Particulate matter-induced epigenetic modifications and lung complications

Abstract

Air pollution is one of the leading causes of early deaths worldwide, with particulate matter (PM) as an emerging factor contributing to this trend. PM is classified based on its physical size, which ranges from PM₁₀ (diameter ≤10 μm) to PM_2.5 (≤2.5 μm) and PM_0.5 (≤0.5 μm). Smaller-sized PM can move freely through the air and readily infiltrate deep into the lungs, intensifying existing health issues and exacerbating complications. Lung complications are the most common issues arising from PM exposure due to the primary site of deposition in the respiratory system. Conditions such as asthma, COPD, idiopathic pulmonary fibrosis, lung cancer and various lung infections are all susceptible to worsening due to PM exposure. PM can epigenetically modify specific target sites, further complicating its impact on these conditions. Understanding these epigenetic mechanisms holds promise for addressing these complications in cases of PM exposure. This involves studying the effect of PM on different gene expressions and regulation through epigenetic modifications, including DNA methylation, histone modifications and microRNAs. Targeting and manipulating these epigenetic modifications and their mechanisms could be promising strategies for future treatments of lung complications. This review mainly focuses on different epigenetic modifications due to PM_2.5 exposure in the various lung complications mentioned above.

Shareable abstract

Particulate matter can lead to changes in the epigenome in the lung that goes above and beyond the acute effect and can lead to significant and drastic changes in the epigenetic map of various immune cells, leading to worsening of various lung diseases. https://bit.ly/4dPdZCy

Introduction

Air pollution is the second largest risk factor causing deaths worldwide. Particulate matter (PM) [1] is a major air pollutant composed of complex physical and chemical materials contributing to air pollution. PM can originate from various sources, both anthropological and natural, including agriculture, mining, demolition, vehicle and machinery, fuel burning, dust storms, volcanic eruptions, and sea salt in coastal areas [2–6]. Due to regional differences in the physical and chemical composition of PM, it can affect our bodies in different ways [1, 7, 8].

PM is primarily classified based on its aerodynamic size, i.e. diameter, with the main categories being PM₁₀ (≤10μm diameter, coarse particles), PM_2.5 (≤2.5μm, fine particles) and PM_0.5 (≤0.5μm, ultra-fine particles). Aerodynamic classification determines how particles move through the air and how they are deposited in the respiratory tract. This size variation results in the deposition of coarse PM in the upper respiratory airway and fine PM in the deeper respiratory airway. The updated air quality guidelines issued by the World Health Organization (WHO) in 2021 introduced revised limits for PM limits [9].

According to the latest Global Burden of Disease Study, PM pollution poses a more serious health risk than previously thought. The latest report indicates that the burden of PM pollution has increased by 44.6% compared to 2017. In addition, the burden of disease attributable to PM has increased significantly from the thirteenth leading risk factor for early death in 1990 to the seventh in 2019. This same study showed a declining trend in global harmful environmental risks, with the exception of PM pollution. This shows how important it is to study and implement a possible solution to reduce PM pollution and mitigate its associated health complications [10].

PM can mainly be classified into two categories, namely primary and secondary. PM first released into the atmosphere by anthropogenic and natural sources is called primary PM. In contrast, secondary PM forms as a result of chemical alterations to primary PM. These chemical changes arise due to the interaction of molecules such as nitrogen oxides, sulphur dioxide and ammonia in the presence of sunlight, temperature and moisture [11]. Both primary and secondary PM contribute to the adverse effects caused by PM; simultaneously, their severity increases as more chemical components are present. Due to the higher chemical complexity of anthropogenic emissions, they are seen to have a more significant impact on health [12]. PM is classified as a carcinogen by the International Agency for Research on Cancer, a subsidiary of the WHO [13]. PM also affects a variety of other health complications, namely congenital disabilities and premature births, cardiovascular diseases, neurological complications, and metabolic disorders [10, 14–17].

This review will primarily address PM_2.5-related epigenetic modifications in various lung inflammatory diseases. We focus on the lungs and their associated complications because they are the primary site of PM_2.5 deposition [18–20]. Furthermore, we chose PM_2.5 over other PM sizes because it is significantly associated with a wider range of evaluated complications than any other PM size [21]. In addition, in terms of the environmental factors of PM_2.5, it can stay suspended in the air for long periods and can be carried by the wind, increasing the likelihood of PM_2.5 exposure [22].

Search strategy

Data for this review were identified using PubMed searches (https://pubmed.ncbi.nlm.nih.gov/) and other relevant reference articles from the research and review articles used in this review. PubMed searches included the following keywords: “PM_2.5”, “asthma”, “COPD”, “lung infections”, “bacterial lung infections”, “viral lung infections”, “lung cancer”, “therapeutics”, “epigenetic modification”, “DNA methylation”, “histone modification” and “microRNAs”. This review mainly focused on articles published in the past 5 years.

Principles of epigenetics

Epigenetic modifications are heritable changes that occur in gene expression that are not caused by DNA sequence alteration; these include DNA methylation, histone modification and microRNAs. These modifications shape an organism's phenotype and can be modulated using pharmaceuticals [23–25] (figure 1).

FIGURE 1.

Epigenetic mechanisms. DNA methylation is addition of methyl groups by various DNA methyltransferases (DNMTs) to DNA, leading to gene silencing. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally by degrading the mRNA translation. Histone phosphorylation results after the addition of phosphate groups to the histones by kinases, influencing gene expression. Histone acetylation is the addition of an acetyl group to histones by histone acetyltransferases (HATs), resulting in an open chromatin and thus gene activation. Histone lactylation is the incorporation of lactate groups to histones and this results in altered gene expression. Histone ubiquitination is attachment of ubiquitin to histones, affecting both gene activation and gene repression based on the site of ubiquitination. Histone methylation is the addition of methyl groups to histones by histone methyltransferases (HMTs) and is associated with either gene activation or repression based on the site of methylation. Histone sumoylation is the addition of the small-ubiquitin-like modifier (SUMO) protein to histones resulting in transcriptional repression. Ac: acetyl group; E1: ubiquitin-activating enzyme; E2: ubiquitin-conjugating enzyme; E3: ubiquitin ligase; CoA: coenzymeA; K: lysine; La: lactate; Me: methyl group; P: phosphoryl group; SAM: S-adenosyl methionine; Ub: ubiquitin.

DNA methylation

DNA methylation involves the methylation of cytosine and adenine nucleotides, typically silencing genes and reducing transcription [26, 27]. This process occurs at cytosine-phosphate-guanine (CpG)-rich sites in 70% of vertebrate promoters. DNA methyltransferase (DNMT) enzymes transfer the methyl group from S-adenyl methionine to DNA. 5-Methyl cytosine (5mC) forms by methylation of a cytosine residue's fifth carbon and this modification is linked to gene repression [26, 28–30]. Three DNMTs exist, namely DNMT3a, DNMT3b and DNMT1. DNMT3a and DNMT3b establish new DNA methylation in unmethylated DNA regions. They are the primary enzymes responsible for independent gene repression. At the same time, DNMT1 maintains parental DNA methylation in new cells and continues gene silencing in daughter cells [27].

Hydroxy-methylation is another methylation process, in which the 10–11 translocation enzyme family oxidises 5mC to 5-hydroxymethyl cytosine (5hmC) and 5hmC to 5-formyl cytosine and 5-carboxyl cytosine, resulting in DNA demethylation and the activation of gene transcription [31, 32]. Researchers consider 5hmC to be an epigenetic biomarker, which is lost in cutaneous T-cell lymphoma [33].

Histone modifications

Histone modifications are post-translational changes to lysine residues on histone tails [34]. In 1997, Luger et al. [35] discovered the nucleosome's atomic structure, namely an alkaline protein core (histone octamer) wrapped in 146 bp of DNA, composed of two pairs of H3–H4 and two pairs of H2A–H2B [36]. Histone modifications involve the covalent binding of lysine residues to either methyl, acetyl, phosphoryl, ubiquitin or other groups of histone-modifying enzymes [37] (table 1).

TABLE 1.

Examples of histone modifications and their regulatory effect

Modification	Histone	Residue	Gene activation	Gene silencing
Acetylation	H2A	K5	+
	H2B	K5, K12, K15, K20	+
	H3	K4, K9, K14, K18, K23, K27	+
	H4	K8, K16	+
Methylation	H3	K4, K79, R17	+
	H3	K9, K27		+
	H4	R3	+
	H4	K20		+
Ubiquitination	H2A	K119		+
	H2B	K120	+
Sumoylation	H4	K12		+
Lactylation	H3	K18	+

Histone methylation

Histone methylation is the addition of methyl groups to histone arginine and lysine residues on histones H3 and H4 by histone methyltransferases (HMTs). HMTs use S-adenosyl methionine (SAM) as a substrate for transferring methyl groups to lysine and arginine residues for methylation. HMTs are divided into histone lysine methyltransferases (KMT) and protein arginine methyltransferases (PRMTs). KMT has a conserved catalytic domain, namely su(var)3-9, enhancer-of-zeste and trithorax (SET) [37]. SET adds one, two or three methyl groups from SAM to histone lysine residues [38]. Meanwhile, PRMTs transfer methyl groups from SAM to arginine residues in histones and nonhistone proteins [39]. Overall, histone methylation does not alter the charge of the protein and, hence, does not block DNA association. It regulates transcription activation by influencing histone reader–protein binding [40].

Histone methylation can function as both a permissive and repressive epigenetic modification [41]. H3K4, H3K36 and H3K79 are permissive modifications, whereas H3K9, H3K27 and H4K20 are repressive [41, 42]. Histone demethylase (HDMT), a demethylase enzyme, also plays an essential role in histone methylation. It removes histone methylation and, depending on the position of the residue it functions on, it can activate or deactivate gene expression [42]. For example, lysine-specific demethylase 1 promotes pulmonary fibrosis by functioning against H3K9 and H3K4 methylations [43].

Histone acetylation

Histone acetylation adds an acetyl group to histone lysine residues using acetyl coenzyme A and histone acetyltransferase (HAT) enzymes [37]. HATs are grouped into five families: Gcn5-related N-acetyltransferases, MYST(MOZ, Ybf2/Sas3, Sas2, Tip60), p300/CBP, TAF250 and steroid receptor co-activators [44]. Moreover, based on their location within the cell, HATs are classified into type A-HATs and type B-HATs. Type A-HATs in the nucleus modify histones in nucleosomes to regulate transcription. Type B-HATs, found in the cytoplasm, acetylate free histones [45–48]. Regardless of the type of HAT, histone acetylation is a permissive function, facilitating gene expression [49, 50].

Histone acetylation on H3 and H4 is widely studied [51–53]. For example, higher acetylation of H3 and H4 in the interleukin (IL)-13 locus, which increases IL-13 expression in T-helper (Th) 2 cells, is observed in children with allergic asthma. In addition, H3 acetylation in the forkhead box p3 (Foxp3) locus of regulatory T-cells (Tregs) are observed in allergic asthma.

Histone deacetylation is carried out by histone deacetylases (HDACs) or lysine deacetylases, which remove acetyl groups from histones and other proteins [37]. Histone deacetylation is a repressive modification and blocks gene expression [49, 50]. 18 HDACs have been identified in mammals [54], split into classes I, IIa, IIb, III and IV. HDACs are present in the nucleus and cytoplasm [37, 55].

Histone ubiquitination

Histone ubiquitination is an epigenetic mechanism that involves the addition of ubiquitin to lysine residues. It is a three-step process, starting with ubiquitin activation by ubiquitin-activating enzyme (E1). During this step, ubiquitin is bound to ATP, activating the acyl-adenylation of the C-terminus of the ubiquitin molecule. Afterwards, the ubiquitin-conjugating enzyme (E2), by its highly conserved ubiquitin-conjugating catalytic domain, catalyses the transfer of the ubiquitin from E1 to E2. Ligation to the target protein is carried out by ubiquitin ligase E3. It forms an isopeptide bond between the glycine residue of the ubiquitin C-terminus and the protein [56]. Ubiquitination primarily affects histone cores H2A and H2B. H2A's mono-ubiquitination at lysine 119, creating H2Aub1, regulates transcription and DNA repair [57, 58]. On the other hand, the ubiquitination of H2B at lysine 120, which forms H2Bub1, triggers transcription [59]. Various cancers, such as thyroid cancer, are correlated with H2Bub1. Loss of H2Bub1 reduces the tumour suppressor gene CDC73 (cell division cycle 7) and promotes cancer progression [60, 61].

Histone phosphorylation

Histone phosphorylation is a typical post-translational modification at histone's serine and tyrosine residues [62]. Methylation sites H3K9 and H3K27, which share the same subsequent serine, are phosphorylated, forming the ketide synthase domain [63]. Histone phosphorylation regulates cell cycle progression, DNA damage repair and asymmetric cell division [64, 65]. It is also associated with cancer progression and H3S10ph (phosphorylation of serine 10 on histone H3) is a central histone phosphorylation often observed in this context. The increased H3S10ph observed during cancer plays a role in chromosome condensation and cytokinesis [66, 67].

Histone sumoylation

Histone sumoylation is the covalent attachment of the small-ubiquitin-like modifier (SUMO) protein (∼12 kDa) to lysine residues of its substrate [68]. SUMO is part of the ubiquitin-like polypeptides superfamily [69]. Sumoylation, like ubiquitination, is a three-step process involving activating enzyme E1, conjugating enzyme E2 and ligases E3 [70]. Four SUMO proteins (SUMO 1, 2, 3 and 4) are known [71]. Histone sumoylation regulates chromatin structure, transcription, kinetochore assembly and DNA repair [72]. A study conducted by Leonen et al. [73] explains the involvement of histone sumoylation in other histone modifications, such as acetylation and methylation. Histone sumoylation, H4K12, reduces H4 acetylation and H3K4 methylation, thereby obstructing transcription.

Histone lactylation

Zhang et al. [74] recently discovered histone lysine lactylation (Kla) through mass spectrometry. Kla is an epigenetic modification that the enzyme P300 catalyses by adding lactate to lysine residues, leading to direct stimulation of gene transcription [75]. Lactate, a byproduct of glycolysis, is a precursor for histone lactylation [74]. Histone lactylation is observed in various complications, including inflammation, cancers and fibrosis [76]. A recent study by Wang et al. [77] has shown that histone lactylation of lysine 18 on H3 (H3K18la), activates the reparative mechanisms in monocytes after myocardial infarction, thereby helping with immune homeostasis and repairing damage.

MicroRNA

MicroRNAs (miRNAs) are noncoding short RNAs with about 20 nucleotides that affect gene expression [78]. MiRNAs are found in plasma, serum and extracellular vesicles (EVs) and can be transferred from one cell to another [79]. Lin4 miRNA was first discovered in 1993 and regulated the lin4 protein in Caenorhabditis elegans [80, 81]. MiRNAs are also involved in epigenetic modifications, altering the phenotype without changing the genetic makeup [82].

MiRNAs target different mRNAs by binding to the 3′ UTR regions of mRNAs and subsequently modify the expression of a specific target mRNA. The production of miRNAs is predominantly controlled by two enzymes known as DROSHA and DICER [83]. Firstly, the miRNA is transcribed by RNA polymerase II, called primary miRNA (pri-miRNA). This pri-miRNA is then processed by the enzyme DROSHA, which cleaves and reduces the size of the precursor miRNA to about 70–100 nucleotides, forming a hairpin-shaped RNA known as precursor miRNA (pre-miRNA) [84]. DICER processes this pre-miRNA, producing a short double-stranded miRNA molecule [85]. One of the strands is subsequently cleaved by RNA-induced silencing complex, resulting in an active miRNA [86].

PM_2.5-related epigenetic modifications in asthma

One of the main complications of asthma is the imbalance of anti-inflammatory and pro-inflammatory T-cells, i.e. Treg/Th1 and Th17/Th2_, respectively [87]. PM_2.5 significantly increases airway resistance, the pulmonary inflammatory response and the number of inflammatory cells in bronchoalveolar lavage fluid (BALF) [88, 89]. This induces damage and shedding of airway epithelial cells, causing airway hyper-responsiveness, excessive mucus secretion and airway remodelling characterised by fibrosis and collagen deposition [90–95]. PM_2.5 induces epigenetic changes through DNA methylation, histone modification and miRNA in asthma-related genes, thereby altering their functions and exacerbating asthma [96] (figure 2).

FIGURE 2.

Particulate matter with a diameter ≤2.5 μm (PM_2.5)-induced asthma progression results in regulatory T-cell (Treg)/T-helper (Th) 1 and Th17/Th2 imbalance. a) Effect of PM_2.5 on Th17 cell: PM_2.5-induced epigenetic modification upregulates the expression of interleukin (IL)-17 and IL-22. This activates neutrophils and promotes airway remodelling, which promotes asthma. b) Effect of PM_2.5 on Th2 cell: PM_2.5-induced epigenetic modification upregulates the expression of IL-13, IL-5 and IL-4. Results in eosinophilia, increased mucus production and activation of plasma cells. c) Effect of PM_2.5 on Treg cell: PM_2.5-induced epigenetic modification downregulates the expression of transforming growth factor-β (TGF-β) and IL-10, blocking the anti-inflammatory functions and promoting asthma. d) Effect of PM_2.5 on Th1 cell: PM_2.5-induced epigenetic modification downregulates the expression of interferon (IFN)-γ, thereby reducing the inhibitory functions of Th1 cells and promoting asthma. FOXP3: forkhead box p3; GATA: gata-binding protein; miRNA: microRNA; RORγt: retinoid-related orphan receptor; STAT: signal transducer and activator of transcription.

DNA methylation

DNA methylation is correlated with the severity of asthma [26]. Exposure to PM_2.5 can cause methylation in essential inflammation-regulating genes, namely interferon (IFN)-γ, IL-4, IL-10 and Foxp3 [97–100]. Furthermore, hyper-methylation of Foxp3 is associated with lower Treg levels, thereby disrupting the differentiation of Treg cells through the aryl hydrocarbon receptor (AhR)–glutamate oxaloacetate transaminase 1 pathway [88, 98]. This leads to the lower suppressive capacity of Treg cells [101]. In addition, PM_2.5 exposure-induced DNA methylation results in the decreased expression of signal transducer and activator of transcription (STAT) 5 and increased expression of STAT3 and retinoid-related orphan receptor (RORγt) [102]. Due to the epigenetic modifications described above, Th0 is differentiated to pro-inflammatory Th17 and Treg differentiation is inhibited. This affects the Treg/Th₁₇ imbalance and further exacerbates asthma [98, 99, 102].

Moreover, PM_2.5 exposure causes DNA methylation in the promoter region of the tumour necrosis factor (TNF)-α-induced protein 8-like 2 (TIPE2) gene, leading to elevated gene expression. TIPE2 inhibits activation of mechanistic target of rapamycin complex 1, reducing its inhibitory effect on phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signalling pathway, thereby enhancing M2 polarisation of macrophages. Activated macrophages release IL-23 and transforming growth factor-β (TGF-β1), promoting Th17 cells and contributing to the Th cell imbalance [103].

A study by Xu et al. [104] has identified approximately 26 CpG islands and 33 differentially methylated regions linked to PM_2.5. These regions are related to several genes involved in inflammation and diseases, including asthma, high blood pressure and several more. Another similar study discovered a CpG site in the Notch4 gene, which functions as a decisive gene against inflammation [105]. Upregulation of Notch4 activates downstream pathways, including Hippo and Wnt. Hippo and Wnt pathway activation leads to the disruption of anti-inflammatory Tregs towards pro-inflammatory Tregs, exacerbating asthma inflammation [101, 106]. All these implicated genes have been associated with regulating inflammatory responses in asthma. In addition, the use of DNMT inhibitors has been studied as a treatment against PM_2.5-exacerbated asthma. 5-Azacytidine (5-Aza), a DNMT inhibitor, shows promising results in alleviating PM_2.5-exacerbated asthma by inhibiting DNA methylation [102].

Histone modification

Histone modifications, including histone methylation and histone acetylation, are found to be highly associated with promoting asthma [107]. PM_2.5 exposure enhances the H3K27ac in monocytes and is responsible for upregulating pro-inflammatory mediators such as TNF, IL-6 and IL-8 [108]. In addition, the combination of PM_2.5 and cold shock intensifies asthma exacerbation by hyper-acetylating H3K9 and H3K14 in the IL-4 gene promoter within CD4⁺ T-cells. This is correlated with the increase in Th2 cells, further promoting the Th1/Th2 ratio imbalance. Simultaneously, there is an increase in the expression of HAT P300 and a decrease in the expression of HDAC1, further validating the hyper-acetylation described earlier [109].

Several studies have also shown the effects of using histone deacetylases such as sirtuins (SIRTs) to reduce the Th2-mediated immune response, thus favouring asthma treatment [110]. SIRT1 and SIRT6 are examples of SIRTs that have been shown to influence asthma progression [111, 112]. SIRT1 reduces the airway inflammation caused by PM exposure [113]. However, PM_2.5 exposure lowers the expression of SIRT1, promoting airway inflammation. Salidroside, a plant extract from Rhodiola rosea, is found to activate the SIRT1 expression after PM_2.5 exposure and reduce inflammation and apoptosis [112]. Contrastingly, SIRT6 promotes airway inflammation and asthma severity by mediating the expression of IL-17A. SIRT6 facilitates the binding of RORγt to the promoter region of IL-17A and leads to increased transcription of IL-17A. The use of SIRT6 inhibitors is successful in regulating asthma progression in mice [111].

MiRNA

Exposure to PM_2.5 impacts the expression of several miRNAs associated with genes and pathways related to asthma [114]. miRNAs can exert positive and negative effects on the progression of PM_2.5-induced asthma. As discussed earlier, one of the main complications of asthma is the imbalance of anti-inflammatory and pro-inflammatory T-cells and associated cytokines. PM_2.5 causes downregulation of miR-31, leading to lower expression of both Foxp3 and IL-10, thereby impairing Treg function in asthma [97]. In addition, PM_2.5 activates nuclear factor-κB (NF-κB) by the reactive oxygen species (ROS)/PI3K/Akt pathway-dependent downregulation of miR-331 expression. This sustainable activation of the NF-κB signalling upregulates the expression of miR-146a and STAT6 and downregulates STAT4. These changes in transcription factors promote pro-inflammatory cytokine production, thereby exacerbating lung injury following PM_2.5 exposure [94, 97, 115].

Conversely, miR-224 can positively impact asthma incidence and T-cell imbalance. MiR-224 decreases airway inflammation and remodelling in asthmatic mice exposed to PM_2.5. Toll-like receptor 2 (TLR2), the target gene of miR-224, hinders the secretion of inflammatory molecules from Th17 cells [116]. Targeting miR-224 can alleviate PM_2.5-induced asthma. However, further research and validation are necessary regarding using miRNAs as therapeutics.

Furthermore, PM_2.5 can also regulate the antioxidant and apoptotic pathways by regulating the expression of miR-206 and miR-486 [92, 117]. PM_2.5-induced upregulation of miR-206 inhibits the expression of antioxidant enzymes such as superoxide dismutase 1 and increases the ROS levels, resulting in further deterioration of respiratory inflammation and asthma [92, 118]. Similarly, miR-486, an miRNA that plays a role in apoptosis regulation, is downregulated in PM_2.5-exposed alveolar epithelial cells [117]. MiR-486 targets phosphatase and tensin homologue and forkhead box protein O1, which are known to activate apoptosis [117, 119, 120]. Therefore, PM_2.5-induced downregulation of miR-486 promotes alveolar epithelial cell cytotoxicity and treatment strategies that involve administering miR-486 can effectively mitigate PM_2.5-induced cell cytotoxicity [117].

A recent study by Zheng et al. [121] found that PM_2.5 exposure upregulated EV-packaged let-7i-5p in childhood asthma. This miRNA results in cytotoxicity and induces lung cell contractility by inhibiting dual specificity protein phosphatase 1 and promoting asthma. Researchers could potentially use the detection of EV-packaged let-7i-5p to diagnose asthma in children exposed to high levels of PM_2.5.

PM_2.5-related epigenetic modifications in COPD

COPD mainly affects elderly individuals exposed to PM, cigarette smoke, tobacco smoke and air pollution [122]. COPD differs from asthma primarily in that COPD involves irreversible airway obstruction, whereas asthma is characterised by reversible airway obstruction, typically improving after treatment [123, 124]. PM_2.5 exposure alters epigenetic modification, metabolism and pro-inflammatory cytokines in COPD patients [125]. It significantly increases IL-17, IL-6, IL-8 and TNF-α levels as well as other inflammatory cytokines in the lung tissues of both human and murine models, thereby worsening COPD symptoms [126–128]. Moreover, PM_2.5-induced COPD has other harmful effects, including higher oxidative stress, inflammation, increased mucus and collagen production, airflow obstruction, inflammatory cell infiltration, and alveolar wall damage [129–131] (figure 3).

FIGURE 3.

Particulate matter with a diameter ≤2.5 μm (PM_2.5) exposure exacerbates COPD. PM_2.5 exposure activates different cells and favours the progression of COPD. Alveolar macrophages activated by PM_2.5 release matrix metalloproteinases (MMPs) and other cytokines, including of transforming growth factor-β (TGF-β) and interleukin (IL)-33. Epithelial cells activated by PM_2.5 release family with sequence similarity 13-member A (FAM13A), a protein that impairs lung repair through Wnt/β-catenin signalling. HDAC2: histone deacetylase 2; SIRT1: sirtuin 1; Th: T-helper cell.

DNA methylation

DNA methylation as an epigenetic modification in COPD includes DNA hypomethylation and gene promoter hypermethylation. It also reduces the activity of DNMTs at several genes responsible for cytokine production and oxidative stress [132]. 19 differentially methylated CpG islands and their corresponding genes related to PM_2.5 exposure and COPD were identified. These genes explicitly regulate inflammation and metabolic factors in response to external toxicants such as PM_2.5 [133]. Another study identified a differentially methylated region on the gene family with sequence similarity 13-member A (FAM13A), which is associated with lung repair [105]. β-Catenin signalling helps airway repair and is an essential repair pathway determining COPD development [134]. FAM13A interferes with the Wnt pathway, inducing β-catenin degradation, affecting the airway repair mechanism and favouring COPD progression [105, 134].

Histone modification

In terms of histone modifications, PM_2.5 exposure can initiate epigenetic changes by histone methylation, acetylation and phosphorylation of genes concerning COPD and lung injury [132]. Histone modifications associated with COPD include H3K9ac, H3K9me, H3K27me, H3K27ac, H3K4me and H3S10ph [132, 135]. Alterations in the levels of H3K9ac, H3K9me and H3K27me mediated by long noncoding RNA-IL17R (lnc-IL7R) in the promoter region of cell senescence gene p21^CIP1/WAF1 leads to a shift in chromatin state, resulting in cell cycle arrest, senescence and apoptosis. PM_2.5 exposure on a normal individual upregulates lnc-IL7R, negatively regulating p21^CIP1/WAF1 gene expression. This reduced p21^CIP1/WAF1 gene expression is epigenetically regulated by increased methylation of H3K9 and H3K27 and decreased acetylation of H3K9. This mechanism is reversed in the case of COPD patients, i.e., PM_2.5 reduces lnc-17R, further promoting p21^CIP1/WAF1 gene expression through increased acetylation of H3K9 and reduced methylation of H3K9 and H3K27. This further worsens the effect of PM_2.5 on COPD [135].

Moreover, PM_2.5 upregulates IL-33 through an AhR-dependent pathway and enhances H3K27ac in macrophages, which plays a vital role in the progression of COPD [125]. Furthermore, H3K4me and H3S10ph modifications have also been detected in PM_2.5-exposed COPD patients, indicating their involvement in COPD progression. Additional research is required to understand the details of these histone modifications, particularly histone phosphorylation, in COPD.

Another consequence of PM_2.5 exposure is the downregulation of HDAC. One such example is the reduction of HDAC2 due to PM_2.5 exposure. This results in M2 polarisation of alveolar macrophages and upregulation of TGF-β, matrix metalloproteinase (MMP)-9 and MMP-12 in lung tissue, causing lung function deterioration, alveolar wall destruction and airway remodelling [136].

A similar study showed a reduction in SIRT1, another HDAC causing reduced enzymes related to NAD⁺ synthesis in macrophages after PM_2.5 exposure. This led to an increase in H4Kac acetylation and activation of pro-inflammatory genes [137]. SIRT1 has a protective role by deacetylating histones and inhibiting the activity of transcription factors, such as NF-κB and activator protein 1 (AP-1), thereby blocking the transcription of inflammatory genes [138].

In contrast, SIRT6, an HDAC, promotes airway inflammation in macrophages after PM_2.5 exposure. SIRT6 blockade can decrease the airway inflammation caused by PM_2.5 [139]. As a result, researchers have shown that targeting HDACs can be considered a therapeutic target for COPD. For example, resveratrol, which targets SIRT1, can alleviate PM-induced COPD symptoms by activating SIRT1 and reducing the expression of pro-inflammatory genes [137, 140].

MiRNA

PM_2.5 exposure results in a differential expression of miRNAs. Some are highly expressed, while others show reduced expression [128]. MiRNAs such as miR-223-5p are upregulated after PM_2.5 exposure, while miR-194-3p is downregulated [141]. These miRNAs are significant in COPD as the miR-223-5p is associated with reduced Treg function and miR-194-3p is associated with reduced lung function, further exacerbating COPD [141, 142].

In addition, miRNA miR-149-5p helps to suppress inflammation by targeting TGF-β-activated kinase 1 binding protein 2 (TAB2) in epithelial cells induced by PM_2.5. It inhibits the promoter effect of TAB2 on mitogen-activated protein kinase (MAPK) and NF-κB signalling pathways [143].

Another set of noncoding RNAs are long noncoding RNAs which influence PM_2.5-induced COPD. Lnc-RNA Meg3 increases the expression of p53 in PM_2.5-treated cells and causes cell apoptosis and autophagy [144]. It binds to the 3′ UTR region of miR-218 and blocks proliferation, inhibits apoptosis and reduces the levels of inflammation cytokines. One study showed that miR-218 can be considered as a therapy in PM_2.5-induced COPD [145].

As previously mentioned, PM_2.5 reduces lnc-IL7R expression, which activates the p21^CIP1/WAF1 gene, leading to cell cycle arrest, senescence and apoptosis [135]. Reduced lnc-IL7R expression in airway epithelial cells indicates inflammation, which can serve as a marker of COPD [146, 147]. Analysis of differentially expressed miRNAs can be used as a biomarker for both PM_2.5 exposure and COPD.

PM_2.5-related epigenetic modifications in idiopathic pulmonary fibrosis (IPF)

Air pollution is a notable risk element for both the progression and deterioration of pulmonary fibrosis [148]. IPF is a chronic lung disease characterised by scarring of lung tissues. Scarring causes stiffening, which reduces lung elasticity and makes it difficult to breathe. Consequently, the lungs cannot effectively transfer oxygen into the bloodstream, leading to symptoms such as shortness of breath and chronic cough. IPF is a permanent and progressive condition more commonly seen in older individuals [149, 150]. PM_2.5 exposure results in severe lung injury and fibrosis and increases hospital death risk due to pulmonary fibrosis [151, 152]. PM_2.5 exposure causes lung inflammation, incrementing immune cells, macrophages, neutrophils, eosinophils and lymphocytes in BALF and lung tissues [153, 154]. PM_2.5 causes lung fibrosis by increasing collagen deposition and fibrosis scores [155]. It upregulates IL-1β, TGF-β1, IL-6 and TNF-α in BALF. This leads to collagen deposition in small airways, resulting in chronic lung inflammation and fibrosis [156–159]. Epithelial–mesenchymal transition (EMT) is an important mechanism that promotes pulmonary fibrosis. EMT causes a reduction in the epithelial marker CDH1 (E-cadherin) and elevation of mesenchymal markers, CDH2 (N-cadherin) and vimentin, as well as fibrotic markers such as collagen I and α-smooth muscle actin [148, 160–162]. The same changes were observed in normal lung epithelial cells and lung tissue after long-term exposure to PM_2.5 [163].

DNA methylation

Exposure to PM_2.5 leads to DNA methylation modifications and alters the transcription of various genes, such as alpha-actinin-4, C-X-C motif chemokine ligand 1, microtubule affinity regulating kinase 2, Abl-binding protein, presenilin-1, proteasome subunit alpha 3 and proteasome 26S subunit, non-ATPase 1. These alterations induced by PM_2.5 are implicated in the onset of pulmonary fibrosis and other respiratory complications [164].

Exposure to PM_2.5 induces a complex cascade of molecular events contributing to pulmonary fibrosis. PM_2.5-triggered nuclear factor erythroid 2-related factor 2 (Nrf2) expression in epithelial cells plays a pivotal role in lung fibrosis. The dysregulation of methylation and demethylation by methyltransferase-like 3 (METTL3) and AlkB homologue 5 (ALKBH5) exacerbates the fibrotic response. PM_2.5 elevates METTL3, which is tightly linked to the m6A-regulated EMT. YT521-B homology domain-containing family proteins 2 (YTHDF2) promotes EMT by detecting these m6A modifications, further worsening pulmonary fibrosis [154, 156, 161]. Furthermore, METTL3-dependent oxidative stress-induced growth inhibitor 1 modification is a critical mechanism influencing apoptosis, cell cycle arrest and autophagy [165].

A similar study using dust particles showed an increased expression of type-1 (COL-I) and type-3 (COL-III) collagen and altered expression of DNMT1, DNMT3a, DNMT3b, methyl-CpG binding domain protein 2 and methyl-CpG binding protein 2 in murine lung tissue [166]. Thymocyte differentiation antigen-1 (Thy-1), a fibrosis inhibitor [167], is hypermethylated and downregulated. Pre-treatment with DNMT inhibitor 5-aza-20-deoxycytosine (5-aza-dC) restores the Thy-1 level, reduces expression of COL-I and COL-III, and reduces pulmonary fibrosis. The inhibition of DNA methylases such as 5-aza-dC is a potential candidate for treatment [166]. These findings show the significance of DNA methylation processes in the molecular pathways and can be correlated with PM_2.5-induced pulmonary fibrosis.

Histone modification

The expression of histone-modifying enzymes such as HDAC and HDMT are altered in pulmonary fibrosis due to PM_2.5 exposure [42, 43, 168]. HDAC3 is a histone-modifying enzyme that plays a sentinel role in PM_2.5-induced fibrosis. PM_2.5 promotes lung fibrosis through the activation of TGF-β/Smad signalling pathways. Meanwhile, HDAC3-deficient mice showed prolonged TGF-β/Smad activation after PM_2.5 exposure, resulting in fibrosis. The in vitro experiment also supported the same result as the above in vivo experiment [168]. Similarly, HDMT, namely, lysine-specific demethylase 1 (LSD1), also promotes pulmonary fibrosis by activating the TGF-β/Smad signalling pathway. LSD1 mediates this by functioning between the balance of H3K4 methylation-mediated activation and H3K9 methylation-mediated inhibition, which activates TGF-β/Smad signalling and results in fibrosis [43].

MiRNA

PM_2.5 exposure induces pathological alteration and pulmonary fibrosis in mice by modulating miRNAs. PM_2.5 exposure downregulates the miRNA, miR-494-3p, and upregulates the target gene, i.e., YTHDF2. YTHDF2 inhibits E cadherin expression, resulting in EMT progression and fibrosis [161]. Another example is Has-miR-760, which contributes to haem-oxygenase 1 upregulation to resist PM_2.5-induced lung injury. Hsa-miR-760 upregulation has an anti-apoptotic function and can potentially be a therapeutic target [169]. An integrated study involving mRNA and miRNA analysis using Kyoto Encyclopedia of Genes and Genomes annotation shows the influence of PM_2.5 in lung dysfunction. The study showed the genes CD19, Pik3cd and CD8b1, involved in B-cell receptor signalling and cell-adhesion molecules, and their corresponding miRNAs miR-466i-5p, miR-203–5p and miR-7a-5p, as the critical epigenetic regulation happening after PM_2.5 exposure. The alterations in the genes mentioned above due to PM_2.5 exposure result in lung dysfunction and pulmonary fibrosis [170].

PM_2.5 also influences the reduction of ALKBH5, an RNA demethylase that can affect miRNA expression. A study by Zhang et al. [171] showed reduced expression of ALKBH5 after PM_2.5 exposure, sequentially reducing the miRNAs (miR-21a-5p, miR-590-5p, miR-361-3p, miR-340-5p and miR-202-3p) that target the Yes-associated protein (YAP1) pathway. Activation of the YAP1 pathway leads to extracellular matrix production and mechanical stiffness and results in pulmonary fibrosis.

A different study shows the influence of lncRNA in pulmonary fibrosis. let-7d-5p, an lncRNA from adipose stem cell-derived EVs as a treatment for pulmonary fibrosis. It reduces inflammation, ROS production, apoptosis, necrosis, and lung injuries caused by PM_2.5. It also inhibits TGF-βRI and alleviates the complications of pulmonary fibrosis [172].

PM_2.5-related epigenetic modifications in lung cancer

Another complication caused by PM_2.5 exposure is lung cancer. It known that PM_2.5 is a carcinogen and its exposure is linked to the incidence and consequences of lung cancer [13]. Furthermore, mice exposed to PM_2.5 exhibited histopathological alterations, EMT, increased ROS and lung DNA damage [173, 174]. This led to genetic modifications and induced epigenetic alterations, resulting in chronic inflammatory conditions, ultimately contributing to the initiation and complications of lung cancer [175, 176]. Moreover, PM_2.5 is associated with disruptions of various metabolic pathways, including the dysregulation of lipogenesis, leading to the accumulation of lipid droplets in lung cells, thereby promoting lung adenocarcinoma [163]. A study conducted by Liu et al. [177] highlighted that PM_2.5 exposure, even after lung cancer treatment such as lobectomy, can affect the survival rate of cancer patients. Consequently, maintaining improved air quality is essential for the proper recovery of patients (figure 4).

FIGURE 4.

Particulate matter with a diameter ≤2.5 μm (PM_2.5)-induced lung cancer. PM_2.5 alters the expression of various genes through DNA methylation and by altering the microRNAs (miRNAs) that target various genes affecting lung cancer progression. AHRR: aryl hydrocarbon receptor repressor; DLEC: deleted in lung and oesophageal cancer 1; Me: methyl group; NEAT1: nuclear paraspeckle assembly transcript 1; Pol II: polymerase II; RAD51: DNA repair protein RAD51 homologue 1; SOX2: sex-determining region Y-box 2; TNS3: tensin 3.

DNA methylation

DNA methylation is one of the most heavily studied epigenetic changes in lung cancer. Studies on PM_2.5 exposure and nasal methylome have revealed specific and regional DNA methylation changes in the cell cycle, cancer and immune/inflammatory pathways [178]. Genotoxicity induced by PM_2.5 is observed with either hypermethylation of specific genes involved in DNA damage repair and cancer progression, namely DNA repair protein RAD51 homologue 1 (RAD51) [179], sex-determining region Y (SRY)-box 2 (SOX2) [180] and deleted in lung and oesophageal cancer 1 (DLEC1) [181], or hypomethylation of genes such as aryl hydrocarbon receptor repressor [182], 8-oxoguanine DNA glycosylase [176, 179] and N-α-acetyltransferase 10 [183]. Significantly, irrespective of the methylation state, all these alterations were associated with the progression of lung cancer. For example, RAD51 is an essential protein in the homologous recombinational DNA repair pathway and the repair of DNA double-stranded breaks [184]. Similarly, SOX2 is an oncogenic transcription factor associated with several cancers [180, 185].

DLEC1 is a tumour-suppressor gene that is widely recognised as a cancer biomarker [181, 186]. It is involved in cancer prevention by increasing apoptosis and cell cycle arrest. DLEC1 hypermethylation downregulates the gene and, as a result, favours cancer progression. An interesting study found that physical exercise can mitigate DLEC1 hypermethylation caused by PM_2.5 exposure, reducing the chance of developing lung cancer [181].

On a different note, PM_2.5 is found to modify the methylation levels of various CpG islands of genes linked to the susceptibility and prognosis of lung cancer, including 15-lipoxygenase 2 (15-LOX2), ubiquitin-specific peptidase 43, signal recognition particle receptor subunit B, G protein subunit beta 2 like 1, small nucleolar RNA, C/D box 96A, prolyl 4-hydroxylase subunit alpha 2, lethal(3) malignant brain tumour-like protein 1 and retinoblastoma 1 [105, 187, 188]. In light of this, the methylation patterns of the genes present in nonsmokers can serve as markers for varying levels of exposure to PM_2.5 and those who are in pre-cancerous stages, even before a clinical diagnosis of lung cancer. Therefore, altered methylation patterns at gene promoters can be potential biomarkers for assessing disease risk.

Histone modifications

Despite numerous studies highlighting the impact of PM_2.5 on lung cancer, there is limited research examining the effect of PM_2.5 resulting in histone modification and lung cancer progression.

MicroRNA

Exposure to PM_2.5 impacts various metabolic pathways, including those related to lipid, purine and pyrimidine metabolism. These metabolic changes are influenced by differentially expressed miRNAs, which are associated with apoptosis, DNA damage and damage repair, and all linked to cancer [163, 179].

PM_2.5 exposure correlates with specific miRNAs, such as miR-17, miR-18a, miR-20a, miR-200a3p and miR-582-3p [163, 173, 187, 189, 190]. Notably, miR-17, miR-18a and miR-20a belong to the miR-17/92 cluster, recognised as an oncogene-related miRNA. These miRNAs play a role in 15-LOX2 gene inhibition, contributing to high proliferation and overexpression in various solid cancers, including lung cancer [187]. PM_2.5 exposure leads to an increased expression of the miR-200 family, promoting the proliferation and migration of lung cancer cells. Additionally, miR-200a3p is involved in cell migration by affecting tensin 3 expression [189]. Furthermore, PM_2.5 upregulates miR-582-3p, activating the Wnt/β-catenin signalling pathway, enhancing EMT transformation and promoting lung cancer [190]. A separate study showed that PM_2.5 exposure increases the expression of nuclear paraspeckle assembly transcript 1 (NEAT1), CD133 and CD44 in epithelial cells, which are associated with cancer, favouring progression by helping tumour growth and migration. MiR-582-5p was found to target NEAT1, inhibit its expression and protect cells from developing cancer characteristics [173].

Differential expression analysis studies by Ning et al. [174] and Eaves et al. [191] identified several differentially expressed miRNAs in response to PM_2.5 exposure. A subset of these miRNAs was associated with inflammatory/oxidative stress, with 13 miRNAs specifically linked to lung cancer, as outlined in table 2.

TABLE 2.

Summary of lung complications, their particulate matter with a diameter ≤2.5 μm (PM_2.5)-regulated microRNAs (miRNAs) and their effects

Disease	miRNA	State	Effect	Reference
Asthma	miR-31	↑	Downregulation of Foxp3 and IL-10, impairing regulatory T-lymphocyte function	[97]
	miR-331	↓	Activation of NF-κB by the ROS/PI3K/Akt pathway	[115]
	miR-146a	↑	Contributes to pro-inflammatory cytokine production, exacerbating lung injury following PM2.5 exposure	[97]
	miR-224	↓	Increasing airway inflammation and remodelling in asthmatic mice exposed to PM2.5 through TLR2 upregulation	[116]
	miR-206	↑	Inhibition of SOD1 expression and increase of ROS levels	[92]
	miR-486	↓	Promotion of alveolar epithelial cell cytotoxicity	[117]
	let-7i-5p	↑	Inhibition of DUSP1, resulting in cytotoxicity and the induction of lung cell contractility, and promoting asthma	[121]
COPD	miR-155	↑	Inhibition of FOXO3a, resulting in oxidative stress
	miR-149-5p	↓	Triggering inflammation through TAB2 on MAPK and NF-κB signalling	[143]
Pulmonary fibrosis	miR-494-3p	↓	Upregulation of target genes such as YT521-B, resulting in inhibition of E cadherin expression, EMT progression and fibrosis	[161]
	hsa-miR-760	↑	Apoptotic resistance activity by stabilising HMOX mRNA	[169]
	miR-21a-5p, miR-590–5p, miR-361–3p, miR-340–5p, miR-202–3p	↓	Activation of YAP1 pathway leading to extracellular matrix production and mechanical stiffness resulting in pulmonary fibrosis	[171]
Lung cancer	miR-17, miR-18a, miR-20a	↑	15-LOX inhibition, resulting in higher proliferation rate	[187]
	miR-200a3p	↑	Involved in cell migration by affecting TNS3 expression	[189]
	miR-582-3p	↑	Activating the Wnt/β-catenin signalling pathway, enhancing EMT transformation and promoting lung cancer	[190]
	miR-582-5p	↓	Targets NEAT1 and inhibits its expression	[173]
	miR-615-5p, miR-7663-3p, miR-411-3p, miR-93-3p, miR-20b-3p, miR-3971, let-7a-1-3p, miR-8118	↓	Linked to pathways of lung cancer development	[174]
	miR-344g-5p, miR-27a-5p, miR-7013-5p, miR-6996-5p, miR-466m-3p	↑	Linked to pathways of lung cancer development	[174]

Up (↑) and down (↓) arrows correspond to upregulation and downregulation, respectively. 15-LOX: 15-lipoxygenase; Akt: protein kinase B; DUSP1: dual specificity protein phosphatase 1; EMT: epithelial–mesenchymal transition; FOXO: forkhead box protein O; HMOX: haem-oxygenase; IL: interleukin; MAPK: mitogen-activated protein kinase; NEAT1: nuclear paraspeckle assembly transcript 1; PI3K: phosphatidylinositol 3-kinase; ROS: reactive oxygen species; SOD1: superoxide dismutase 1; TAB2: transforming growth factor-β activated kinase 1 binding protein 2; TLR2: Toll-like receptor 2; TNS3: tensin 3; YAP1: yes-associated protein.

As discussed earlier, PM_2.5 is associated with an alteration in lipid metabolism. D-limonene, a naturally occurring compound usually seen in citrus fruit peels [192], mitigates the impact of PM_2.5 exposure on lipid metabolism, suggesting its potential as a chemo-preventive agent to reduce the risk of lung cancer. This mediation involves miR-195, which could serve as a biomarker for monitoring the use of D-limonene [163]. Therefore, using miRNAs as predictive markers for identifying individuals at early risk of developing lung cancer due to PM_2.5 is promising [193] (table 2).

PM_2.5-related epigenetic modifications in lung infections

PM exposure is one of the main factors that can worsen respiratory diseases. PM_2.5 exposure has been shown to negatively influence the infectivity and prognosis of both bacterial and viral lung infections [194]. Moreover, PM_2.5 has the potential to modulate the pro-inflammatory cytokine, including IL-8, IL-6 and TNF-α production, in cases of subsequent bacterial or viral infection. This results in the production of a hyperinflammatory response against the infection [195, 196].

Bacterial lung infections

PM_2.5 has been shown to influence a variety of bacterial lung infections, including those caused by Pseudomonas aeruginosa, Pneumococcus and Mycobacterium. PM_2.5 harms the respiratory system, weakens immunity and can lead to heightened inflammation due to secondary infection caused by P. aeruginosa. This can cause severe lung damage, often linked to the activation of the NF-κB pathway [197]. PM_2.5 exposure impairs macrophage functions during pneumococcal infection, reducing phagocytosis and pro-inflammatory cytokine production. In a study by Chen et al. [198], a mouse model exposed to both PM_2.5 and Pneumococcus, PM_2.5 disrupted the pulmonary immune response, leading to leukocyte infiltration. Additionally, PM_2.5 inhibited the PI3K/Akt and MAPK pathways, suppressing CXCL10 and CXCR3 levels. This compromised macrophage activity exacerbates pneumococcal infectivity and worsens pulmonary pathogenesis. A study by Min et al. [199] showed that higher PM_2.5 exposure results in significantly higher tuberculosis recurrence. All things considered, further research is required to investigate the epigenetic mechanisms associated with exposure to PM_2.5 and the subsequent increased susceptibility to secondary bacterial infections.

Viral lung infections

Studies have shown that prior exposure to PM_2.5 augments future influenza viral infections [200, 201]. Ma et al. [202] studied the molecular link between PM_2.5 and influenza A virus infection. PM_2.5 exposure lowers the ability of macrophages to produce IL-6 and IFN-β. This is driven by alterations in H3K4 and H3K9 methylation in the promoter regions of IL-6 and IFN-β due to lysine demethylase 6A downregulation. This reduced secretion of IL-6 and IFN-β exacerbates the illness caused by influenza virus.

Furthermore, exposure to PM_2.5 changes cytokine production in epithelial cells and macrophages, including IL-1β, IL-6, IL-8 and replication markers induced by influenza viruses. NF-κB and TLR4 control these alterations mentioned above. PM_2.5 exposure also suppresses NOD-like receptor pyrin domain containing 3 inflammasome and AhR–TCDD-inducible poly(ADP-ribose) polymerase signalling, affecting influenza immunity [201, 203]. These PM_2.5-exposed changes can be epigenetically controlled but require further investigation. Recently, it was found that PM_2.5 exposure promoted the infection rate of severe acute respiratory syndrome coronavirus 2. PM_2.5 upregulates the angiotensin-converting enzyme 2 receptor, which the virus uses to enter the human body. This affects the human body and increases the severity of coronavirus disease 2019 [204–206]. All these studies highlight the effect of PM_2.5 in altering the epigenetic makeup and facilitating disease prognosis. The higher the exposure to PM_2.5, the greater the effect on lung infections.

Emerging therapeutic strategies for PM_2.5-induced lung complications

As discussed in the previous sections, PM_2.5 exposure results in various epigenetic modifications and severely complicates disease prognosis. Therapies to specifically target these changes can be promising. The use of counteracting enzymes, such as HDACs to counteract the effects of HATs and demethylases to counteract the effects of DNMTs, is encouraging [110]. Additionally, specific inhibitors tailored to block such epigenetic modifications are also effective [207]. Studies have shown that the efficiency of DNMT inhibitors such as 5-Aza and 5-Aza-dC in PM_2.5-induced lung complications is very good. 5-Aza prevents DNA methylation in asthma caused by PM_2.5 exposure. Moreover, 5-Aza restores Treg/Th17 imbalance by upregulating STAT5, Foxp3 and Treg transcription factors, and reducing STAT3 and RORγt levels, as well as Th17 transcription factors [102]. Furthermore, 5-Aza-dC prevents pulmonary fibrosis by reversing the hypermethylated state of the Thy-1 gene, a fibrosis inhibitor. It also reduces the expression of COL-I and COL-III, contributing to pulmonary fibrosis [166, 167].

Focusing on therapeutics based on histone-modifying enzymes has also been promising. Studies focusing on various histone-modifying enzymes such as SIRTs show potential. SIRTs are histone deacetylases that modify histone acetylation, silencing any downstream genes involved in inflammation. There are several SIRTs, such as SIRT1, SIRT2, SIRT3 and SIRT6. These SIRTs can be pro-inflammatory, anti-inflammatory or both, based on the location of the modification. SIRT blockers can be used as a therapy for pro-inflammatory SIRT modification [110, 139]. SIRT2 has been found to be pro-inflammatory and its inhibitors, such as SIRT2 antagonist AGK2, is a promising target [208]. Similarly, SIRT6, which promotes inflammation in asthma by increasing IL-17A expression, was found to be inhibited by OSS_128167, and successfully treated asthma by reducing IL-17A expression [111]. On the other hand, SIRT1 has an anti-inflammatory effect by inhibiting the activity of pro-inflammatory transcription factors such as NF-κB and AP-1, thereby reducing airway inflammation caused by PM exposure [113, 138]. As discussed earlier, salidroside, a plant extract from Rhodiola rosea, is found to activate SIRT1 expression after PM_2.5 exposure and reduce inflammation and apoptosis in lung epithelial cells [112]. A study involving resveratrol, which targets SIRT1, demonstrated a similar effect to salidroside in activating SIRT1 and treating COPD [137, 140]. SIRT3 agonist melatonin was found to reduce PM_2.5-induced ferroptosis in a murine model by activating Nrf2 signalling [209, 210]. In addition to the abovementioned epigenetic modifiers, tectoridin, a phytochemical isolate from Belamcanda chinensis, has been shown to have a protective effect by activating Nrf2 signalling and positively impacting PM_2.5-induced lung injury in mice [211].

On the other hand, studies have shown that targeting miRNAs can also alleviate PM_2.5-induced lung complications. MiR-224 can positively impact asthma incidence and restore Th cell imbalance in asthmatic mice exposed to PM_2.5. Moreover, miR-224 hinders the secretion of inflammatory cytokines such as IL-17A from Th17 cells [116]. Another miRNA, miR-218, blocks proliferation, inhibits apoptosis and reduces the levels of inflammation cytokines in human bronchial epithelial cells. Thus, miR-218 can be considered as a therapy in PM_2.5-induced COPD [145]. A different study has shown the influence of EVs in treating pulmonary fibrosis. Let-7d-5p, an lncRNA from adipose stem cell-derived EVs, was shown to reduce inflammation, ROS production, apoptosis, necrosis and lung injuries caused by PM_2.5. It also inhibits TGF-βRI and alleviates the complications of pulmonary fibrosis [172].

Bergapten (5-methoxysporalen), a furocoumarin mostly found in bergamot essential oil, was found to restore Th1/Th2 and Treg/Th17 imbalance and normalise cytokine levels in PM_2.5-exposed combined allergic rhinitis and asthma syndrome. It functions by reducing the activation of STAT3, the main transcription factor for Th17 cells. Further studies on bergapten are necessary to determine if it explicitly counteracts any epigenetic modifications resulting from PM_2.5 exposure [212]. The studies mentioned above, focusing on specific epigenetic modifications to alleviate PM2.5-induced lung complications, show promise. This brings hope for improved treatments for the more complex and chronic lung conditions mentioned in this review.

Conclusion

PM_2.5 exposure and epigenetic alterations can disrupt the expression of several genes, particularly those related to immune regulation, thereby contributing to lung complications. Further research into the specific mechanisms by which PM_2.5 induces these epigenetic changes is crucial. By intervening in these mechanisms, we can look into possible therapeutics to mitigate the effect of PM_2.5 on lung complications. Several epigenetic modifications, including DNA methylation, histone modification and microRNA, can be used as biomarkers for identifying lung complications resulting from PM_2.5 exposure.

Questions for future research

• Further research should determine the robust epigenetic changes that contribute to specific lung complications due to PM_2.5 exposure. How can these epigenetic modifications be used as biomarkers for early detection of lung complications caused by PM_2.5?

• Treg/Th1 and Th17/Th2 imbalance is one of the causes of PM_2.5-induced asthma. How can we mitigate this imbalance to reduce the effect of PM_2.5 resulting in asthma?

• Are there any shared immune mechanisms underlying the various lung complications caused by PM_2.5 exposure?