022). PM2.5-induced airway hyper-responsivenessis involved in the kallikrein-bradykinin pathway (Caoet al., 2020), and activation of bromodomain-containing
protein 4 (Lu et al., 2021) and TRPA1/TRPV1 (Wanget al., 2019). In some in vitro studies, DEP, PM2.5, or its
extracts increased CD86 expression in antigen-presenting
cells (Honda et al., 2021), antigen-presenting activity forovalbumin-specific T cell proliferation (Koike andKobayashi, 2005), TCR expression, splenocyte
proliferation (Honda et al., 2017) and mast cell
degradation (Devouassoux et al., 2002). These reactions
involving the eosinophils, antigen-presenting cells, T cells
and mast cells can act in concert like an orchestra andaggravate allergic inflammation in the lungs.
Studies have also been conducted to narrow down thehealth-impacting components of PM2.5. Ti andendotoxin/β-glucan were identified by analyzing in vitro
biological responses and components of PM2.5 collectedfrom Asia with relatively high positive correlations(Onishi et al., 2018; Chowdhury et al., 2019). Detectionof Ti and TiO2 in the atmosphere from e-waste recycling
facilities and high traffic roads has also been reported(Yasar et al., 2021; Gallego-Hernández et al., 2020).
Sagawa et al., (2021) revealed that TiO2 is taken up by
alveolar macrophages and that the necroptosis of alveolar
macrophages that phagocytose TiO2 particles is involvedin acute lung inflammation. Endotoxins and β-glucans as
biological components of PM2.5 can influence
exacerbation of asthma (He et al., 2017; Zheng et al.,2020).
Moreover,among
polycyclicaromatichydrocarbons (PAHs), quinone alone or combined
exposure to quinones and particles in PM2.5 have induced
cell death or reduced viability of airway epithelial cells(Honda et al. 2022, 2023). Benzo[a]pyrene disrupts
immune response via an increase of CD86 expression on
antigen-presenting cells (Chowdhury et al., 2007) inaddition to being carcinogenic (Moorthy et al., 2015).
Levoglucosan, mannosan and galactosan are characteristic
components of open-burning plants, with a positive
correlation with mutagenicity (Van Den Heuvel et al.,2018), however, few studies have focused on therelationship between the PM2.5 components of open
burning and health effects. Future research should clarify
the components that determine the health effects of PM
arising from open burning.

23

2. Effects of PM on COVID-19
Coronavirus disease 2019 (COVID-19) is aninfectious disease caused by severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) and is a major
public health concern on a global scale. Epidemiologicalstudies suggesting a link between COVID-19 and air
pollution have been reported from around the world.
Specifically, it has been noted that exposure to wildfire
smoke may promote COVID-19 morbidity (Centers for
Disease Control and Prevention, 2023), and exposure toPM2.5 and PM10 concentrations in the air are positively
correlated with the number of COVID-19 cases, theseverity of cases and deaths, whether short-term on theorder of days or long-term on the order of years (Fattorini
and Regoli, 2020; Yao et al., 2020; Prinz and Richter,2022; Shao et al., 2022; Xu et al., 2022).
There are several explanations for these results,
including the theory that SARS-CoV-2 adheres toairborne particles, such as PM, and is transported anddiffused that way (Liu et al., 2020; Nor et al., 2021) andthe theory that exposure to ambient PM may also reduce
resistance to infection in the population (Maleki et al.,2021). However, the exact mechanism is unknown.
Upon SARS-CoV-2 entry into cells, the spike protein(S-protein) on the viral surface binds to the receptor
protein angiotensin-converting enzyme 2 (ACE2)
expressed on the host cell. Subsequently, the S-protein isdegraded through the action of proteolytic enzyme
transmembrane protease 2 (TMPRSS2), exposing thefusion active domain within the S-protein, which fuses theviral membrane to the host cell membrane and allows theviral genome to enter the cell (Hoffmann et al., 2020;
Jackson et al., 2022).
Variations in the expression of ACE2 and TMPRSS2
are thought to influence the development of COVID-19
and other diseases (Saheb Sharif-Askari et al., 2020), andincreased expression of ACE2 and TMPRSS2 in the lungs
has been reported in smokers, who have a higher
incidence of severe COVID-19 (Chakladar et al., 2020).
Moreover, smoke exposure increases the expression of
ACE2 in the airways in animal models (Yilin et al., 2015).
This means that the expression of ACE2 and TMPRSS2
varies depending on environmental factors.
Thus, we hypothesized that PM might be involved in
the pathogenesis of COVID-19 by affecting theexpression of ACE2 and TMPRSS2 and verified thishypothesis in animal studies (Sagawa et al., 2021).
Mice from the Male Institute of Cancer Researchwere intratracheally administered 500 µg of PM particles(PM fine: 0.3 to 2.4 µm particle size, PM coarse: >2.4 µm
particle size) collected in Yokohama, Japan, and dispersedin phosphate-buffered saline (PBS). Twenty-four hours
later, their lung tissues were collected and immunostained for ACE2 and TMPRSS2. The results showed thatcompared to those in the PBS control group, the number

24

A. HONDA and T. SAGAWA

of cells expressing ACE2 and TMPRSS2 increased in thelung tissues of mice intratracheally administered PM,
especially in the alveolar region. Furthermore, multiplex
immunostaining, including Mac-3, a marker ofmacrophages, and proSP-C, a marker of type II alveolar
epithelial (AT2) cells, showed an increase in cells
co-expressing ACE2 and TMPRSS2 in macrophages andAT2 cells, but especially in AT2 cells.
In human lung tissues, ACE2 and TMPRSS2 areexpressed in macrophages and AT2 cells, and these cells
are usually the ones that get infected with SARS-CoV-2(Bertram et al. 2012; Adachi et al. 2020). In particular,
AT2 cells have diverse physiological functions, including
the secretion of surfactants, and it is assumed that
SARS-CoV-2 infection of these cells causes severe
disease.
The results of this study may provide a possible
explanation for the association between PM and
COVID-19. Elucidating the effects of PM on COVID-19
is crucial for future environmental and hygienic measures,and further research, both epidemiological andexperimental, should be developed in this regard.
Acknowledgments
This work was supported by CREST, JST(JPMJCR19H3). We thank Prof. Hirohisa Takano for his
supervision.
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Akiko HONDA
Akiko Honda is an assistant professor at Kyoto
University. Currently, she is engaged in
toxicological research on elucidating the healtheffects of environmental pollutants andenvironmental chemicals.

Tomoya SAGAWA
Tomoya Sagawa is a researcher at Kyoto
University and the Kyoto Prefectural Universityof Medicine. Along with his work as a clinician,he conducts research on the effects of particulatematter on cells and tissues.

(Received 30 June 2023, Accepted 28 December 2023)