Ann Am Thorac Soc. 2025 Mar 11. doi: 10.1513/AnnalsATS.202406-625OC. Online ahead of print.

ABSTRACT

Background The epidemiology of adult interstitial lung disease (ILD) is uncertain, given heterogeneous estimates from prior studies. The objective of this study was to define the incidence, prevalence, and mortality of ILD over a 10-year period using population-based data. Methods We created an administrative ILD cohort in Alberta, Canada between 2010-2019 using population-based administrative data (inpatient, ambulatory, and outpatient physician billing databases) for a repeat cross-sectional study. Case definitions were developed from an established ILD cohort and applied to the general population, with performance characteristics tested using a nested case-control design. Age-and sex-standardized annual incidence and point prevalence rates were estimated for ILD overall and within diagnostic sub-groups, with trends over time, per 100,000 at-risk adults and to permit comparisons with other studies, per 100,000 total population. Cox models estimated risk of death or lung transplantation. Results Between 2010-2019, 31,492 incident and 42,549 prevalent adult ILD cases were identified. The case definition for ILD performed well with 96.8% sensitivity, 98.5% specificity, and positive predictive value 94.3% in the population cohort. Mean age-standardized ILD incidence was 107.9/100,000 at-risk adults, 90.9/100,000 for females and 129.1/100,000 for males. Age-standardized ILD point prevalence increased from 416.5/100,000 at-risk adults in 2010 to 789.7/100,000 in 2019, higher in males vs females, and in rural vs urban areas. Age-standardized mean idiopathic pulmonary fibrosis (IPF) incidence was 36.9/100,000 at-risk and point prevalence was 205.3/100,000 at-risk in 2019. Mean age-standardized ILD incidence and prevalence was 84 and 516.9/100,000 total population, respectively. One-year all-cause mortality for ILD patients decreased from 14.5% in 2011 to 11.7% in 2018 (adjusted rate ratio (RR) for 2018 vs 2011, 0.76; 95%CI 0.67-0.86). One-year all-cause mortality for IPF similarly decreased from 20.9% in 2011 to 14.7% in 2018 (adjusted RR for 2018 vs 2011, 0.71; 95%CI 0.59-0.85), representing improved survival. Conclusions In this population-based cohort, claims-based case definitions derived from a established ILD cohort performed well to develop an administrative cohort. Incidence remained stable over time, while prevalence increased and mortality decreased, for ILD overall and within the IPF subgroup. These estimates are higher than most prior reports, suggesting an overall underestimate of ILD burden.

PMID:40068156 | DOI:10.1513/AnnalsATS.202406-625OC

Cureus. 2025 Mar 9;17(3):e80290. doi: 10.7759/cureus.80290. eCollection 2025 Mar.

ABSTRACT

OBJECTIVE: This retrospective study aimed to determine the prevalence of progression in fibrotic interstitial lung disease (ILD) and the findings at diagnosis most associated with progression after two years of follow-up in a large Brazilian cohort.

METHODS: This was a retrospective multicenter observational study in Brazil. Progression was defined after two years of follow-up. We excluded patients with an initial peripheral oxygen saturation (SpO2) of less than 88% or an initial forced vital capacity (FVC) of less than 45%. Diagnoses were made by multidisciplinary discussion. Patients with idiopathic pulmonary fibrosis were included for comparison. At least one of the following events was indicative of progressive ILD: (1) a relative decrease in FVC of 10% or more, (2) worsening dyspnea, (3) a greater extent of fibrotic findings on high-resolution computed tomography (HRCT), (4) initiation of oxygen, and (5) death attributed to ILD. Logistic regression analysis was used to identify risk factors for progressive fibrosis.

RESULTS: The mean age of patients was 61.7±12.3 years, and 69.5% had Velcro crackles. The mean FVC was 71.6±15.8%, and 26.1% showed honeycombing on HRCT. After two years of follow-up, 40.5% of patients (n=154) showed disease progression. Fibrotic hypersensitivity pneumonitis (FHP) was the most progressive disease (52%), and connective tissue disease-associated ILD (CTD-ILD) was the least progressive (25%). Multivariate analysis showed that a higher score for dyspnea, crackles, and SpO2 at rest ≤94% and ≤85% at the end of exercise were significant indicators of progression. Diffusing lung capacity for carbon monoxide (DLCO) was measured in 172 cases, with values <55% predicting a high odds ratio for progression (OR=4.03; 2.10-7.69).

CONCLUSION: In Brazil, FHP is the most progressive disease and CTD-ILD is the least progressive after two years of follow-up. The degree of dyspnea, crackles, SpO2 at rest and during exercise, and DLCO at baseline are associated with progressive disease.

PMID:40066320 | PMC:PMC11892080 | DOI:10.7759/cureus.80290

Front Med (Lausanne). 2025 Feb 24;12:1542400. doi: 10.3389/fmed.2025.1542400. eCollection 2025.

ABSTRACT

Rheumatoid arthritis (RA) is a systemic autoimmune disease that affects millions of people worldwide and is characterized by persistent inflammation, pain, and joint destruction. In RA, the dysregulation of the immune system is well documented. However, the genetic basis of the disease is not fully understood, especially when extra-articular organs are involved. Interstitial lung disease (ILD) is a major cause of morbidity and mortality in patients with RA. Notably, RA-ILD shares several risk factors with idiopathic pulmonary fibrosis (IPF), namely male gender, smoking history, usual interstitial pneumonia (UIP) pattern of fibrosis, and association with the MUC5B rs35705950 polymorphism. In addition, other genetic susceptibilities are reported in RA-ILD for some HLA alleles and other less studied polymorphisms. However, the pathobiology of RA-ILD, particularly whether and to what extent genetic and environmental factors interact to determine the disease, remains elusive. In this review, we summarize and critically discuss the most recent literature on the genetics and pathogenesis of RA-ILD. The main clinical aspects of RA-ILD are also discussed.

PMID:40066169 | PMC:PMC11891064 | DOI:10.3389/fmed.2025.1542400

Clin Transl Sci. 2025 Mar;18(3):e70179. doi: 10.1111/cts.70179.

ABSTRACT

SC1011 (sufenidone) is a novel pyridone derivative with therapeutic potential for idiopathic pulmonary fibrosis (IPF). Two Phase 1 studies evaluated the safety and pharmacokinetics of single (SAD) and multiple ascending doses (MAD) of SC1011 immediate-release (IR) and modified-release (MR) oral formulations in healthy adult subjects. In Phase 1a, subjects were randomized to receive oral SC1011 IR or placebo in SAD (50 mg-300 mg) or MAD (100 mg and 200 mg) twice daily for 7 days. The Phase 1b study consisted of three treatment groups that received 100, 150, or 200 mg SC1011 MR twice daily for 7 days. SC1011 IR was absorbed rapidly (mean time to maximum concentration, Tmax ≤ 1 h) and eliminated rapidly (mean terminal half-life, t1/2: 1.23-2.64 h) following 50-300 mg single-dose administrations. Reduced maximum plasma concentration (Cmax), delayed Tmax, and comparable total exposure were observed with the MR formulation compared with the IR formulation. Both formulations demonstrated dose-proportional pharmacokinetics at the applied dose ranges, and no obvious accumulation of systemic exposure was observed upon repeated administration. All treatment-emergent adverse events (TEAEs) with both formulations were mild or moderate in severity, and gastrointestinal reactions were the most frequently reported TEAEs. The tolerability of SC1011 was markedly improved with the MR formulation. Exposure-adverse event (AE) analysis with the most frequent AEs identified Cmax rather than total exposure as a good predictor of AEs. Compared to the IR formulation, SC1011 MR demonstrated improved exposure and tolerability, supporting its further development in patients with IPF.

PMID:40065557 | DOI:10.1111/cts.70179

Respir Res. 2025 Mar 10;26(1):97. doi: 10.1186/s12931-025-03164-2.

ABSTRACT

BACKGROUND/RATIONALE: Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive disease of unknown origin. Establishing the epidemiology of IPF has been challenging due to diagnostic complexity, poor survival, low prevalence, and heterogeneity of ascertainment methodologies.

OBJECTIVES: This research aimed to estimate the rates of IPF in central and western Pennsylvania and to pilot the use of capture recapture (CR) methods to estimate the disease incidence.

METHODS: We identified adults ≥ 30 years old diagnosed with IPF (by ICD-9/10 coding) between 2013 to 2021 from two health systems (UPMC Health System and Penn State Health) participating in the PaTH Clinical Research Network. We extracted information on patients' sex, race, date of birth and 3-digit zip code from electronic health records (EHR). Incidence rate of IPF among Pennsylvania residents was calculated using three case definitions (broad and two restricted) and piloted the use of CR in estimating IPF incidence.

RESULTS: IPF incidence rates were 8.42, 6.95 and 4.4 per 100,000 person-years for the unrestricted (n = 3148), partially restricted (n = 2598) and fully restricted (n = 1661) samples, respectively. Low case overlap between two sites resulted in a highly inflated estimate of IPF incidence, using the CR methodology.

CONCLUSIONS: The rate of IPF in central and western Pennsylvania was similar to previously published statistics. The application of CR to IPF epidemiology could be further investigated in health systems with greater overlap of patients utilizing more than one system.

PMID:40065350 | DOI:10.1186/s12931-025-03164-2

Int J Biol Macromol. 2025 Mar 8:141890. doi: 10.1016/j.ijbiomac.2025.141890. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblasts accumulation and uncontrolled extracellular matrix (ECM) deposition. Here, we reported that activating transcription factor 4 (ATF4), a multifunctional transcription regulatory protein, is overexpressed in IPF lungs and mouse fibrotic lungs, mainly in myofibroblasts and macrophages. Haplodeletion of Atf4 in mice or blockage of Atf4 with Atf4 shRNA-loaded lentiviruses in mice reduced bleomycin (BLM)-induced pulmonary fibrosis (PF) in vivo. Mechanistically, we found that ATF4 directly binds to the promoter of Acta2 (encodes α-SMA), and promotes lung fibroblasts activation and myofibroblasts accumulation. Additionally, ATF4 regulates macrophage M2 program, and promotes TGFβ1 secretion by directly influencing Tgfb1 gene expression in macrophages, subsequently enhances crosstalk between macrophages and lung fibroblasts. These data suggest that strategies for inhibiting ATF4 may represent an effective treatment for PF.

PMID:40064253 | DOI:10.1016/j.ijbiomac.2025.141890

Cureus. 2025 Feb 5;17(2):e78594. doi: 10.7759/cureus.78594. eCollection 2025 Feb.

ABSTRACT

Although several studies have reported that poor nutritional status is associated with a worse prognosis in patients with interstitial lung disease (ILD), the beneficial impact of nutritional therapy has not yet been established. We report a case of idiopathic pulmonary fibrosis (IPF) in which nutritional therapy played an important role alongside drug therapy. A 71-year-old Japanese male was diagnosed with IPF and started on nintedanib. However, he experienced appetite loss, leading to significant weight loss and disease progression. Consequently, nintedanib was discontinued, and a dietitian introduced a high-fat, high-protein nutritional therapy. His condition improved, allowing nintedanib to be restarted after a period of cessation. Following multiple nutritional education sessions, his condition stabilized without further appetite loss. These findings suggest that when determining treatment strategies for patients with ILD, clinicians should incorporate appropriate nutritional management during long-term treatment with effective anti-ILD agents to optimize patient outcomes.

PMID:40062119 | PMC:PMC11889364 | DOI:10.7759/cureus.78594

bioRxiv [Preprint]. 2025 Feb 26:2025.02.24.639173. doi: 10.1101/2025.02.24.639173.

ABSTRACT

INTRODUCTION: The aging lung enters into a state of irreversible cellular growth arrest characterized by senescence. While senescence is beneficial in preventing oncogenic cell proliferation, it becomes detrimental when persistent, promoting chronic inflammation and fibrosis through the senescence-associated secretory phenotype (SASP). Such senescence-related pathophysiological processes play key roles in lung diseases like chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). However, few models accurately represent senescence in the human lung.

METHODS: To generate a human lung senescence in vitro model, we first generated a human induced pluripotent stem cell (hiPSC)-derived lung organoid (LO) system which was dissociated into monolayers and air-liquid interface (ALI) cultures to enhance visualization and allow uniform exposure to agents. Cellular senescence was induced using doxorubicin, a DNA-damaging agent. Senescence markers, such as β-galactosidase (β-gal) activity, SASP cytokine production and secretion, cell morphology, proliferative capacity, and barrier integrity were evaluated to validate the senescent phenotype.

RESULTS: The doxorubicin-induced senescent hiPSC-derived lung cells demonstrated the hallmark characteristics of cellular senescence, including increased β-gal activity and increased production of the pro-inflammatory SASP cytokine IL-6 and increased secretion of TNF-α. Senescent cells displayed enlarged morphology, decreased proliferation, and reduced wound repair capacity. Barrier integrity was impaired with decreased electrical resistance, and increased permeability, as well as expression of abnormal tight junction proteins and increased fibrosis, all consistent with the senescent lung.

CONCLUSION: Our hiPSC-derived lung cell senescent model reproduces key aspects of human lung senescence and offer an in vitro tool for studying age-related lung disease mechanisms and therapeutic interventions. This model has potential applications in exploring the impact of environmental factors (e.g., toxins, infectious pathogens, etc.) on the senescent lung and assessing treatments that could mitigate pathologies associated with pulmonary aging including barrier impairment, inflammation and fibrosis.

PMID:40060424 | PMC:PMC11888323 | DOI:10.1101/2025.02.24.639173

JCI Insight. 2025 Mar 10;10(5):e187172. doi: 10.1172/jci.insight.187172.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) causes remodeling of the distal lung. Pulmonary remodeling is histologically characterized by fibrosis, as well as appearance of basal cells; however, the involvement of basal cells in IPF remains unclear. Here, we focus on the long noncoding RNA MIR205HG, which is highly expressed in basal cells, using RNA sequencing. Through RNA sequencing of genetic manipulations using primary cells and organoids, we discovered that MIR205HG regulates IL-33 expression. Mechanistically, the AluJb element of MIR205HG plays a key role in IL-33 expression. Additionally, we identified a small molecule that targets the AluJb element, leading to decreased IL-33 expression. IL-33 is known to induce type 2 innate lymphoid cells (ILC2s), and we observed that MIR205HG expression was positively correlated with the number of ILC2s in patients with IPF. Collectively, these findings provide insights into the mechanisms by which basal cells contribute to IPF and suggest potential therapeutic targets.

PMID:40059822 | DOI:10.1172/jci.insight.187172

Lung. 2025 Mar 9;203(1):40. doi: 10.1007/s00408-025-00797-4.

ABSTRACT

PURPOSE: We used data from the IPF-PRO Registry of patients with idiopathic pulmonary fibrosis (IPF) to identify characteristics that predicted survival for a further > 5 years.

METHODS: Participants had IPF that was diagnosed or confirmed at the enrolling center in the previous 6 months. Patients were followed prospectively. A Classification And Regression Tree (CART) was used to identify predictors of survival > 5 versus ≤ 5 years following enrollment. The following variables, assessed at enrollment, were considered: age; body mass index (BMI); former smoker; current smoker; time from first imaging evidence, symptoms, or diagnosis of IPF to enrollment; forced vital capacity (FVC) % predicted; diffusing capacity of the lungs for carbon monoxide (DLco) % predicted; antifibrotic drug use; supplemental oxygen use; history of cardiac disease; pulmonary hypertension; COPD/emphysema; and rural location.

RESULTS: The analysis cohort comprised 819 patients, of whom 278 (33.9%) survived > 5 years. DLco % predicted, supplemental oxygen use and FVC % predicted were the most important variables for predicting survival > 5 versus ≤ 5 years after enrollment. The importance of these variables (scaled such that the most important had an importance of 100%) was 100%, 78.2% and 74.2%, respectively. The optimism-corrected area under the curve (AUC) of the CART was 0.72, with an accuracy of 0.72.

CONCLUSION: Among patients enrolled in the IPF-PRO Registry, a decision tree that included DLco % predicted, oxygen use and FVC % predicted facilitated the prediction of survival > 5 years. Understanding predictors of longer-term survival may facilitate conversations with patients about their prognosis and treatment.

PMID:40059108 | DOI:10.1007/s00408-025-00797-4

BMC Pulm Med. 2025 Mar 7;25(1):103. doi: 10.1186/s12890-024-03425-8.

ABSTRACT

RATIONALE: Forced vital capacity (FVC) has been utilized as a surrogate for vital capacity (VC) in monitoring the progression of restrictive pulmonary disorders, particularly in clinical trials of idiopathic pulmonary fibrosis (IPF). A dose-response relationship between decreased FVC and mortality in IPF has also been established. Since 2005, total lung capacity (TLC) has been routinely required to differentiate and diagnose restrictive pulmonary disorders. However, the relationship between changes in TLC change and the risk of mortality remains unclear.

OBJECTIVES: To investigate and quantify the relationship between changes in TLC and the risk of mortality in patients with restrictive pulmonary disorders.

METHODS: This study employed a systematic review and meta-analysis following the PRISMA 2020 guidelines.

RESULTS: A total of 26 studies were included in the meta-analysis, comprising a combined sample of 16,579 subjects, which included 7,961 females, 4,460 subjects in the relative low TLC group, and 12,119 subjects in the high TLC group. A reduced TLC was associated with an increased risk of all-cause mortality, as indicated by both unadjusted and adjusted hazard ratios. The unadjusted hazard ratio (95% CI) was 1.76 (1.32, 2.35), while the adjusted hazard ratio (95% CI) was 1.70 (1.31, 2.20). The risk ratio (RR) estimated from the studies that reported both the number of participants and deaths was RR (95% CI) = 2.01 (1.56, 2.60). The included studies demonstrated significant heterogeneity.

CONCLUSION: A low TLC at baseline, in comparison to individuals with relatively higher TLC, may increase the risk of all-cause mortality by at least 42-70% in cases of restrictive pulmonary disorders, although this conclusion is primarily based on observational studies, which carry low to moderate certainty.

PMID:40055715 | DOI:10.1186/s12890-024-03425-8

Respir Investig. 2025 Mar 6;63(3):314-321. doi: 10.1016/j.resinv.2025.02.001. Online ahead of print.

ABSTRACT

BACKGROUND: The interobserver agreement regarding airway-centered fibrosis (ACF), the key diagnostic feature of fibrotic hypersensitivity pneumonitis (fHP) has not been sufficiently addressed to date. We applied digital image analysis to investigate this issue and extracted histological features of ACF to correlate with fHP diagnosis.

METHODS: A total of 111 selected glass slides from 17 fHP and 30 idiopathic pulmonary fibrosis (IPF) were scanned and seven expert pulmonary pathologists were tasked with digital annotation of ACF. Interobserver agreement on annotated ACF was assessed using Fleiss' kappa value. ACF recognized by majority of pathologists (4 or more) were considered as consensus ACF (cACF), and their frequencies were compared between fHP and IPF cases.

RESULTS: Fleiss' kappa agreement in ACF recognition was 0.32 among seven pathologists. A significant difference between cryobiopsy and VATS specimens regarding an average ACF count per slide (p = 0.012) was found. The number of cACFs in a single case ranged from 0 to 20 (mean 5.71) for fHP cases and 0 to 13 (mean 1.80) for IPF cases (p = 0.011). When limited to surgical biopsies, the average number of cACF was 10.3 for fHP vs. 1.68 for IPF (p < 0.001). The common characteristic features of cACF in fHP were their confinement to the vicinity of respiratory bronchioles, frequent association with peribronchiolar metaplasia, and mild to moderate lymphocytic infiltration.

CONCLUSIONS: The recognition of ACF varies widely among pathologists. We identified common histologic features of ACF in fHP cases, proposing criteria for ACF recognition in fHP.

PMID:40054038 | DOI:10.1016/j.resinv.2025.02.001

Rev Med Chil. 2024 Oct;152(10):1060-1066. doi: 10.4067/s0034-98872024001001060. Epub 2025 Feb 3.

ABSTRACT

Organized pneumonia (OP) is an uncommon disease included in the group of idiopathic interstitial pneumonias. It can be cryptogenic (COP) or secondary to various etiologies. Its diagnosis is complex and not standardized. There are no published Chilean series. We present a cohort of patients with pneumonia in organization treated at the National Thoracic Institute (INT).

AIM: To describe the characteristics of patients with OP in a Chilean center.

METHODS: Pathological registries from the INT were reviewed between 2013 and 2022. Clinical and radiological information was obtained from hospital records. Each case was reviewed by the research team. Data are described by means, absolute and relative frequencies.

RESULTS: From an initial list of 203 biopsies, 69 were obtained with clinical/radiological symptoms compatible with OP. The mean age of these subjects was 62 years, of which 33 (47.8%) were men and 36 (52.2%) women. Biopsies were obtained by transbronchial biopsy in 49 (71%) cases and surgical biopsy in 19 (27.5%) cases. In terms of etiology, 37 (53.6%) of them were considered cryptogenic, 12 (17.4%) secondary to the use of medication / drugs and 11 (15.9%) cases associated with connective tissue disease. Regarding treatment, 36 (52.2%) patients received oral steroids and 10 (14.5%) were treated with a mix of corticosteroids and immunosuppressors. In the long-term follow-up, there were 23 deaths in just over 6 years.

CONCLUSIONS: The reported series has similar characteristics to those reported in the literature. Most of the cases described in this series were classified as COP. The most common underlying etiologies were connective tissue diseases and medications. The most used treatment was corticosteroid alone or mixed with immunosuppressors.

PMID:40052979 | DOI:10.4067/s0034-98872024001001060

Heliyon. 2025 Feb 14;11(4):e42667. doi: 10.1016/j.heliyon.2025.e42667. eCollection 2025 Feb 28.

ABSTRACT

Little is known about differences in interstitial lung disease (ILD) diagnosis by geographic location. The aim of this study is to evaluate differences in cross-sectional ILD diagnosis between patients in urban and rural areas.

METHODS: This is a retrospective analysis of participants (n = 1992) in the Pulmonary Fibrosis Foundation (PFF) Patient Registry. Diagnoses were grouped as follows: idiopathic pulmonary fibrosis (IPF); idiopathic interstitial pneumonia other than IPF (IIP, non-IPF); connective tissue disease-associated ILD (CTD-ILD); fibrotic hypersensitivity pneumonitis (fibrotic HP); exposure-related ILD; and other ILDs. Patient-reported zip codes were mapped to county Federal Information Processing Series (FIPS) codes using data from U.S. Department of Housing and Urban Development (HUD). Frequencies of ILD diagnoses were compared between urban and rural groups using two-sample Z-test with 0.05 significance level. County-level variables including occupation and fuel use were then compared by ILD diagnosis using analysis of variance (ANOVA) with 0.05 significance level.

RESULTS: Median age at consent was 69 years, 63 % were male, and 89.5 % were white. By county classification, 12 % resided in a rural area. Rates of IPF, IIP (non-IPF), and CTD-ILD diagnosis were similar between urban and rural residents, however rates of fibrotic HP and exposure-related ILD were higher among rural residents. Residence in a county with coal fuel use or wood fuel use was higher among those with exposure-related ILD (p < 0.0001 and p = 0.0001, respectively).

CONCLUSION: ILD diagnoses differ in urban versus rural ILD patients, with fibrotic HP and exposure-related ILD being significantly more prevalent among residents in rural areas. Type of fuel use also was associated with fibrotic HP and exposure-related ILD.

PMID:40051848 | PMC:PMC11883350 | DOI:10.1016/j.heliyon.2025.e42667

Eur J Pharmacol. 2025 Mar 4:177461. doi: 10.1016/j.ejphar.2025.177461. Online ahead of print.

ABSTRACT

INTRODUCTION: & Aim: Novel treatments for idiopathic pulmonary fibrosis (IPF) are needed urgently. A better understanding of the molecular pathways activated by TGFβ1 in human lung tissue may facilitate the development of more effective anti-fibrotic medications. This study utilized proteomic analysis to test the hypothesis that TGFβ1 induces pro-fibrotic effects on human lung parenchyma proteome, and to evaluate the viability of this model for testing novel therapeutic targets.

METHODS: Non-fibrotic human lung parenchymal tissue from 11 patients was cultured for 7 days in serum-free (SF) media supplemented with TGFβ1 (10 ng/mL) or vehicle control, and the putative antifibrotic KCa3.1 ion channel blocker senicapoc or vehicle control. The tissue was homogenized, digested for bottom-up proteomics, and analysed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Principal component analysis, differential expression analysis, pathway analysis, and drug repurposing analysis were performed.

RESULTS: TGFβ1 stimulation for 7 days induced a strong fibrotic protein response relevant to IPF pathology. A total of 2,391 proteins were quantified, 306 upregulated and 285 downregulated (FDR-adjusted p-value<0.05). Of these, 118 were upregulated and 28 downregulated at log2(FC)>0.58. These changes were attenuated by senicapoc (100 nM). Drug repurposing analysis identified 265 drugs predicted to inhibit the effects of TGFβ1 in this model. These included clotrimazole, a KCa3.1 blocker, and nintedanib, a drug licenced for the treatment of IPF, providing validation of this approach.

CONCLUSION: A pro-fibrotic proteome is induced in human lung parenchyma exposed to TGFβ1, sensitive to pharmacological intervention. This approach has the potential to enhance therapeutic drug screening for IPF treatment.

PMID:40049575 | DOI:10.1016/j.ejphar.2025.177461

Respir Med. 2025 Mar 4:108028. doi: 10.1016/j.rmed.2025.108028. Online ahead of print.

ABSTRACT

OBJECT: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with characterized by progressive fibrosis. Galectin-3(Gal-3) is a B-galactoside binding lectin plays a central role in inflammation and fibrosis. In our study, we aimed to define levels of serum galectin-3 protein in IPF patients by comparing them with healthy subjects. We also aimed to show that galectin-3 concentrations can be used as a diagnostic and prognostic biomarker in the serum of IPF patients and that the use of galectin-3 inhibitors in combination with antifibrotic treatments may be useful in the therapeutic management of fibrosis.

METHODS: 44 patients with IPF and 35 control patients who were followed up in our outpatient clinic between 2016 and 2022 were evaluated, anamnesis, spirometric measurements and galectin-3 results were recorded. Patients were grouped according to their antifibrotic treatment.

RESULTS: The mean galectin-3 level in the patient group was 8.4 ng/ml and in the control group was 8.2 ng/ml. Serum levels were 8.9 ng/ml in pirfenidone users and 8.2 ng/ml in nintedanib users. Gal-3 was found to be higher in patients taking pirfenidone compared to nintedanib, but there was no statistically significant difference (p>0.05).

CONCLUSION: Galectin-3 levels were found to be slightly higher in IPF patients compared to healthy subjects. In addition, gal-3 levels decreased as the follow-up period increased in IPF patients in our study. Considering that the patients were receiving pirfenidone or nintedanib treatment during the follow-up period, it may be possible that galectin-3 levels decreased as exposure to these drugs increased. Further studies are needed to clarify these mechanisms.

PMID:40049461 | DOI:10.1016/j.rmed.2025.108028

Exp Cell Res. 2025 Mar 4:114494. doi: 10.1016/j.yexcr.2025.114494. Online ahead of print.

ABSTRACT

BTBD8 contributes to the pathogenesis of inflammatory bowel disease through regulating intestinal barrier integrity and inflammation. However, its role in idiopathic pulmonary fibrosis (IPF) remains unknown. Here we investigated whether BTBD8 plays a role in bleomycin-induced pulmonary fibrosis. Pulmonary fibrosis was induced in wild-type (WT) and Btbd8 knockout (KO) mice by intratracheal instillation of bleomycin. The mice were sacrificed on day 7 or 12. Subsequently, the progression of bleomycin-induced pulmonary fibrosis was assessed. We found that Btbd8 KO mice are more susceptible to bleomycin-induced pulmonary fibrosis, with more severe body weight loss and pulmonary injury, increased collagen deposition and myofibroblast accumulation. We further demonstrated that BTBD8 functions in pulmonary fibroblasts to suppress the conversion of fibroblasts to myofibroblasts. Moreover, Btbd8 deficiency promotes the infiltration of inflammatory cells and the secretion of pro-inflammatory cytokines in IPF mouse model. These results highlight the critical role of BTBD8 in the pathogenesis of bleomycin-induced pulmonary fibrosis in mice, and suggest that BTBD8 may alleviate bleomycin-induced fibrosis by suppressing the differentiation of fibroblasts to myofibroblast, as well as inflammatory responses.

PMID:40049313 | DOI:10.1016/j.yexcr.2025.114494

Environ Int. 2025 Feb 28;197:109354. doi: 10.1016/j.envint.2025.109354. Online ahead of print.

ABSTRACT

Exposure to fine particulate matter (PM2.5) is associated with increased morbidity and mortality among patients with idiopathic pulmonary fibrosis (IPF). Pathological alterations in IPF typically originate in the subpleural regions of the lungs. However, it was unclear how PM2.5 affected subpleural pulmonary fibrosis. In this study, atmospheric PM2.5 and carbon blacks were utilized as representative particulate matter to investigate these effects. Mouse models and cell models were made to investigate macrophage chemotaxis changes under PM2.5 exposure in vivo and in vitro. The findings indicated that PM2.5 promoted macrophage aggregation in the subpleural region of lung and aggravated bleomycin-induced pulmonary fibrosis in mice. At the same time, we uncovered for the first time that PM2.5 exposure led to an upregulation of midkine, which subsequently enhanced the production of monocyte chemotactic protein-1 (MCP-1) through the cell surface receptor Syndecan 4 (SDC4) in pleural mesothelial cells (PMCs), thereby, inducing macrophage aggregation in subpleural region of lung. Furthermore, our results indicated that PM2.5 and bleomycin facilitated macrophage M1 polarization and the production of profibrotic inflammatory factors, culminating in fibrotic alterations in PMCs, lung fibroblasts, and alveolar epithelial cells. Finally, we demonstrated that inhibition of midkine ameliorated lung function and mitigated pulmonary fibrosis in vivo. In conclusion, our findings elucidated that midkine acted as a novel MCP-1 activator, mediating PM2.5-aggravated experimental pulmonary fibrosis, and suggested that the midkine/SDC4/MCP-1 signal should be a new therapeutic target for the treatment of PM2.5-related IPF.

PMID:40049042 | DOI:10.1016/j.envint.2025.109354

Eur J Med Chem. 2025 Mar 1;289:117463. doi: 10.1016/j.ejmech.2025.117463. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a deadly lung disease characterized by fibroblast proliferation, excessive extracellular matrix buildup, inflammation, and tissue damage, resulting in respiratory failure and death. Recent studies suggest that impaired interactions among epithelial, mesenchymal, immune, and endothelial cells play a key role in IPF development. Advances in bioinformatics have also linked epigenetics, which bridges gene expression and environmental factors, to IPF. Despite the incomplete understanding of the pathogenic mechanisms underlying IPF, recent preclinical studies have identified several novel epigenetic therapeutic targets, including DNMT, EZH2, G9a/GLP, PRMT1/7, KDM6B, HDAC, CBP/p300, BRD4, METTL3, FTO, and ALKBH5, along with potential small-molecule inhibitors relevant for its treatment. This review explores the pathogenesis of IPF, emphasizing epigenetic therapeutic targets and potential small molecule drugs. It also analyzes the structure-activity relationships of these epigenetic drugs and summarizes their biological activities. The objective is to advance the development of innovative epigenetic therapies for IPF.

PMID:40048798 | DOI:10.1016/j.ejmech.2025.117463

MMWR Morb Mortal Wkly Rep. 2025 Mar 6;74(7):109-115. doi: 10.15585/mmwr.mm7407a1.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), a progressive lung disease characterized by scarring and worsening lung function, has a poor prognosis. A recent systematic review estimated that 21% of IPF deaths might be attributable to occupational exposures. To describe IPF mortality among U.S. residents aged ≥15 years who were ever employed, by industry and occupation, CDC conducted an exploratory analysis of 2020-2022 multiple cause-of-death data. During 2020-2022, a total of 67,843 (39,712 [59%] male and 28,131 [41%] female) decedents had IPF, suggesting that during this 3-year period, 8,340 IPF deaths in males and 5,908 deaths in females might have been associated with occupational exposures. By industry group, the highest proportionate mortality ratios among males were among those employed in utilities (1.15) and among females, were among those employed in public administration (1.12). By occupation group, the highest IPF mortality rates among males were among community and social services workers (1.23) and among females among farming, fishing, and forestry workers (1.24). Estimates of elevated IPF mortality among workers in specific industries and occupations warrant confirmation, control of known exposure-related risk factors, and continued surveillance to better understand the full range of occupational exposures that might increase risk for developing IPF.

PMID:40048397 | DOI:10.15585/mmwr.mm7407a1