Air Pollution and Interstitial Lung Disease
Article information
Abstract
This review article explores the multifaceted relationship between air pollution and interstitial lung diseases (ILDs), particularly focusing on idiopathic pulmonary fibrosis, the most severe form of fibrotic ILD. Air pollutants are mainly composed of particulate matter, ozone (O3), nitrogen dioxide (NO2), carbon monoxide (CO), and sulfur dioxide (SO2). They are recognized as risk factors for several respiratory diseases. However, their specific effects on ILDs and related mechanisms have not been thoroughly studied yet. Emerging evidence suggests that air pollutants may contribute to the development and acute exacerbation of ILDs. Longitudinal studies have indicated that air pollution can adversely affect the prognosis of disease by decreasing lung function and increasing mortality. Lots of in vitro, in vivo , and epidemiologic studies have proposed possible mechanisms linking ILDs to air pollution, including inflammation and oxidative stress induced by exposure to air pollutants, which may induce mitochondrial dysfunction, promote cellular senescence, and disrupt normal epithelial repair processes. Despite these findings, effective interventions to mitigate effects of air pollution on ILD are not well established yet. This review emphasizes the urgent need to address air pollution as a key environmental risk factor for ILDs and calls for further studies to clarify its effects and develop preventive and therapeutic strategies.
Introduction
Interstitial lung disease (ILD) encompasses a range of conditions characterized by abnormal collagen deposition, interstitial proliferation, inflammatory cell infiltration, and sometimes fibrosis of the lungs [1]. ILDs can be classified into several types based on their etiology and morphologic pattern on biopsy or high-resolution computed tomography (HRCT) [2]. Some ILDs can result from environmental exposures such as hypersensitivity pneumonitis (HP), asbestosis, and silicosis. If the cause cannot be identified, it is termed idiopathic interstitial pneumonia (IIP), including idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis related ILD, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, acute interstitial pneumonia, and idiopathic pleuroparenchymal fibroelastosis. Apart from varying causes, ILDs commonly present with progressive hypoxemia, respiratory failure, and progressive pulmonary fibrosis, leading to mortality.
Although the pathogenesis of ILD remains unclear, repeated lung injuries by infection, cigarette smoking, and environmental or occupational exposures may lead to aberrant wound-healing process, which can result in progressive scarring and fibrosis of the lung tissue in some forms of ILD [3]. Inhaled environmental materials are known to cause several ILDs such as HP and pneumoconiosis, and smoking-related ILDs. While air pollution has been acknowledged to have a role in the development and exacerbation of chronic lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) [4], its impact on ILDs has been relatively understudied. This article aims to summarize recent studies about health effects of air pollution on patients with ILD, with a focus on IPF.
Air Pollution and Effects on Respiratory Health
Air pollution refers to contamination of the indoor or outdoor environment by any chemical, physical, or biological agent that alters natural characteristics of the atmosphere. Common air pollutants include particulate matter (PM), ozone (O3), nitrogen dioxide (NO2), carbon monoxide (CO), and sulfur dioxide (SO2) [5]. It originates from a wide array of sources, including household fuel combustion, industrial smokes, vehicle emissions, power generation, burning of waste, agricultural activities, and other numerous sources.
The respiratory track is the main entry point for ambient air pollution into the body. Deposition of particles in the respiratory track depends largely on their size. Small particles can penetrate deeper into the respiratory bronchiole or even into the lung, while large particles can be deposited in the upper airways. In fact, coarse PM of 10 μm or less in diameter (PM10) can penetrate the bronchi and PM of 2.5 μm or less in diameter (PM2.5) can reach the alveoli, which may have relevant effects on ILDs. Air pollutants have been extensively associated with respiratory morbidity and mortality, particularly in chronic respiratory diseases such as asthma and COPD [6-12]. Exposure to air pollutants has been associated with impaired lung growth in children [6]. In patients with asthma, air pollution is associated with poorly controlled asthma symptoms [7] and increases of emergency department visits and hospitalizations [8]. Otherwise, in COPD, air pollution has been identified as a risk factor for its incidence [9], decline in lung function parameters [10], hospitalization and mortality [11,12]. In addition, a large retrospective study on 448,850 participants of a Cancer Prevention Study in the United States has found that elevated O3 concentrations are significantly associated with an increased risk of death from respiratory causes, showing a relative risk (RR) of death of 1.040 for every 10 parts per billion (ppb) increase in O3 concentration [13]. Among 73,711 participants of the same cohort residing in California, exposure to NO2 was positively associated with an increased risk of lung cancer mortality, with an RR of 1.111 and a 95% confidence interval (CI) ranging from 1.020 to 1.210 [14].
Effects of Air Pollution on ILD
Effects of air pollution on ILDs including IPF are not as comprehensively understood as for chronic airway diseases. In this context, we intend to thoroughly investigate and describe critical ways in which air pollution adversely effects ILDs.
1. Development of ILDs
Some ILDs have a clear etiology, whereas IIP is of unknown cause, though environmental factors, including air pollution, may contribute to both. Several potential environmental risk factors, such as cigarette smoking and dust exposure, have also been reported [15,16].
Conti et al. [17] firstly reported the association between exposure to air pollution and IPF incidence in Italy. While no association was detected with PM10 or O3, an increment of 10 μg/m3 in NO2 concentration was associated with an increase of IPF incidence rate by 7.93% to 8.41% depending on the season, with a significant impact during the cold season. Afterward, several studies have reported the relationship between air pollutants and incidence of IPF [18,19]. In a population-based prospective cohort study including 402,042 participants who were free of IPF at baseline in the United Kingdom Biobank, 2,562 cases of IPF were identified [18]. It found that SO2 concentration showed a linear association with the development of IPF, with each 1 μg/m3 increase in ambient SO2 having hazard ratio (HR) for incident IPF of 1.67 (95% CI, 1.58 to 1.76) [18]. In addition, a synergistic additive interaction between genetic susceptibility and ambient SO2 level was found. Those with a high genetic risk and a high ambient SO2 exposure had a higher risk of developing IPF than those who had a low genetic risk and a low SO2 exposure (HR, 7.48; 95% CI, 5.66 to 9.90). Using the same cohort, Cui et al. [19] have found additive interactions of genetic susceptibility for IPF incidence with NO2, Nitrogen oxides (NOx), and PM2.5. The HR of IPF for each interquartile range increase in NO2, NOx, PM2.5, and PM10 was significantly increased in subjects with a higher genetic risk. On the other hand, higher ammonium levels and black carbon along with PM2.5 and O3 might be associated with an increased incidence of ILD in patients with rheumatoid arthritis (RA). In a study of 280,516 patients newly diagnosed with RA, 2,194 cases of RA-associated ILD were detected [20]. The onset of RA-ILD was linked to exposure to PM2.5 and O3, with age, sex, and coexistence of COPD adjusted HR of 1.50 (95% CI, 1.45 to 1.55) for PM2.5 and 1.03 (95% CI, 1.01 to 1.04) for O3. Moreover, adjusted HRs of ammonium and black carbon for the time to RA-ILD onset were 1.38 (95% CI, 1.36 to 1.40) and 1.26 (95% CI, 1.23 to 1.28), respectively.
In addition to clinically overt ILDs, the Multi-Ethnic Study of Atherosclerosis (MESA) study revealed that subclinical ILD findings such as interstitial lung abnormalities (ILAs) and high attenuation areas (HAAs) observed on chest computed tomography were also associated with air pollution [21]. The risk of developing ILA increased 1.77-fold for each 40 ppb increase in NOx level (95% CI, 1.06 to 2.95; p=0.03). Additionally, HAA showed a tendency to increase annually by 0.43% with every 5 μg/m3 rise in PM2.5 level (95% CI, –0.08% to 0.94%; p=0.10) and by 0.45% for each 10 ppb increase in NO2 (95% CI, –0.02% to 0.92%; p=0.06).
2. Acute exacerbation
IPF follows a chronic progressive course, though its natural history remains unpredictable. While majority of patients experience gradual progression, some patients experience sudden and unexpected deterioration of the disease, known as an acute exacerbation (AE) [2,22]. Before antifibrotic therapy became the mainstream treatment for IPF, the prognosis was extremely poor, with approximately 50% of patients dying within 2 to 3 years after diagnosis [2]. Among non-IPF ILDs, especially those with progressive pulmonary fibrosis, mortality rates are similar to those observed in IPF [23,24].
In 2014, data from a South Korean IPF cohort showed a significant association between the risk of AE and increased levels of O3 and NO2 measured at a monitoring station near the residential address in previous 6 weeks [25]. Afterward, this relationship has been validated with other cohorts [26-28]. Average pollutant levels including CO, NO2, SO2, PM10, and PM2.5 for all regions in Santiago, Chile were significantly related to the risk of hospitalization for IPF [26]. In Japan, a study of 152 patients with surgically diagnosed IPF revealed that increased exposure to NO and PM2.5 at 30 days before an AE was significantly associated with the incidence of AE [27]. Specifically, a 10-unit increase in NO and PM2.5 level correlated with an odds ratio (OR) of 1.46 (95% CI, 1.11 to 1.93) or 2.56 (95% CI, 1.27 to 5.15), respectively [27]. In a French cohort of 192 IPF patients, the onset of AE was significantly associated with an increased mean level of O3 prior to 6 weeks, with a HR of 1.47 (95% CI, 1.13 to 1.92) per 10 μg/m3. Mortality was also significantly associated with increased levels of exposure to PM10 and PM2.5, with HRs of 2.01 (95% CI, 1.07 to 3.77) and 7.3 (95% CI, 2.93 to 21.33) per 10 μg/m3, respectively [28]. Research results on the effects of major air pollutants on AE are summarized in Table 1.
Effects of air pollution on acute exacerbation in interstitial lung disease
3. Lung function and disease progression
The detailed summary of research results on how major air pollutants affect lung function are outlined in Table 2. A longitudinal study has analyzed the association of lung function changes in 175 IPF patients identified from 2007 to 2013, with average concentrations of PM10 and PM2.5 measured based on geocoded residential address [29]. It found that every 5 μg/m3 increase in PM10 level corresponded to a decrease in forced vital capacity (FVC) by 46 cc/year (95% CI, 12 to 81; p=0.008). In addition, for each increment of 5 μg/m3 in PM2.5 level, the use of supplemental oxygen required to maintain saturation >88% during the 6-minute walk test increased by 1.15 L/year (95% CI, 0.03 to 2.26; p=0.044). However, PM2.5 did not significantly affect the change of FVC. Conversely, a prospective study that monitored FVCs of 25 IPF patients on a weekly basis for up to 40 weeks showed that elevated levels of NO2 and PM (both PM2.5 and PM10) were inversely correlated with lower baseline FVC [30]. However, these pollutants did not significantly affect the change in FVC over time.
Impact of air pollution on lung function
Among 1,424 patients with fibrotic ILDs in the United States, 5-year prior PM2.5 exposure was associated with decreases of FVC and diffusing capacity of lungs for carbon monoxide (DLCO). Each increase of 1 μg/m3 in 5-year PM2.5 exposure was associated with an addition-al 0.4% or 0.28% decrease in FVC or DLCO percentage estimated per year, respectively [31]. Recently, among 946 IPF patients in Korea whose long-term individual-level exposure to air pollutants at their home addresses were estimated, 547 (57.8%) patients experienced progression defined as a relative decline in FVC ≥10% [32]. A 10 ppb increase in NO2 level was associated with a 10.5% increase in the risk of progression with HR of 1.105 (95% CI, 1.000 to 1.219). In a study involving 181 patients with systemic sclerosis (SSc)-associated ILD, progression was defined as either a relative decrease in FVC of at least 10% or a decrease in FVC of 5% to 10% associated with a decrease in DLCO of at least 15% from baseline [33]. At 12- and 24-month, progression was observed in 25% (27/105) and 43% (48/113), respectively. Exposure to O3 was associated with an increased risk of progression with an OR of 1.10 (95% CI, 1.02 to 1.19). Moreover, mean O3 concentration over 5 years preceding the diagnosis of SSc-associated ILD was also associated with a more extensive form of ILD defined by over 30% ILD extent on HRCT or 10% to 30% extent with a FVC under 70% of predicted value (OR, 1.12; 95% CI, 1.05 to 1.21).
4. Lung cancer
IPF is regarded as a risk factor for the development of lung cancer, and both diseases share risk factors such as older age, male sex, and smoking history [34,35]. The prevalence of lung cancer in IPF ranges from 2.7% to 48%, which is approximately six to eight times higher than that in the general population [35,36].
Recently, in a Korean IPF cohort including 1,085 patients from Asan Medical Center, it was found that high NO2 levels significantly increased the risk of lung cancer with HR of 1.219 after a median follow-up of 4.3 years. It also found that high NO2 levels (≥21 ppb) was associated with a 2-fold increase in lung cancer incidence compared to low NO2 levels (<21 ppb) [37]. However, in the general population, some studies reported an increased risk of lung cancer with NO2 exposure [38,39], while some studies did not [40,41]. In a Korean general population study, NO2 exposure was not significantly associated with lung cancer risk [41]. On the contrary, a meta-analysis of 20 studies found that NO2 exposure was associated with an increased incidence of lung cancer with an RR of 1.04 per 10 μg/m3 increase (95% CI, 1.01 to 1.08) in the general population [42].
Whether the effect of NO2 on lung cancer is specific to IPF or the general population is not clearly revealed. The underlying mechanism is not well understood either. However, NO2 exposure in IPF may accelerate the development of lung cancer through a repetitive epithelial injury, chronic inflammation, lung tissue damage, and the remodeling process [19,43,44]. Although the pathogenetic link between IPF and lung cancer remains unclear, these two diseases share biologic signaling pathways such as transforming growth factor β (TGF-β) [44,45]. These singling pathways can enhance epithelial-mesenchymal transition (EMT) and cause tissue damage and abnormal repair, leading to fibrosis and carcinogenesis [46]. An in vivo study has shown that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β, leading to a progenitor-like state in epidermal growth factor receptor mutant alveolar type II cells, promoting tumorigenesis [47]. Exposure to traffic related air pollution can significantly decrease deoxyribonucleic acid (DNA) methylation and increase methylation of a series of tumor suppressor genes [48].
5. Mortality
Research findings on the relationship between major air pollutants and mortality risk are summarized in Table 3. Sese et al. [28] have reported that long-term cumulative exposure to PM10 and PM2.5 is significantly associated with the risk of mortality in 192 French IPF patients. The mortality was significantly associated with increased exposure to PM10 (HR, 2.01; 95% CI, 1.07 to 3.77 per 10 μg/m3) and PM2.5 (HR, 7.93; 95% CI, 2.93 to 21.33 per 10 μg/m3), but not with increased exposure to NO2. However, opposite result was recently reported. Among 1,114 IPF patients in Korea with a median follow-up period of 3.8 years, 69.5% died or underwent lung transplantation [49]. A 10 ppb increase in NO2 level was associated with a 17% increase in overall mortality (HR, 1.172; 95% CI, 1.030 to 1.344; p=0.016). This association was much stronger in elderly males (≥65 years), with an HR of 1.305 (95% CI, 1.072 to 1.598). However, the risk of mortality was not associated with PM10 level. These inconsistent results might be due to the use of regional monitoring stations in the prior study and the use of a predictive model in the later research that incorporated additional adjustments based on these stations derived from addresses, regions, and spatial variables. PM could be deposited deeply in the respiratory tract and PM2.5 could reach the alveoli, thereby inducing systemic inflammation and oxidative stress. PM concentration is related to widespread regional emissions. However, outdoor NO2 is more related to local sources.
Effects of air pollution on mortality
Some studies have investigated effects of air pollution on survival in non-IPF ILDs and shown similar results. Goobie et al. [31] have conducted a multicenter, international, prospective cohort involving three cohorts of 6,683 patients diagnosed with fibrotic ILDs, reporting a mortality rate of 28% and a lung transplant rate of 10%. Meta-analysis of pooled individuals from the three cohorts showed that each 1 μg/m3 increase in PM2.5 was associated with a 9% increased risk of mortality (HR, 1.09; 95% CI, 1.05 to 1.13). In addition, increases in exposure to sulfate, ammonium, and black carbon PM2.5 constituents were linked to a higher risk of mortality or transplant. Kim et al. [50] have investigated effects of PM10 and NO2 on survival in RA-ILD. Among 309 patients with RA-ILD (125 [40.5%] died), high PM10 exposure was associated with the risk of mortality (HR, 1.68; 95% CI, 1.11 to 2.52). However, high NO2 exposure was not linked to mortality risk in whole individuals with RA-ILD, although it increased the risk of mortality in female patients (HR, 2.01; 95% CI, 1.02 to 3.96).
Mechanisms of Adverse Effects of Air Pollutants on ILDs
Air pollutants can trigger airway inflammation and induce oxidative stress by generating reactive oxygen species (ROS), which can damage lung tissues both directly and indirectly. Thus, chronic exposure to air pollutants can impair lung function and promote disease progression, resulting in increased mortality. Moreover, beyond the lung, air pollutants can affect systemic organs through inflammatory process. Here, we will discuss the plausible pathophysiological mechanism of how air pollution affects respiratory diseases, particularly ILDs. Figure 1 provides a simplified illustration of this process.
Schematic illustration of pathophysiological mechanism of air pollution on interstitial lung disease. ECM: extracellular matrix.
1. Inflammation
Several in vivo studies have reported that air pollution may contribute to pulmonary fibrosis. Exposure to PM2.5 can lead endoplasmic reticulum stress (ERS) induced autophagy and activate TGF-β/Smad3 pathway and secretion of inflammatory factors and collagen deposition in rat lung epithelial cells [51]. Additionally, in animal models chronically exposed to high concentrations of O3, chronic epithelial changes including fibrosis were confirmed in lung autopsies [52].
In human, Salvi et al. [53] have performed blood sampling and bronchoscopic evaluation for healthy subjects exposed to diesel exhaust for 1 hour. In bronchoalveolar lavage fluid samples, neutrophils, B lymphocytes, histamine, and fibronectin were increased. In bronchial biopsies, CD4 and CD7 T lymphocytes, endothelial adhesion molecules intracellular adhesion molecule-1, and vascular cell adhesion molecule-1 were increased. Moreover, neutrophils and platelets were also significantly increased in peripheral blood, indicating an acute systemic and bronchopulmonary inflammatory response due to short-term diesel exhaust exposure. Afterward, several epidemiologic studies of short-term exposure to traffic related air pollutants such as PM2.5 and organic carbon have consistently demonstrated relationships with both airway and systemic inflammation in healthy individuals [54,55].
On the other hand, in autoimmune disease, PM exposure is thought to induce the development of inducible bronchus-associated lymphoid tissue, leading to the production of pathogenic autoantibodies such as anti-citrullinated protein antibodies in RA [56].
2. Oxidative stress
Inhalation of air pollutants can cause oxidative stress via the production of ROS such as hydroxide radical and superoxide anion [57]. When the body’s intrinsic antioxidant balance to eliminate ROS is overwhelmed by excessive ROS production, cellular damage cannot be avoided. An in vitro study showed that exposure of cultured alveolar epithelial cells to PM2.5 resulted in the generation of ROS and downregulation of nuclear factor erythroid 2-related factor 2 (Nrf-2), a transcription factor responsible for the synthesis of intracellular antioxidants such as superoxide dismutase (SOD2) [58].
Patients with IPF show decreased levels of glutathione (GSH), an antioxidant, in the lower respiratory tract, suggesting that they are more susceptible to excess ROS caused by air pollution [59]. PM may induce oxidative stress in the lung epithelium by impairing mitochondrial function with consequent overproduction of ROS, resulting in increased cellular ROS with inhibition of SOD2 activities and reduction of GSH levels, which may play a key role in the development and progression of IPF [60,61].
3. Telomere shortening
Telomeres are composed of repeated TTAGGG segments of DNA located at the ends of chromosomes. They can prevent DNA degradation [62]. Telomeric DNA regions are particularly sensitive to ROS-induced damage. Telomere shortening can be induced and accelerated by chronic inflammation and increased oxidative stress from exposure to air pollutants [63,64]. A meta-analysis of both short-term and long-term exposure to PM2.5 showed an inverse association between such exposures and telomere length [65]. Air pollution-induced telomere shortening may accelerate cellular senescence, surfactant abnormalities, ERS, and oxidant-antioxidant dysregulation [64,66,67]. These are all potential causes of abnormal alveolar reepithelialization, which are mechanisms responsible for the development of IPF.
4. Mitochondrial dysfunction and cellular senescence
Mitochondrial homeostasis and function are crucial for the normal cellular physiology in various organ systems. PM can induce mitochondrial toxicity including mitochondrial dysfunction, altered biogenesis, and structural changes with consequent overproduction of ROS by mitochondria [61]. Altered mitochondrial function can lead to cell apoptosis and senescence, which are known drivers of aging and IPF [68,69]. Furthermore, mitochondrial dysfunction has been identified in various IPF lung cells including alveolar epithelial cells, fibroblasts, and macrophages, making them more susceptible to activation of profibrotic responses [70].
5. Extracellular matrix remodeling
Pulmonary fibrosis is characterized by uncontrolled deposition of extracellular matrix (ECM) in the interstitium as a result of repeated alveolar epithelial injury. Mesenchymal cells such as myofibroblasts are direct sources of collagen and ECM components. They are considered important in the pathogenesis of IPF. It has been found that urban ambient air pollution in Mexico City can induce platelet-derived growth factor receptors in myofibroblasts and that PM10 exposure can increase protease activity in alveolar epithelial cells by increasing matrix metalloproteinase expression [71,72]. Exposure to PM2.5 on human bronchial epithelial cell line can lead to activation of TGF-β/Smad3 signaling pathway, upregulation of α-smooth muscle actin, collagen type I upregulation, and EMT [73].
Interventional Strategies
Detrimental effects of air pollution have been studied across the natural course of ILDs, ranging from their onset through progression to mortality. However, to date, there has been no research on “potentially modifiable factors” related to the impact of air pollution on ILDs, nor on preventive interventions mediated by these factors. Furthermore, it is unknown whether preventive approaches to general air pollution such as personal masks, high-efficiency particulate air filters, and policy-driven reductions in air pollution could improve clinical outcomes of patients with ILD.
Recently, there has been an interesting study on the association between greening of homes and the risk of developing IPF [74]. It has been reported that greenness as a key contributor of health promotion in urban area can reduce the risk of adverse health outcomes including mortality, cardiovascular disease, obesity, and asthma [75,76]. However, there has been a lack of evidence available to demonstrate the effectiveness of greenness exposure in relieving IPF. Tang et al. [74] have published a study involving 469,348 participants in the United Kingdom Biobank. They used normalized difference vegetation index (NDVI) within 300-, 500-, 1,000-, and 1,500-m buffers (NDVI300m to NDVI1500m) as indicators for greenness. They found that greater exposure to residential greenness was correlated with a reduced incidence of IPF, especially among individuals with a higher genetic risk score. This polygenic risk score included 13 single nucleotide polymorphisms linked to the development of IPF. These findings from a large-scale prospective study may shed light on the importance of urban greenness for reducing the development of IPF as a strategy to prevent harmful effects of air pollution on ILDs.
Conclusion
ILDs are a complex and heterogenous group of diseases. Air pollution is increasingly recognized as a significant environmental risk factor affecting the onset, progression, and mortality of these diseases. Currently, there are no proven preventive approaches specifically designed to reduce the risk from exposure to air pollution in ILDs. However, efforts to minimize exposure are recommended as a means to mitigate subsequent harm. While effects may vary among disease subtypes, further studies using large research cohorts are needed.
Notes
Authors’ Contributions
Conceptualization: Song JW. Methodology: all authors. Formal analysis: all authors. Software: all authors. Validation: all authors. Investigation: all authors. Writing - original draft preparation: Jo YS. Writing - review and editing: all authors. Approval of final manuscript: all authors.
Conflicts of Interest
Jin Woo Song is an associate editor and Yong Suk Jo is an editorial board member of the journal, but they were not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
Funding
This study was supported by a grant (NRF-2022R1A2B 5B02001602) from the Basic Science Research Program and a grant (NRF-2022M3A9E4082647) of the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science & ICT, Republic of Korea. It was also supported by grants from the National Institute of Health research project (2024ER090500) and the Korea Environment Industry & Technology Institute through the Core Technology Development Project for Environmental Diseases Prevention and Management Program funded by the Korea Ministry of the Environment (RS-2022-KE002197), Republic of Korea.