Int J Mol Sci. 2025 Mar 5;26(5):2327. doi: 10.3390/ijms26052327.

ABSTRACT

Filtration bleb (FB) fibrosis represents the primary risk factor for glaucoma filtration surgery (GFS) failure. We reviewed the most recent literature on post-GFS fibrosis in humans, focusing on novel molecular pathways and antifibrotic treatments. Three main literature searches were conducted. First, we performed a narrative review of two models of extra-ocular fibrosis, idiopathic pulmonary fibrosis and skin fibrosis, to improve the comprehension of ocular fibrosis. Second, we conducted a systematic review of failed FB features in the PubMed, Embase, and Cochrane Library databases. Selected studies were screened based on the functional state and morphological features of FB. Third, we carried out a narrative review of novel potential antifibrotic molecules. In the systematic review, 11 studies met the criteria for analysis. Immunohistochemistry and genomics deemed SPARC and transglutaminases to be important for tissue remodeling and attributed pivotal roles to TGFβ and M2c macrophages in promoting FB fibrosis. Four major mechanisms were identified in the FB failure process: inflammation, fibroblast proliferation and myofibroblast conversion, vascularization, and tissue remodeling. On this basis, an updated model of FB fibrosis was described. Among the pharmacological options, particular attention was given to nintedanib, pirfenidone, and rapamycin, which are used in skin and pulmonary fibrosis, since their promising effects are demonstrated in experimental models of FB fibrosis. Based on the most recent literature, modern patho-physiological models of FB fibrosis should consider TGFβ and M2c macrophages as pivotal players and favorite targets for therapy, while research on antifibrotic strategies should clinically investigate medications utilized in the management of extra-ocular fibrosis.

PMID:40076946 | DOI:10.3390/ijms26052327

Int J Mol Sci. 2025 Feb 28;26(5):2218. doi: 10.3390/ijms26052218.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a rare disorder concerning elderly people, predominantly men, active or former smokers, with a progressive nature and leading to premature mortality. The cause of the disease is unknown. However, there are some risk factors, among which genetic predisposition plays a role. The aim of our single-centered observational study was to assess the correlation between single nucleotide polymorphism (SNP) of the MUC5B gene (rs35705950) and the disease course, antifibrotic treatment effect, and survival in patients with IPF. A total of 93 patients entered the study, of whom 88 were treated with either nintedanib or pirfenidone. The GG genotype was found in 28 (30.1%) subjects, while the GT or TT genotypes were found in the remaining 65 (63.4%) and 6 (6.5%) patients, respectively. The T allele minor allele frequency (MAF) accounted for 38.2% of the whole group. Patients with different genotypes did not differ significantly regarding age, sex, pulmonary function tests' results, response to the antifibrotic treatment, or survival. However, we found a survival advantage in female patients and patients with higher pre-treatment TL,co. Treatment with antifibrotics significantly decreased the magnitude of FVC and TL,co decline compared to the time before treatment initiation, regardless of MUC5B status. In conclusion, we found high prevalence of T allele of MUC5B gene in patients with IPF; however, it showed no influence on disease trajectory, survival, or antifibrotic treatment effect in the presented cohort.

PMID:40076835 | DOI:10.3390/ijms26052218

Sci Rep. 2025 Mar 13;15(1):8622. doi: 10.1038/s41598-025-93217-9.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a kind of interstitial lung disease (ILD). It has a high incidence rate and mortality. Its pathogenesis remains unclear. So far, no effective methods have been found for the early diagnosis of IPF. Ferroptosis has been reported to be critical in the initiation and progression of IPF. Therefore, our aim was to identify the hub gene related to ferroptosis co-expressed in the peripheral blood and pulmonary tissue of patients with IPF. Sequencing data were obtained from the Gene Expression Omnibus database. A comprehensive analysis was conducted on the differentially expressed genes (DEGs) to extract ferroptosis-related differentially expressed genes (FRDEGs). The results showed that ferroptosis-related signal paths were highly enriched in IPF, and 10 FRDEGs were identified.The hub gene was predicted through protein-protein interactions (PPI) and Cytoscape. The diagnostic utility of the hub gene was proven by enzyme-linked immunosorbent assay (ELISA) in serum and by immunohistochemistry (IHC) in pulmonary tissues. The results of ELISA indicated that the levels of ATM in the serum of patients with IPF were significantly lower than the normal levels. In contrast, the results of IHC showed that the expression of ATM in the pulmonary tissues of IPF patients exhibited a notably elevated trend. The immune status was assessed by the CIBERSORT method and so was the relevance between ATM and immune cells. These findings unveiled significant differences in various immune cell types in peripheral blood and pulmonary tissue between the IPF group and the control group. Furthermore, ATM was associated with various immune cells. This study suggests that as a ferroptosis-related gene, ATM assumes a pivotal role in the diagnosis and treatment of IPF. This discovery presents a novel approach for the clinical diagnosis and therapy of IPF.

PMID:40075162 | DOI:10.1038/s41598-025-93217-9

Lung. 2025 Mar 12;203(1):43. doi: 10.1007/s00408-025-00800-y.

ABSTRACT

PURPOSE: Toll-like receptor 4 (TLR4) is a transmembrane receptor promoting pro-inflammatory signalling, that is associated with the pathogenesis of pulmonary fibrosis. TLR4 is abundantly expressed on monocytes and the acceleration of TLR4 signalling induces the secretion of soluble TLR4 isoforms (sTLR4) in circulation. The aim of study was to evaluate the association of serum levels of sTLR4 with acute exacerbation (AE) and prognosis of patients with idiopathic pulmonary fibrosis (IPF).

METHODS: This retrospective cohort study included 97 patients with IPF and 76 healthy participants. The association of serum sTLR4 levels with the onset of AE and the prognosis in 97 patients with IPF was analyzed.

RESULTS: No significant difference in sTLR4 serum level was observed between the patients with IPF and healthy participants. Kaplan-Meier curves showed that patients with sTLR4 ≥ 2.2 ng/mL had a significantly higher incidence of AE-IPF and a significantly lower 5-year survival rate. Univariate and multivariate Cox hazard analyses demonstrated that sTLR4 ≥ 2.2 ng/mL was significantly associated with higher incidence of AE and poorer survival. In an exploratory analysis, a weak correlation was observed between sTLR4 levels and monocyte counts, and the incidence of AE-IPF was the highest in the patients with sTLR4 ≥ 2.2 ng/mL and monocyte counts ≥ 381/μL.

CONCLUSION: High sTLR4 level is associated with an increased incidence of AE-IPF and poor prognosis in patients with IPF. The combination of sTLR4 level and monocyte count might be used to stratify patients with IPF according to the risk for AE via reflecting monocyte activation.

PMID:40074958 | DOI:10.1007/s00408-025-00800-y

J Pharmacol Exp Ther. 2025 Feb 5;392(3):103396. doi: 10.1016/j.jpet.2025.103396. Online ahead of print.

ABSTRACT

Pulmonary fibrosis encompasses different chronic interstitial lung diseases, and the predominant form, idiopathic pulmonary fibrosis, remains to have a poor prognosis despite 2 approved therapies. Although the exact pathobiological mechanisms are still incompletely understood, epithelial injury and aberrant wound healing responses contribute to the gradual change in lung architecture and functional impairment. Lysophosphatidic acid (LPA)-induced lysophosphatidic receptor 1 (LPA1) signaling was proposed to be a driver of lung fibrosis, and LPA1 antagonists have shown promising antifibrotic profiles in early clinical development. The novel, potent, and selective LPA1 antagonist, ACT-1016-0707, displayed insurmountable LPA1 antagonism in vitro with slow off-rate kinetics, leading to efficient inhibition of LPA1 signaling even in presence of high concentrations of LPA. This binding property translated into potent and highly efficient prevention of LPA-induced skin vascular leakage by ACT-1016-0707 in vivo, differentiating the compound from surmountable LPA1 antagonists. Furthermore, ACT-1016-0707 attenuated proinflammatory and profibrotic signaling in different lung fibrosis models in vitro and in the bleomycin-induced lung fibrosis model in vivo. Based on these data, ACT-1016-0707 shows potential as best-in-class LPA1 antagonist for treatment of fibrotic diseases. SIGNIFICANCE STATEMENT: ACT-1016-0707 is a potent, selective, and insurmountable lysophosphatidic receptor 1 (LPA1) antagonist demonstrating robust antifibrotic and anti-inflammatory activity in different lung fibrosis models in vitro and in vivo. This study is the first to demonstrate functional in vivo evidence of insurmountable LPA1 antagonist superiority by side-by-side comparison with surmountable LPA1 antagonists in highly controlled conditions, suggesting potential for ACT-1016-0707 as best-in-class LPA1 antagonist for treatment of fibrotic diseases.

PMID:40073729 | DOI:10.1016/j.jpet.2025.103396

HCA Healthc J Med. 2025 Feb 1;6(1):11-21. doi: 10.36518/2689-0216.1802. eCollection 2025.

ABSTRACT

Description Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by gradual destruction and replacement of pulmonary parenchyma with fibrous tissue, which occurs in conjunction with chronic inflammation. It is often considered a prototypical interstitial lung disease and is both the most prevalent and perhaps the most dangerous in that family. Although the disease is uncommon in the general population, its prevalence increases with age and is typically diagnosed around the age of 65. This does not preclude the development of IPF in younger individuals, and the mean survival is 2 to 5 years post-diagnosis regardless of age. Contemporary studies have provided insight into how altered pulmonary parenchyma results in increased susceptibility to opportunistic infections. It has also been demonstrated that pulmonary insults that cause inflammation, such as pneumonia, may accelerate the progression of IPF. Eosinophilic pneumonias are a collection of pulmonary diseases in which eosinophil-mediated inflammation results in respiratory compromise. Early recognition and appropriate intervention are imperative to minimize the risk of residual pulmonary function deficits, a risk that is increased in individuals with separate pulmonary risk factors. While prompt diagnosis and pharmacologic interventions are associated with improved outcomes, patients with IPF remain at risk of deterioration to the point of requiring lung transplantation. Early screening for those at risk continues to be a topic of interest. Despite the prevalence of IPF, its pathogenesis remains poorly understood and few management options are available. In this article, we document a unique case of previously undiagnosed IPF in a young individual that acutely worsened in the setting of acute eosinophilic pneumonia and the involvement of an opportunistic organism, Aspergillus niger. The case section will serve as a transition into a discussion of each of the major pathologic factors at play, supported by a review of recent literature.

PMID:40071189 | PMC:PMC11892399 | DOI:10.36518/2689-0216.1802

Clin Respir J. 2025 Mar;19(3):e70061. doi: 10.1111/crj.70061.

ABSTRACT

INTRODUCTION: Anti-neutrophil cytoplasmic antibody (ANCA) seropositivity strongly correlates to ANCA-associated vasculitis. Patients with idiopathic interstitial pneumonias (IIPs) without systemic vasculitis are sometimes ANCA-positive. Radiological and pathological differences between patients with myeloperoxidase (MPO)-ANCA-positive and those with proteinase 3 (PR3)-ANCA-positive IIPs remain unclear. To determine whether high-resolution computed tomography (HRCT) features and pathology findings differ by ANCA subtype in ANCA-positive IIP patients in a national database. Clinical, radiological, and pathological data were examined along with a web-based multidisciplinary discussion.

METHODS: We reviewed records of 10 MPO-ANCA-positive and 9 PR3-ANCA-positive IIP patients who underwent HRCT and surgical lung biopsy between April 2009 and March 2014. Pulmonologists, chest radiologists, and pathologists evaluated HRCT scans and pathological findings independently. Patterns were classified using ATS/ERS/JRS/ALAT 2011 guidelines for idiopathic pulmonary fibrosis.

RESULTS: HRCT patterns were definite usual interstitial pneumonia (UIP) (n = 8; 42.1%), possible UIP (n = 6; 31.6%), and inconsistent with UIP (n = 5; 26.3%). Pathological patterns were definite UIP (n = 5; 26.3%), probable UIP (n = 8; 42.1%), possible UIP (n = 4; 21.1%), and not UIP (n = 2; 10.5%). HRCT and pathological patterns did not differ between MPO-ANCA-positive and PR3-ANCA-positive IIPs. Radiological features were reticulation (n = 13; 68.4%), nodules (n = 12; 63.1%), honeycombing (n = 10; 52.6%), and increased attenuation around honeycombing (n = 7; 36.8%). Pathological findings were cysts (n = 12; 63.1%), lymphoid follicles with germinal centers (n = 11; 57.9%), and peribronchiolar wall lymphocytic infiltration (n = 11; 57.9%).

CONCLUSION: HRCT and pathological patterns did not differ between MPO-ANCA-positive and PR3-ANCA-positive IIPs. This absence of significant differences suggests a similar mechanism underlying both types of interstitial pneumonia.

PMID:40070290 | DOI:10.1111/crj.70061

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