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 (NO_x), and PM_2.5. The HR of IPF for each interquartile range increase in NO₂, NO_x, PM_2.5, and PM₁₀ was significantly increased in subjects with a higher genetic risk. On the other hand, higher ammonium levels and black carbon along with PM_2.5 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 PM_2.5 and O₃, with age, sex, and coexistence of COPD adjusted HR of 1.50 (95% CI, 1.45 to 1.55) for PM_2.5 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 NO_x 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 PM_2.5 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).

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 PM_2.5 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 PM_2.5 at 30 days before an AE was significantly associated with the incidence of AE [27]. Specifically, a 10-unit increase in NO and PM_2.5 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 PM_2.5, 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.

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 PM_2.5 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 PM_2.5 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, PM_2.5 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 PM_2.5 and PM₁₀) were inversely correlated with lower baseline FVC [30]. However, these pollutants did not significantly affect the change in FVC over time.

Among 1,424 patients with fibrotic ILDs in the United States, 5-year prior PM_2.5 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 PM_2.5 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).

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].

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 PM_2.5 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 PM_2.5 (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 PM_2.5 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.

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 PM_2.5 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 PM_2.5 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).

Several in vivo studies have reported that air pollution may contribute to pulmonary fibrosis. Exposure to PM_2.5 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 PM_2.5 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].

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 PM_2.5 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].

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 PM_2.5 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.

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].

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 PM_2.5 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].