Search Results (752)

Idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis (HP), and systemic sclerosis-associated interstitial lung disease (SSc-ILD) share the same structural outcome: extracellular matrix (ECM) deposition. Whether this shared endpoint reflects shared or distinct molecular programs remains unresolved. Differential expression results from four GEO datasets representing IPF, HP, non-IPF ILD, and SSc-ILD were intersected with the 1027-gene human matrisome masterlist and classified by threshold-defined disease preference. All four diseases shared a 21-gene upregulated matrisome core, and the matrisome fraction rose with cross-disease sharing, from 4.3% of single-disease upregulated genes to 45.7% of genes upregulated in all four (significant Cochran–Armitage trend), and the enrichment persisted when any single cohort was removed. Apparent disease preference was largely attributable to unequal statistical power: of 29 genes measurable in all four datasets, 24 showed a concordant sub-threshold effect in at least one comparator disease. Category composition of the threshold-defined signatures did not differ significantly between diseases, and the exploratory pathway panel is reported within diseases only, because significance scales with cohort size. In a within-cohort comparison of IPF with chronic HP in GSE150910, with platform, cohort, and control population held constant, matrisome genes were over-represented among the 2732 genes separating the two diseases, and 205 matrisome genes distinguished them. Fibrosing ILDs share a cross-cohort ECM core, and the apparent disease preference of the remaining signatures largely reflects differences in statistical power between cohorts. Disease-preferential matrisome expression is nonetheless detectable when disease and study are not confounded, so the limitation lies in threshold-based cross-study intersection rather than in the matrisome compartment itself. Full article

Background/Objectives: Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease that can be accompanied by acute exacerbations. To investigate the predictive value of the prognostic nutritional index (PNI) for acute exacerbation in patients with IPF. Methods: Ninety-seven patients diagnosed with IPF between 03/2019 and 03/2024 were retrospectively evaluated. Patients were divided into two groups according to exacerbation status (acute exacerbation group n = 28, non-acute exacerbation group n = 69). PNI values were calculated. The predictive value of the PNI for acute exacerbation was analyzed between groups. ROC analysis and multivariable logistic regression were performed. Results: Of the 97 patients, 78 (80.4%) were male with a mean age of 71.31 ± 6.61 years. The mean disease duration was 24.77 ± 15.69 months. During follow-up, 28 patients (28.9%) had acute exacerbations. Lymphocyte count and albumin level were significantly lower in the acute exacerbation group (p < 0.001, p < 0.001, respectively). The mean PNI value was significantly lower in the acute exacerbation group (46.62 ± 6.28) compared to the non-acute exacerbation group (52.04 ± 5.46) (p < 0.001). In addition, FEV₁%, FVC%, and DLCO% values were significantly lower in the acute exacerbation group (p < 0.001, p < 0.001, p < 0.001, respectively). In ROC analysis, the cut-off value of PNI ≤ 48.50 had a sensitivity of 64.29% and specificity of 78.26% (AUC:0.744, p < 0.001). In multivariable logistic regression analysis, the PNI (OR = 0.857, p = 0.007) and FVC% (OR = 0.949, p = 0.008) were independent predictors of acute exacerbation. Conclusions: The PNI may serve as a negative biomarker for predicting acute exacerbation risk in IPF patients. This simple, cost-effective parameter could be useful in risk assessment. Full article

Idiopathic pulmonary fibrosis (IPF) remains a progressive and fatal disease despite major advances in antifibrotic therapy. Pirfenidone and nintedanib slow lung function decline, and the PDE4B inhibitor nerandomilast and treprostinil have recently shown promise as next-generation treatments. However, current therapies neither halt nor reverse disease progression, and tolerability issues often limit adherence. We compared the antifibrotic activity and plasma levels of nintedanib administered by either oral gavage or dietary supplementation in a rat model of pulmonary fibrosis. Male Sprague-Dawley rats received intratracheal bleomycin (1 U/kg) on days 0 and 4. From day 7 to day 28, animals were treated with nintedanib (100 mg/kg/day) by either oral gavage or medicated chow. Lung weight, fibrosis biomarkers (procollagen-I, metalloproteinase-7 or MMP7, WNT1-inducible signaling pathway protein or WISP-1), epithelial injury marker KL-6, target engagement biomarkers (Fibroblast Growth Factor 2 or FGF-2, Vascular Endothelial Growth Factor or VEGF), plasma drug levels, and histological fibrosis scores were evaluated. Both administration regimens significantly reduced procollagen-I, WISP-1 and KL-6, and histological fibrosis scores. Oral gavage produced approximately fourfold-higher peak plasma concentrations of nintedanib 30 min after dosing, whereas dietary administration resulted in lower, more stable plasma levels with reduced variability while resulting in comparable antifibrotic efficacy. In conclusion, nintedanib retained robust antifibrotic activity when administered via dietary supplementation despite lower, but continuous, active plasma concentrations. Collectively, these findings indicate that optimizing drug delivery and absorption kinetics may achieve sustained therapeutic efficacy while reducing unnecessary exposure to supratherapeutic concentrations, thereby potentially improving tolerability. Full article

Background/Objectives: To develop and evaluate an automated CT-based framework for the quantitative assessment of fibrotic interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF), using a standardised six-level anatomical protocol and deep-learning lung segmentation. Methods: The segmentation dataset comprised 3315 manually annotated development slices from 92 patients and a non-overlapping internal holdout of 845 slices from 5 patients. A separate 100-study localisation/scoring set yielded a 97-patient agreement cohort (84 IPF, 13 other ILD; 1164 per-level, per-lung observations) after three DICOM-conversion exclusions. YOLO11n-seg masks underwent vessel- and structure-removal fibrosis detection. The radial spatial score was compared with a non-blind expert-adjudicated reference; the per-level Fibrosis Index was an auxiliary read-out. Results: On the five-patient internal segmentation holdout, mean intersection over union (mIoU) was 0.926 ± 0.017; the in-sample development value was approximately 0.95. Model-only latency was 73.8 ± 9.7 ms/slice at batch size 1, and peak throughput was 1.48 ms/slice at batch size 512. In the separate 97-patient agreement cohort, the expert-adjudicated score was identical to the automated score for 967 of 1164 observations (83.1%) and differed for 197 (16.9%). In the modified-score subset, Pearson r was 0.918, mean absolute error was 3.07, and ICC(2,1) was 0.889 (patient-clustered 95% CI 0.828–0.923). The pooled ICC(2,1) was 0.988 (0.982–0.992), but this value was inflated because the 967 unchanged pairs were identical by construction. Sequential end-to-end processing, measured in seven study patients, took a mean of 22.5 s per patient (median 24.0 s, range 17.3–24.9 s); localisation accounted for 88.1% of this time. Conclusions: The framework combined lung segmentation, anatomically standardised sampling, and automated fibrosis scoring. The radial score showed preliminary analytical concordance under non-blind expert adjudication. The fibrosis detector remains a proof-of-concept implementation based on 8-bit windowed images and has not been compared with independently drawn pixel-level fibrosis masks. The radial partition is an exploratory scoring convention and was not compared with alternative partitions or validated against clinical outcomes. Larger external studies using native Hounsfield-unit data and independent blinded readers are required. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by parenchymal scarring, increased tissue stiffness, and impaired gas exchange. This study investigates the fluid dynamics and structural response of central airways in both healthy and fibrosis-inspired lungs under a 50% increased flow demand. A three-dimensional airway geometry was reconstructed from computed tomography (CT) scans up to the fifth bronchial generation using a hybrid modeling approach. Transient computational fluid dynamics (CFD) simulations of inhalation and exhalation were performed using ANSYS Fluent with the SST k-ω turbulence model. A complementary static structural analysis was conducted to assess deformation and stress under pleural pressure loading. The results indicate that fibrosis-inspired lungs required 92% higher inlet pressure losses compared to healthy lungs, highlighting the increased energetic cost of breathing. Flow patterns remained qualitatively similar. Structurally, fibrosis-inspired tissue exhibited 17% lower equivalent elastic strain under the same pressure load, confirming the impact of increased stiffness on bronchial distensibility. Maximum principal stress concentrations of 22.1 kPa were identified at the left main bronchus bifurcation, indicating potential mechanical stress hotspots. Full article

Background: Idiopathic pulmonary fibrosis (IPF) is frequently complicated by pulmonary vascular involvement and right ventricular (RV) dysfunction, both of which adversely affect prognosis. The relationship between impaired gas exchange and echocardiographic indices of RV function, particularly the TAPSE/PAPs (tricuspid annular plane systolic excursion/systolic pulmonary artery pressure) ratio as a marker of RV–pulmonary arterial (RV–PA) coupling, has not been fully characterized. Methods: We retrospectively evaluated 198 consecutive patients with IPF assessed at a single tertiary referral center between 2020 and 2026; 188 with complete pulmonary function testing were included in the main analyses. The primary exposure was gas exchange, measured by single-breath DLCO% (diffusing capacity of the lung for carbon monoxide) and stratified into four categories (Normal ≥ 80%, n = 21; Mild 60–79%, n = 56; Moderate 40–59%, n = 70; Severe < 40%, n = 41). The main outcome measures were echocardiographic indices of RV function—TAPSE, systolic pulmonary artery pressure (PAPs), and the TAPSE/PAPs ratio. Associations were assessed using Pearson’s correlation, one-way ANOVA, and multivariable linear regression adjusted for age, sex, and smoking status, with the Mild group as the reference for categorical analyses. Results: Lower DLCO values were independently associated with higher PAPs (adjusted β = −0.24 mmHg per 1% DLCO, p = 0.004) and with a lower TAPSE/PAPs ratio (adjusted β = +0.005 per 1% DLCO, p = 0.040). Compared with the Mild reference group, patients with Severe DLCO reduction had markedly higher PAPs (+14.6 mmHg, p = 0.002) and a lower TAPSE/PAPs ratio (−0.37, p = 0.002), with attenuated findings in the Moderate category; the small Normal group did not differ significantly from the Mild one. TAPSE alone showed only a weak, non-significant trend (r = 0.195, p = 0.083). Conclusions: In patients with IPF, lower DLCO was independently associated with higher pulmonary artery pressure and, to a lesser extent, with reduced RV–PA coupling (a lower TAPSE/PAPs ratio), whereas RV longitudinal systolic function (TAPSE) appeared preserved. Among pulmonary function parameters, DLCO showed the strongest association with PAPs. In this exploratory, cross-sectional analysis, combined evaluation of DLCO and the TAPSE/PAPs ratio may help characterize right heart involvement in IPF; its value for pulmonary hypertension (PH) screening requires prospective confirmation. Full article

The respiratory tract is a dynamic biological interface where microbiome, environmental exposure, epithelial integrity, and host metabolic regulation converge to maintain pulmonary homeostasis. Once considered sterile, the lung is now recognized as a low-biomass yet structured microbial ecosystem that contributes to immune calibration, colonization resistance, epithelial barrier function, and tissue resilience. Disruption of this equilibrium, known as pulmonary dysbiosis, has been increasingly associated with acute and chronic lung diseases, including cystic fibrosis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, idiopathic pulmonary fibrosis, asthma, bronchiectasis, and lung cancer. In parallel, mitochondria have emerged as central regulators of pulmonary cell function, extending beyond ATP production to control redox signaling, apoptosis, innate immunity, epithelial repair, and inflammatory responses. This review examines the bidirectional crosstalk between the respiratory microbiome and mitochondria as an integrated pathogenic axis in lung disease. Dysbiotic microbial communities and respiratory pathogens can induce mitochondrial stress through toxins, virulence factors, microbial metabolites, and pattern-recognition receptor activation, leading to mitochondrial alteration and the release of mitochondrial damage-associated molecular patterns. Conversely, dysfunctional mitochondria reshape the pulmonary microenvironment by altering oxygen consumption, nutrient availability, cytokine production, redox balance, and barrier repair, thereby favoring pathogen persistence and chronic inflammation. Understanding mitochondria–microbiome interactions may support precision medicine strategies that integrate microbial, metabolic, inflammatory, and bioenergetic biomarkers to improve the diagnosis, prognosis, and treatment of inflammatory-related lung diseases. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by excessive extracellular matrix remodeling and limited therapeutic options. Matrix metalloproteinase-2 is involved in extracellular matrix degradation and tissue remodeling, making it a relevant target for antifibrotic drug discovery. In this study, an MMP2-focused ligand-based pharmacophore model was developed and was applied to screen a curated FDA-approved drug library, leading to the identification of 83 pharmacophore-matching compounds. These compounds were subsequently prioritized through molecular docking against the catalytic site of MMP2, and the five best candidates were further evaluated by molecular dynamics (MD) simulations. Because of the biological relevance of MMP3 in pulmonary fibrosis, these five selected compounds were also profiled against MMP3 as a secondary target. Among them, Regorafenib (S1178) and Capmatinib (S2788) showed the most favorable cross-target profiles and were further supported by MD analysis. From these findings, S1178 and S2788 were proposed as promising MMP2-prioritized compounds with potential MMP3 cross-activity, warranting further experimental validation as candidate antifibrotic MMP modulators. Full article

Background/Objectives: Fibrosing interstitial lung disease (F-ILD) is associated with progressive respiratory impairment and substantial symptom burden. Diaphragmatic ultrasound (DUS) is a non-invasive method for assessing diaphragmatic structure and function, but its clinical role in F-ILD remains uncertain. This systematic review evaluated the available evidence on DUS in adults with F-ILD. Methods: This systematic review was conducted and reported according to the PRISMA guidelines. MEDLINE, Embase, CINAHL, and the Cochrane Library were searched and observational studies evaluating DUS in adults with F-ILD were included. Risk of bias was assessed using the QUADAS-2, and outcome-level certainty of evidence was evaluated by GRADE framework. Results: Six cross-sectional observational studies involving 232 participants were included. Diaphragmatic excursion (DE) was assessed in all six studies, while diaphragm thickness (DT) and thickening fraction (TF) were evaluated in four. Some studies reported abnormalities in DUS parameters during deep breathing and cross-sectional associations with pulmonary function, exercise capacity, dyspnoea, or radiological severity. Substantial heterogeneity in study populations, ultrasound protocols, and outcome reporting precluded meta-analysis. The certainty of evidence was very low. Conclusions: Current evidence suggests that DUS may detect diaphragmatic abnormalities in patients with F-ILD and may have future complementary value alongside established clinical assessments. However, the evidence is limited, heterogeneous, and of very low certainty and does not establish diagnostic accuracy, prognostic value, or usefulness for longitudinal monitoring. Accordingly, DUS cannot currently be recommended for routine clinical implementation in F-ILD, and prospective longitudinal validation is required. Full article

Repair programs are pervasive in idiopathic pulmonary fibrosis (IPF), yet they fail to reach completion. While single-cell and spatial omics have identified cellular states associated with injury-repair programs, a central paradox remains: why do these programs persist without reconstituting functional lung architecture? This review integrates evidence from multiscale omics, spatial analyses, and translational studies to propose a lesion-centered “non-resolving repair” framework that explains IPF progression. We argue that disease progression is driven by the persistence of cellular repair programs after the pathways required for maturation, state exit, and microenvironmental reset have become compromised. These compartment-specific failures converge within spatially organized lesion units, where aberrant cellular activity and matrix distortion reinforce one another, embedding failed repair within tissue architecture. This perspective shifts the focus from cataloging disease-associated cell states toward evaluating failed biological transitions and regional resolution capacity. Clinically, it reframes antifibrotic therapy around overcoming spatial barriers to repair and highlights the need for translational endpoints that distinguish marker suppression from structural stabilization and functional tissue reconstruction. Delineating which lesional niches retain resolution capacity will be essential for identifying where repair-oriented interventions may still re-engage organized tissue repair in IPF. Full article

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease driven by aberrant extracellular matrix deposition, with the activity of transforming growth factor-beta 1 (TGF-β1) orchestrating fibrogenesis. Current therapies are limited by severe adverse effects, highlighting the unmet need for safer treatments. In this study, the therapeutic potential of chlorogenic acid (CGA) in a murine model of pulmonary fibrosis was evaluated. Methods: Pathology was induced on day 0 via subcutaneous osmotic minipumps delivering bleomycin (BLM) for one week, followed by pump removal on day 10. Therapeutic interventions with intragastric CGA (60 mg/kg) were administered daily from days 14 to 20. Lung tissue samples obtained on day 21 were analyzed via histological, immunohistochemical, and RT–PCR methods. Results: Histological analysis via H&E and Masson’s trichrome staining revealed that CGA treatment significantly attenuated alveolar thickening, restored the alveolar space, and reduced the total cell density and Ashcroft fibrosis score. Furthermore, CGA markedly decreased collagen deposition. Quantitative RT–PCR and immunohistochemical assays revealed that CGA effectively decreased the expression of Col1a1, TGF-β1, and the myofibroblast marker alpha-smooth muscle actin (α-SMA). Conclusions: CGA exerts important therapeutic effects by decreasing the expression of TGF-β1 and the activation of myofibroblasts, indicating that this natural polyphenol is a promising candidate for mitigating the progression of pulmonary fibrosis. Full article

Trained immunity (TI) represents a form of immune memory in innate immune cells, driven by sustained epigenetic and metabolic reprogramming that potentiates innate immune responses. Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by persistent alveolar injury and pathological tissue remodeling. Given the central role of macrophages in IPF pathogenesis, we hypothesized that inducing TI could functionally reprogram these cells and attenuate fibrosis. In a murine model of pulmonary fibrosis induced by bleomycin, prior induction of TI via β-glucan enhanced autophagic activity in macrophages and reduced pathological collagen deposition. This trained response restricted bleomycin-triggered mitochondrial DNA release and suppressed the mitochondrial apoptosis pathway, thereby promoting macrophage survival. The protective effects were diminished by administration of the AMPK inhibitor Compound C. Our findings indicate that TI promotes mitophagy correlating with the AMPK-ULK1 signaling axis, thereby reducing alveolar macrophage apoptosis and uncovering a potential therapeutic strategy for pulmonary fibrosis. Full article

Background: Idiopathic pulmonary fibrosis (IPF) is closely associated with fibroblast proliferation, macrophage polarization, and the accumulation of extracellular matrix (ECM). Targeting CSF-1R can rebalance macrophages, reduce ECM deposition, and block pro-fibrotic signaling. Methods: A Fab fragment targeting CSF-1R was screened via phage display. After sequence optimization, it was constructed into an IgG1 antibody (BC006). In vitro activity, domain binding, and signaling blockade were investigated, and in vitro safety indicators were evaluated. Efficacy was assessed using an induced IPF organoid-on-a-chip and bleomycin-induced mouse model. In vivo safety evaluation was conducted in cynomolgus monkeys. Results: BC006 showed an EC₅₀ value of 226 ± 57 nM and a KD of 30 ± 2 nM. It specifically bound to the Ig4-5 domain of CSF-1R by inhibiting receptor dimerization without blocking ligand binding. It could dose-dependently inhibit the differentiation of monocytes into M2 macrophages and exert anti-IPF effects. In the induced IPF organoid-on-a-chip model, BC006 maintained lung barrier function and decreased α-SMA and Collagen I. It also improved lung function and attenuated the degree of fibrosis in the mouse model. Moreover, BC006 had no ADCC, CDC, cytokine release, or hemagglutination, and demonstrated favorable safety profiles in cynomolgus monkeys. Conclusions: BC006 is a novel anti-fibrosis antibody specifically targeting the CSF-1R Ig4-5 domain and offers a new therapeutic strategy for IPF. Full article

Zoonotic bacterial pathogens are transmitted through various routes and are traditionally associated with acute febrile illnesses that may include pulmonary complications. However, in some survivors, the disease extends beyond the acute phase, leading to the remodeling of pulmonary architecture and driving progressive fibrosis. Although no direct cases have been reported, these pathogens may plausibly predispose injured lungs to carcinogenesis, similar to the well-recognized phenomenon of tuberculosis-associated scar cancer. As such long-term sequelae remain largely overlooked in current clinical practice, their potential contribution to fibrotic and malignant lung disease represents a critical and underexplored knowledge gap. This review proposes a unified mechanistic framework linking acute pathogen-mediated alveolar damage to chronic pulmonary fibrosis and subsequent lung carcinogenesis. We delineate four convergent biological pillars driving this continuum: (1) pathogen persistence establishing chronic Interleukin-1β (IL-1β)/Tumor necrosis factor-α (TNF-α)-mediated inflammation; (2) sustained TGF-β signaling and mechanotransduction driving progressive extracellular matrix remodeling; (3) unresolved reactive oxygen species (ROS) generation causing profound oxidative DNA damage; and (4) aberrant epithelial–mesenchymal transition (EMT) that perpetuates fibrosis and generates pre-malignant cell populations. Together, these sequelae alter lung biomechanics, suppress local immune surveillance, and create a mutagenic environment that is highly conducive to malignant transformation. Although direct epidemiological data is still emerging, the significant mechanistic overlap with idiopathic pulmonary fibrosis (IPF) presents a compelling rationale for shared oncogenic risk. We advocate for a paradigm shift in clinical practice, emphasizing the potential value of long-term surveillance for survivors of severe pulmonary infections. By integrating infectious diseases, pulmonology, and oncology, this framework highlights a neglected cause of fibrotic lung disease and establishes a foundation for future translational research. Full article

Objectives: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with increasing prevalence and mortality. High-resolution computed tomography (HRCT) is routinely performed in IPF assessment and can provide additional quantitative information. However, the prognostic utility of these HRCT-based parameters in IPF remains uncertain. This study aimed to investigate the prognostic value of quantitative HRCT findings in predicting mortality among patients with IPF. Methods: In this retrospective cohort study, 48 patients diagnosed with IPF between 2014 and 2024 were analyzed. Demographics, pulmonary function tests, HRCT findings, and quantitative measurements, including coronary artery calcium (CAC) score; densities of hepatic, paraspinal muscle, and lumbar vertebral bone mineral; and HRCT-derived fibrosis scores, were collected at baseline and after at least two years. The primary outcome was all-cause mortality. Results: The mean age was 66.8 ± 8.5 years; 77.1% were male. During a median follow-up of 63.3 months, 22 patients (45.8%) died, mainly from IPF-related causes (71.4%). Non-survivors had significantly higher HRCT fibrosis scores both at diagnosis (p = 0.006) and at two years (p = 0.002). Fibrosis scores increased significantly over time in non-survivors (p = 0.019). CAC scores rose in both groups, with a greater increase in non-survivors, but their independent prognostic value was limited after adjustment. Multivariable analysis identified male sex (hazard ratio [HR]: 5.46, p = 0.031) and second-year fibrosis score (HR: 1.10, p < 0.001) as independent predictors of mortality. Conclusions: HRCT-derived fibrosis burden is an independent predictor of mortality in IPF, alongside male sex. While other HRCT-based measures showed limited prognostic significance, longitudinal increases in CAC scores suggested potential cardiovascular implications. Full article