Introduction Asthma and chronic obstructive pulmonary disease (COPD) impose substantial morbidity and health system burden in Canada. Within Vancouver Coastal Health (VCH), a large and geographically diverse health authority in British Columbia, variation in service availability, access and care coordination creates barriers to prevention and high-quality chronic respiratory disease management. This project sought to document healthcare professionals’ (HCPs’) experiences and recommendations to inform a regional strategy to improve asthma and COPD care.Methods We conducted a qualitative quality improvement project using occupation-specific virtual focus groups (March to September 2021) with HCPs involved in asthma and COPD prevention and care across VCH. Purposive sampling targeted diversity in profession, practice setting and geography (urban, suburban, rural and remote). Results were analysed thematically in NVivo using iterative coding and team-based refinement.Results 54 HCPs participated across 10 focus groups, including respiratory physicians (n=9), respiratory therapists (n=19), family physicians (n=11), nurse practitioners (n=2), nurses (n=7), pharmacists (n=6) and one registered dietitian (n=1). Themes aligned with a socio-ecological framework and spanned (1) patient-level barriers (financial insecurity, language barriers, comorbid mental health and substance use, medication beliefs and adherence, smoking and vaping), (2) health system barriers (limited access to spirometry and pulmonary rehabilitation, fragmented transitions and unlinked electronic records, workforce and resource constraints) and (3) environmental barriers (medication coverage and formulary restrictions, poor air quality as an exacerbation trigger). HCPs recommended expanding community-based services (including mobile diagnostics and rehabilitation), strengthening prevention and cessation supports, improving medication access and inhaler education, and building integrated pathways and information systems to support continuity across settings.Conclusions Frontline HCP perspectives identify actionable, system-level opportunities to improve asthma and COPD prevention and care within a complex health authority. This work provides implementation-oriented insights to inform regional strategy and offers a replicable approach for engaging HCPs to strengthen chronic respiratory care.

Outdoor air pollution exposure is a well-established driver of respiratory disease, while growing evidence highlights an important role for genetic susceptibility. Building on this expanding body of work, our review synthesises findings across studies and provides an integrated overview. Here, we present a structured literature review summarising study characteristics and statistically significant single nucleotide polymorphisms (SNPs) reported in gene-environment interaction studies of air pollution related respiratory outcomes. By consolidating this evidence, the review clarifies current findings and supports more rigorous, evidence-based risk stratification in future observational and intervention studies. We included 48 peer-reviewed studies in humans published between 2014 and 2024 that examined gene-environment interactions involving SNPs, outdoor air pollution exposure and respiratory outcomes. Studies primarily evaluating particulate matter with aerodynamic diameter <2.5 µm and <10 μm, and nitrogen dioxide included respiratory end-points, such as asthma, COPD and lung-function measures. The majority of analyses used regression-based methods, supplemented by mixed-effects and generalised estimating equation models. Candidate gene studies (particularly in the glutathione S-transferase (GST) family) along with polygenic risk scores and genome-wide interaction approaches identified 89 SNPs across 53 genes. Replicated variants involved pathways in oxidative stress detoxification (e.g. rs1695 (GSTP1) and rs2266637 (GSTT1)) and inflammatory responses (e.g. rs1800629 (TNF), rs3804099 (TLR2) and rs848 (IL13)), consistently modifying pollution-related lung function decline and airway inflammation. By consolidating key genes, study designs and analytic methods, this review provides a curated SNP list to inform future genetic risk stratification. We highlight the need for studies in ancestrally diverse populations, controlled human exposure designs, and multi-omics approaches to strengthen mechanistic understanding of gene-environment interactions in respiratory health.

BACKGROUND:The growing popularity of cannabis smoking in an era of legalisation has prompted concerns about respiratory health. OBJECTIVE:To investigate clinical and airway epithelial transcriptomic features associated with cannabis smoking. METHODS:This cross-sectional study analysed data from 139 cannabis-smoking participants categorised by joint-year exposure (low: ≤5; moderate: >5-20; high: >20 joint-years) and 57 never-smokers. We evaluated respiratory symptom questionnaire scores, lung function measurements, chest computed tomography and hyperpolarised 129Xenon pulmonary magnetic resonance imaging measurements across groups. We compared the expression of immune response signatures and mucin genes in airway epithelial brushings collected from bronchoscopy. Using air-liquid interface cell cultures, we quantified epithelial mucin 5AC (MUC5AC) protein and correlated its expression with clinical outcomes. RESULTS:Among cannabis-smoking participants (48% male, median age of 27 years), 84% reported current or former cigarette smoking or vaping. Cannabis-smoking groups reported worse respiratory symptoms than never-smokers. High joint-year cannabis-smoking participants showed lower pre-bronchodilator forced expiratory volume in 1 s to forced vital capacity ratio, lower forced expiratory flow at 25-75% of the forced vital capacity, more radiographic emphysema and more ventilation abnormalities than never-smokers. Airway epithelial brushings from cannabis-smoking participants demonstrated an increased type 2 immune response, decreased type 17 immune response and higher MUC5AC gene expression than non-cannabis-smoking participants. Epithelial MUC5AC protein expression in cell cultures correlated with worse clinical outcomes and imaging abnormalities. CONCLUSIONS:Cannabis smoking, particularly at high exposures, is associated with worse respiratory symptoms, lower lung function, functional imaging abnormalities and dysregulated immune responses in the airway epithelium. These observations suggest respiratory harm associated with cannabis smoking and underscore the concerns for future respiratory morbidities related to persistent cannabis use.

BACKGROUND:Allergic rhinitis (AR) involves nasal inflammation from aeroallergens that is treatable with nasal corticosteroids. However, the efficacy of nasal corticosteroids after diesel exhaust (DE) exposure and effects on nasal epigenetic age acceleration (EAA) are unknown. OBJECTIVE:To investigate the effects of nasal budesonide on AR-related nasal inflammation and nasal EAA after DE exposure. METHODS:In this double-blinded randomized crossover trial, 20 healthy nonsmokers with AR used once-daily 256 µg budesonide and placebo nasal spray for at least 4 weeks each, with an intervening washout of at least 4 weeks. Initial exposure and re-exposure to allergen and DE were completed over consecutive days in separate periods, preceded by at least 2 weeks of pretreatment/washout. Nasal lavage fluid, nasal brushings, peak nasal inspiratory flow (PNIF), and Total Nasal Symptom Score (TNSS) were collected at treatment baselines, and before and 24 hours after each exposure. PNIF and TNSS were also collected 0.5 hours after exposure. Nasal cytokines and EAA were quantified using multiplex assays and Illumina EPIC arrays, respectively. RESULTS:Reductions in nasal interleukin-5 from budesonide pretreatment persisted 24 hours after initial exposure and re-exposure to allergen and DE, despite their proinflammatory effects. Reductions in interleukin-17A persisted 24 hours after initial DE exposure. Budesonide increased PNIF 24 hours after initial exposure and re-exposure to allergen, and at 0.5 hours after initial exposure and 24 hours after re-exposure to DE. Allergen-induced TNSS was suppressed by budesonide at 0.5 and 24 hours after re-exposure. Budesonide and allergen/DE exposures modulated nasal EAA across different clocks. CONCLUSION:In AR, prophylactic nasal budesonide spray attenuated nasal inflammation and modulated nasal EAA and PNIF before and after repeated acute exposures to allergen and DE. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT04342039 (URL: https://clinicaltrials.gov/study/NCT04342039).

Climate change-driven increases in forest fires pose a major global health risk due to exposure to smoke containing hazardous gases and fine particulates, emphasizing the need for physiologically relevant in vitro airway models for studying smoke-induced responses. Microfluidic lung-on-a-chip technologies provide a strong foundation for in vitro airway modeling and ongoing developments are expanding their ability to incorporate multicellular organization, extracellular matrix complexity, and physiologically relevant exposure methods. This work presents the optimization and integration of a photopolymerizable gelatin methacrylate (GelMA)-based hydrogel into a microfluidic airway-on-a-chip that models the human small conducting airways and supports controlled aerosol exposure to wood smoke. The GelMA hydrogel was optimized to support fibroblast encapsulation, endothelial adhesion, and robust mechanical stability. The device combines the hydrogel with a compartmentalized microchannel layout, and sacrificial molding to create a 3D organotypic airway culture featuring a multilayer architecture, 3D stromal matrix, and a perfusable vasculature-like lumen. Coupling the platform with a custom aerosol exposure system enables precise, biomimetic exposure to whole wood smoke. Proof-of-concept studies using transforming growth factor beta 1 (TGF-β1) and whole wood smoke elicited expected inflammatory and fibrotic responses, validating the platform’s physiological relevance for inhalation studies and investigating smoke-induced airway remodeling and inflammation.

To address the increasing concern regarding woodsmoke (WS) exposure and better understand its effects on human health, a WS generation system was built in the Air Pollution Exposure Laboratory to facilitate future controlled human exposure studies. Ground lodgepole pine was burned to generate WS, with PM2.5 concentrations of approximately 500 µg/m3 obtained. The WS produced by this system was characterized and directly compared with diesel exhaust (DE) generated and collected at the same facility. For gases, WS showed slight increases in CO and CO2 compared with filtered air (FA), whereas DE had significantly higher levels of NOx, CO, CO2, and total volatile organic compounds than FA. The non-refractory composition of WS aerosols was approximately 98% organics, 0.2% ammonium, 1.3% nitrate, and 0.2% sulfate. Among the organic species, the fraction of oxygenated species was much higher in WS aerosols than in DE aerosols. Moreover, WS aerosols had higher concentrations of Cd compared with DE aerosols. Greater oxidative potential was also observed for WS compared with DE, with dithiothreitol consumption rates of 0.0090 nmol/min/µg. This study established a controlled human exposure platform for WS and described the methods used for analyzing and comparing the concentrations, particulate morphologies, chemical compositions, and oxidative potentials of different lab-generated pollutants. The observed differences between WS and DE in oxidative potential and amounts of gases, organic species, and metals provide a foundation for investigating how specific air pollution components differentially impact human health.

Background:Air pollution is a major threat to human health globally, but physicians' awareness of its specific health impacts and the extent they educate patients remain poorly understood. Methods:We sought out the perceptions of general practitioners and pulmonologists regarding their role in managing impacts of air pollution on patients. We also assessed the educational and behavioural gaps, and contextual challenges relevant to respiratory health management from these professional perspectives. Computer-assisted telephone interviews were conducted across eight countries (Brazil, Canada, China, France, Germany, India, Mexico and the United States) with 600 physicians (primary care and respiratory medicine specialties). Results:While 95% of respondents agreed that it was their role to assess and manage air pollution exposure and proactively educate patients, fewer reported concrete demonstrations of this role in practice. Over half (55%) recommended medical treatment addressing exposure, and 20% engaged in normal monitoring but without preventive action for patients exposed to air pollution. Only 11% recommended concrete lifestyle changes for patients. In addition, 34% of respondents were unsure whether they should prioritise only acute cases for counselling. Significant country differences in awareness of air pollution health impacts and management were found. Inadequate integration of air quality indices in patient care and costly protective equipment were identified as systemic barriers. Conclusion:Although general practitioners and pulmonologists recognise their role in assessing, managing and educating patients about air pollution exposure, their perception of this role and competencies within it indicate the need for educational support translating to impactful practice.

Predicting lung cancer risk would enhance prevention trials. Although the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial demonstrated reduced lung cancer incidence with interleukin (IL)-1β inhibition, the high number needed to treat (NNT) to prevent lung cancer limits its use in unselected populations. Using machine learning, we identified a 14-protein plasma signature predicting lung cancer more than 5 years before diagnosis. The signature, validated across eight cohorts, was elevated in current smokers and individuals exposed to particulate matter (PM) and linked to lung myeloid and alveolar cells. In epidermal growth factor receptor (EGFR)-driven lung adenocarcinoma, diverse epithelial lineages converged on a keratin8+/claudin4+ alveolar transitional state (KAC), whose transcriptional programs correlated with signature emergence. Components of the signature were induced by PM, oncogenic EGFR, or IL-1β, whereas IL-1β inhibition restrained PM-driven KAC expansion and early tumorigenesis. In CANTOS, the signature identified individuals who seemed to benefit more from anti-IL-1β therapy, lowering the NNT threshold and nominating circulating signals of tumor promotion for prevention.

BACKGROUND:The specific inhalation challenge (SIC) is the reference standard for diagnosing occupational asthma (OA) but is not widely used globally. OBJECTIVE:We aimed to develop a more practical clinical model to diagnose OA in workers exposed to low-molecular-weight (LMW) agents. METHODS:We conducted a diagnostic study using clinical interview variables and non-SIC tests as predictors. OA was defined by positive SIC. Retrospective data from Quebec and British Columbia were used to develop logistic models. External validation included centers with routine SIC (Finland, Poland) and expert-confirmed OA (Ontario, Turkey, England). RESULTS:The clinical interview model included male sex, isocyanate exposure, work-related rhinoconjunctivitis, smoking status, and exposure duration <10 years. The clinical interview model can correctly discriminate a positive from a negative SIC in 65% of the cases (area under the receiver operating characteristic curve [AUC] = 0.65). Adding diagnostic tests to the clinical interview model improved the AUC to 0.73 for the nonspecific bronchial hyperreactivity (NSBHR), 0.80 for the serial peak expiratory flow (PEF), and 0.81 for NSBHR plus serial PEF. Combining the clinical interview with serial PEF was the model of choice, showing strong internal validity (shrinkage 0.93) and adequate calibration (Hosmer-Lemeshow P > .05). In Finland/Poland, AUCs were 0.61 for the clinical interview alone and 0.72 with serial PEF; in England, 0.73 and 0.81; and in Ontario/Turkey, 0.60 and 0.68, respectively. Calibration was adequate in all centers. CONCLUSION:A novel model, comprising clinical features and serial PEFs, can predict positive SIC caused by LMW agents. It can guide referrals or diagnosis when SIC is unavailable or unnecessary.

Rationale: Fibrotic interstitial lung diseases are progressive disorders characterized by lung scarring and declining respiratory function. Repeated injury and dysregulated epithelial-mesenchymal crosstalk are implicated in disease pathogenesis but remain incompletely understood. Three-dimensional (3D) organoids incorporating epithelial-mesenchymal crosstalk provide a physiologically relevant platform for investigating these mechanisms. Here, we present a 3D tri-co-culture alveolar organoid model and evaluate its responses to two profibrotic stimuli, TGF-β and bleomycin. Methods: CI-huArlo, NCI-H441, and MRC-5 cells were co-cultured for 14 days to generate alveolar-like organoids. Cell marker expression was assessed by immunofluorescence (IF). To test injury response, organoids were exposed to TGF-β (50 ng/mL) or bleomycin (20 μg/mL) for 48 hours and characterized. Supernatants were collected to assess interleukin 8 (IL-8) and procollagen I by ELISA. qPCR assessed expression of CDKN1A and COL1A1 following treatments. Bulk RNA sequencing (RNA-seq) evaluated the transcriptomic responses to fibrotic stimulus. Results: Cellular marker expression was confirmed using IF for aquaporin-5 (alveolar type I cell marker) and TE-7 (fibroblast marker). Bleomycin exposure reduced viability and significantly increased IL-8 (126.3 ± 16.86 vs. 48.88 ± 4.470 pg/mL; p = 0.0002; N=6), with no change in secreted procollagen I compared to control. TGF-β stimulation significantly increased secreted procollagen I (149.6 ± 27.07 vs. 53.38 ± 5.672 pg/mL; p <0.0001; N=6) without affecting viability or IL-8 release. qPCR resulted in no change in CDKN1A expression, while COL1A1 expression was increased with TGF-β treatment compared with control and bleomycin. RNA sequencing demonstrated distinct and reproducible transcriptional responses to TGF-β and bleomycin. TGF-β induced 750 significantly upregulated and 641 downregulated genes, including increased COL1A1, COL4A1, FN1, and TGFB1, with enrichment of epithelial-mesenchymal transition and TGF-β signalling programs. In contrast, bleomycin induced 953 significantly upregulated and 552 downregulated genes relative to untreated controls and was characterized by p53 signalling, DNA-damage responses, and reduced cell-cycle progression. Reference-state analysis further indicated reduced normal alveolar epithelial signatures following both treatments, with TGF-β producing the strongest aberrant basaloid and myofibroblast-associated signatures. Conclusions: Tri-culture alveolar-like organoids exhibited stimulus-specific responses in a 3D multicellular system, supporting their use for mechanistic studies of epithelial-mesenchymal crosstalk, environmental exposures, and therapeutic responses.

BACKGROUNDThere are no known serum biomarkers that provide mechanistic insight or prognostic enrichment for post-COVID-19 pulmonary fibrosis.METHODSWe tested associations of serum biomarkers with radiographic fibrosis-like abnormalities (reticulation, traction bronchiectasis, or honeycombing) on thoracic computed tomography (CT) scans 4 months, 15 months, and 3 years after hospitalization in an American discovery cohort of severe-to-critical COVID-19 survivors, and externally validated findings in 2 Canadian cohorts of moderate-to-critical COVID-19 survivors. In the discovery cohort, we investigated the dose-response relationship of the biomarker with CT-derived airway-to-lung ratio. We performed single-cell RNA sequencing (scRNA-seq) of transbronchial lung biopsies from COVID-19 survivors obtained 3 years after COVID-19 hospitalization and conducted immunofluorescence analysis of COVID-19 lung explants.RESULTSAmong 150 discovery cohort participants, only higher levels of circulating club cell secretory protein-16 (CC16, encoded by the SCGB1A1 gene) at hospital discharge, 4 months, 15 months, and 3 years were associated with thoracic CT fibrosis-like abnormalities in cross-sectional and longitudinal analyses. Higher CC16 levels were associated with thoracic CT fibrosis-like abnormalities in 2 validation cohorts (n = 56 and n = 37). CC16 levels were linearly associated with increased airway-to-lung ratio. scRNA-seq revealed increased proportions of epithelial cells expressing SCGB1A1 and SCGB1A1/MUC5B in COVID-19 survivors with fibrosis. Immunofluorescence analysis of COVID-19 lung explants demonstrated increased numbers of SCGB1A1-expressing epithelial cells only in small (<100 μm) airways, with 3-fold more CC16/MUC5B-coexpressing cells in respiratory bronchioles..CONCLUSION. Higher CC16 levels are associated with CT fibrosis-like abnormalities for up to 3 years following moderate-to-critical COVID-19. Increased CC16 reflects dysregulated small airway epithelial progenitor cell remodeling and increased expansion of CC16+MUC5B+ epithelial cells in respiratory bronchioles after COVID-19.TRIAL REGISTRATIONNot applicable.FUNDINGDepartment of Defense, NIH, and Japan Society for the Promotion of Science for Young Scientists.

Air pollution is a major threat to respiratory health. In this article, we review the current literature on accessible interventions that could help patients build resilience against this threat. We explore the potential benefits of antioxidant-rich diets, including supplements such as fish oil, vitamins C, D and E, and prebiotics, which have shown promise in reducing inflammation and oxidative stress, thereby mitigating air pollution-related respiratory decline. Nasal washes are commonly used to clear nasal passages, which could help to clear pollutants from the nasal passages and improve mucociliary clearance. Furthermore, medications such as nonsteroidal anti-inflammatory drugs and intranasal corticosteroids have been reported to reduce pollutant-related airway inflammation and lung function deterioration triggered by pollutant exposure. Given the generally favourable safety profile of these interventions, they are reasonable to consider in consultation with a care provider. Further research is needed to establish optimal dosing, safety and long-term efficacy, particularly for those exposed to chronic air pollution. Healthcare professionals should work together to further identify and implement effective interventions to mitigate the impact of air pollution on respiratory health.

Climate change is increasing the frequency and severity of wildfires globally, causing significant woodsmoke (WS) emissions. Vehicles emit sizable amounts of toxic traffic-related air pollution (TRAP), for which diesel exhaust (DE) is a model. Both WS and DE contain particulate matter < 2.5 microns (PM2.5), which deeply penetrates the lungs causing respiratory epithelial inflammation that drives health effects. Regulations focus on PM2.5 concentration, despite emerging research that highlights how composition mediates health effects. As WS and DE are compositionally distinct, we conducted the first head-to-head comparison of effects on the transcriptomes of air-liquid interface cultured primary human bronchial epithelial cells (HBEC). Differentiated donor-matched HBEC transwells were exposed for 2-hours to filtered air (FA; control), or WS (furnace tube burning pine) or DE (Hatz 1B30E generator) both diluted to 300 µg/m3 of PM2.5. WS had higher ultrafine PM, whereas DE exposure contained significantly higher NO2, CO, and O3. RNA sequencing showed that WS exposure resulted in 159 (↑50, ↓109) differentially expressed genes, while DE modulated 439 (↑264, ↓175) compared to FA exposure. WS was associated with small ribosomal subunit and cytochrome complex related genes, while DE exposure was associated with HIF-1 signaling, respiratory chain complex and interferon alpha/beta signaling/ISG15-protein conjugation, suggesting how TRAP exposure may enhance infection risk. We also analyzed exposure effects on protein immune-mediators. We demonstrate that two major air pollution sources modulate different genes and pathways in HBECs, with minimal overlap. This informs the debate regarding the regulatory focus on concentration and assumptions that similar concentrations of air pollution have indistinct effects.

Background The role of epigenetic aging in the environmental pathogenesis and prognosis of fibrotic interstitial lung disease (fILD) is unclear. We evaluated whether ambient particulate matter ≤2.5 μm (PM 2.5 ) and neighbourhood disadvantage exposures are associated with accelerated epigenetic aging, and whether epigenetic age is associated with adverse clinical outcomes in patients with fILD. Methods This multicentre, international, cohort study included patients with fILD from the University of Pittsburgh (UPitt, n=306) and University of British Columbia (UBC, n=170). Five-year PM 2.5 exposures were estimated using satellite-derived models. Neighbourhood disadvantage was calculated using U.S. and Canadian Census-based metrics. Epigenetic age difference (EAD=epigenetic age – chronological age) was calculated using GrimAge analysis of blood DNA methylation data. Linear models assessed associations of exposures with EAD. Cox models assessed associations of EAD with transplant-free survival. Causal mediation analysis evaluated EAD mediation of exposure-survival relationships. Results Median epigenetic age was 11.7 years older than chronological age in patients with fILD. In combined cohort analysis, each interquartile range (IQR) PM 2.5 increase was associated with 2.88 years (95%CI 1.39–4.38, p<0.001) increased EAD. In UPitt, each IQR neighbourhood disadvantage increase was associated with 1.16 years (95%CI 0.22–2.09, p=0.02) increased EAD. Increased EAD was associated with worse transplant-free survival (HR=1.17 per 1-year increase EAD, 95%CI 1.10–1.24, p<0.001), with EAD mediating 40% of PM 2.5 -survival relationship and 59% of neighbourhood disadvantage-survival relationships. Epigenetic age was also more strongly associated with transplant-free survival than chronological age. Conclusions Epigenetic age acceleration is associated with worse survival and mediates adverse exposure impacts in fILD.

BACKGROUND:Individuals may experience persistent symptoms after recovering from coronavirus disease 2019 (COVID-19), a condition referred to as post COVID-19 condition (PCC). Patient-reported outcome measures (PROMs) evaluate a patient's health status and can be used to quantify symptom severity from the patient's perspective. The impact of COVID-19 vaccination and variant of infection on PCC is not well understood. We therefore sought to explore vaccination and variant trends among individuals with PCC and investigate their association with abnormal PROMs. METHODS:Patients seen at Post-COVID-19 Clinics across British Columbia, Canada between March 2020 - Oct 2022 were included in the study. Those who had persistent symptoms, at least one abnormal PROM, and completed a baseline questionnaire within 6 months of infection were included. The following PROMs were used: Fatigue Severity Score, University of California San Diego Shortness of Breath Questionnaire, Post Traumatic Stress Disorder (PTSD) Score, Generalized Anxiety Disorder-2 and Patient Health Questionnaire-2. Vaccination status was categorized based on the number and timing of vaccinations relative to SARS-CoV-2 infection. Logistic regression was used to evaluate the association between COVID-19 vaccination status or SARS-CoV-2 variant and the likelihood of reporting abnormal PROMs. RESULTS:The study included 1,587 participants (mean age 52 ± 15 years, 45% male, 58% vaccinated). In the adjusted models, full vaccination among non-hospitalized patients was associated with a reduced likelihood of reporting PTSD. Hospitalized patients infected with the alpha and delta variants were more likely to report dyspnea, while those infected with the gamma variant were less likely to report PTSD. CONCLUSIONS:Patients who were partially or fully vaccinated did not have increased risk of reporting common PCC symptoms. Infection with the alpha and delta variants was associated with increased likelihood of reporting dyspnea, which may be related to the severity of acute illness and associated impairments in lung function.

Rationale: Particulate matter ⩽2.5 μm (PM2.5) adversely impacts patients with fibrotic interstitial lung disease (fILD). Objectives: We sought to determine whether PM2.5-associated epigenetic alterations contribute to the environmental pathogenesis of fILD. Methods: A retrospective two-cohort study applied satellite-derived PM2.5 and constituent exposure matching to the residential location of patients with fILD. Robust linear regressions were used to evaluate cohort-specific, epigenome-wide differential blood DNA methylation with increasing pollutant exposures (Illumina MethylationEPIC BeadChip). Cox and linear regressions were used to evaluate associations of cytosine-phosphate-guanine (CpG) loci with transplant-free survival and lung function. A Wilcoxon test was used to evaluate cartilage-associated protein (CRTAP) levels in fILD and control lungs. Measurements and Main Results: The University of Pittsburgh cohort (n = 306) had 5-year median PM2.5 exposures of 12.1 μg/m3 compared with 5.1 μg/m3 in the University of British Columbia cohort (n = 170). Higher pollutant exposures in the University of Pittsburgh cohort were associated with lower methylation at cg25354716, annotated to CRTAP, a critical extracellular matrix remodeling enzyme. Higher exposures in the University of British Columbia cohort were associated with higher methylation at cg01019301, annotated to TLN2 (talin-2), a cytoskeletal protein involved in fibroblast migration. A 10% increase in cg25354716 methylation was associated with a hazard ratio of 0.81 for death or lung transplantation in the meta-analyzed cohorts (95% confidence interval = 0.69-0.96; P = 0.01), whereas the same change in cg01019301 was associated with a hazard ratio of 1.36 (95% confidence interval = 1.07-1.74; P = 0.01). CRTAP protein was more abundant in lungs from patients with fILD compared with those from donor controls (P < 0.001). Conclusions: PM2.5 is associated with altered blood DNA methylation in fILD. This work identifies novel pollution-sensitive targets that hold potential for therapeutic modulation in fILD.