Search Results (914)

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

Skeletal muscle dysfunction and exercise intolerance are major extrapulmonary manifestations of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), yet their severity is not fully predicted by pulmonary impairment. This narrative review examines extracellular vesicles (EVs) as candidate mediators of lung–muscle communication within a broader network of inflammatory, metabolic, vascular, nutritional, and inactivity-related mechanisms. The evidence is asymmetrical. COPD provides direct human skeletal muscle evidence for quadriceps microRNA dysregulation, impaired protein synthesis and mitochondrial function, oxidative stress, and abnormalities of the regenerative microvascular niche; however, none of these observations demonstrates delivery of pathogenic cargo from the lung by EVs. In IPF, EV-mediated epithelial–mesenchymal signalling, fibroblast activation, and profibrotic remodelling are well supported within the lung, whereas skeletal muscle effects remain indirect. Accordingly, the lung–muscle EV axis should be viewed as a biologically plausible, evidence-weighted hypothesis rather than an established causal pathway. Progress will require experiments that identify the cellular source of EVs, trace their vascular transit and skeletal muscle uptake, and demonstrate functional cargo transfer using EV-depletion, rescue, and integrated muscle readouts. Conventional size and morphology measurements do not reliably distinguish muscle- from lung-derived EVs; source discrimination currently depends more on molecular cargo and cell-associated markers. Hypoxia and transient or sustained oxygen desaturation may modify EV release and cargo through HIF- and redox-sensitive signalling, but disease-specific evidence connecting these changes to lung-to-muscle transfer in COPD or IPF remains limited. Full article

Background/Objectives: The diagnosis of interstitial lung disease (ILD) is challenging and frequently delayed. Clinically accessible and minimally invasive diagnostic tools are needed to expedite the diagnosis of ILD while minimizing risk to patients. Fibresolve is an imaging artificial intelligence (AI) tool recently approved by the Food and Drug Administration (FDA) for use in ILD diagnosis and made available to clinicians. The objective of this study was to describe its utility in clinical practice. Methods: We conducted a prospective, observational study of patients across the United States (US) in whom Fibresolve was utilized during routine clinical practice between July 2024 and June 2026. Information on patient demographics, Fibresolve test results (positive = suggestive of idiopathic pulmonary fibrosis (IPF); negative = unsupportive of IPF), and disease management pre- and post-Fibresolve utilization were collected, including the use of ILD-specific pharmacotherapy and planned and/or completed invasive diagnostic procedures. Results: There were 209 patients that underwent evaluation with Fibresolve across 47 medical centers. Of those, 16 were academic centers (n = 57 patients), and 31 were community-based (n = 152 patients). Fibresolve was positive in 89/209 (42.6%) patients. The percentage of patients receiving ILD-specific pharmacotherapy increased significantly following Fibresolve utilization (12.5% to 44.4%, p < 0.001). Pre-Fibresolve, 59/154 (38.3%) patients had an invasive diagnostic procedure planned; post-Fibresolve, only 12/77 (15.6%) patients had an invasive procedure performed (p < 0.001). Conclusions: In this real-world study evaluating the use of an FDA-authorized imaging tool for ILD diagnosis in diverse clinical practices across the US, we found that following utilization of Fibresolve, there was a statistically significant increase in the percentage of patients receiving guideline-directed therapy for ILD, and previously-planned invasive diagnostic procedures were avoided in many cases. These findings support the use of Fibresolve as an adjunct for ILD diagnosis in clinical practice. Full article

Chronic lung diseases, including asthma, chronic obstructive pulmonary disease, bronchiectasis, and idiopathic pulmonary fibrosis, are clinically distinct but share epithelial injury, host-defense, inflammatory, and remodeling processes. We integrated European-ancestry genome-wide association study (GWAS) summary statistics for these four diseases using genomic structural equation modeling to construct a multivariate chronic lung disease (mvCLD) factor. Variant-level association testing was combined with genomic control assessment, locus annotation, GWAS-by-subtraction, fine-mapping, transcriptomic prioritization, pathway enrichment, single-cell spatial mapping, and heritability partitioning. For discovery, across 6,255,777 autosomal variants, mvCLD identified 2067 genome-wide significant variants, 30 loci, and 53 lead variants. Five lead variants were genome-wide significant for mvCLD but not for any component disease and showed high-confidence fine-mapping support. For gene prioritization, transcriptomic and gene-level analyses prioritized 21 candidate genes, including ORMDL3, GSDMB, IL18RAP, IL18R1, IL1R1, SMAD3, and CLEC16A. In exploratory functional analyses, enrichment analyses converged on interleukin, cytokine-receptor, JAK-STAT, interleukin-4/interleukin-13, thymic stromal lymphopoietin, asthma, and lung fibrosis pathways. Exploratory single-cell spatial mapping, based on a mouse embryonic atlas, showed the strongest overall enrichment in the lung annotation, although cross-dataset cell-type and tissue analyses did not reach significance after false discovery rate correction; heritability partitioning implicated conserved and active regulatory elements. These findings support a shared epithelial–immune and cytokine-regulatory genetic architecture across major chronic lung diseases and nominate biologically coherent candidate genes and pathways for future functional and translational studies. Full article

Background: Pulmonary hypertension (PH)-complicating interstitial lung disease (ILD) is a devastating condition that severely limits exercise capacity, diminishes quality of life (QOL), and ultimately determines survival. The pathophysiological assessment of ILD-PH has traditionally focused on right ventricular (RV) parameters reflecting RV pressure overload and dysfunction. However, under extreme RV pressure overload where blood supply to the left heart is severely restricted, the prognostic role of left ventricular (LV) function—which is ultimately responsible for maintaining systemic cardiac output—remains poorly understood. This study aimed to comprehensively evaluate the hemodynamics of ILD patients using non-invasive transthoracic echocardiography, to determine the prognostic importance of LV functional parameters, particularly left ventricular ejection fraction (LVEF). Methods: This single-center, retrospective, observational study included 415 ILD patients diagnosed and treated at the Kanagawa Cardiovascular Respiratory Center. All patients underwent transthoracic echocardiography at diagnosis, from which parameters such as estimated right ventricular systolic pressure (RVSP), tissue Doppler-derived Average e’, and LVEF were obtained. A multivariable Cox proportional hazards model was applied to evaluate the association between these echocardiographic parameters and all-cause mortality. To account for the prognostic impact of the underlying disease, we conducted a stratified analysis of idiopathic pulmonary fibrosis (IPF) and non-IPF cohorts. Furthermore, to evaluate LV function under the most severe hemodynamic compromise, a subgroup analysis was restricted to IPF patients with elevated RVSP (≥median). Results: During a median follow-up of 27.2 months, 75 (18.1%) of the 415 patients died. In the multivariable Cox analysis of the overall cohort, a decreased Average e’ (HR 0.861, p = 0.0038) emerged as a strong independent predictor of poor prognosis. Stratified analysis revealed that in the non-IPF group (n = 208, 15 events), none of the variables achieved statistical significance. Conversely, in the IPF group (N = 207, 60 events), both LV diastolic function (Average e’, p = 0.0199) and LV systolic function (LVEF, HR 0.969, 95% CI 0.940–0.998, p = 0.0305) were extracted as significant prognostic predictors. Most notably, in the stepwise multivariable model restricted to the “IPF with high RVSP” subgroup (N = 104), the prognostic significance of diastolic function (Average e’) was lost (p = 0.4577), whereas LVEF (HR 0.965, 95% CI 0.936–0.995, p = 0.0229) emerged as the sole independent predictor of mortality. Conclusions: In the overall ILD-PH cohort, reduced LV diastolic function (Average e’) is a strong independent predictor of mortality. While elevated RVSP and low BMI showed a trend toward worsening prognosis, they were not statistically significant in multivariable analysis. The prognostic contribution of LV function is primarily driven by the IPF patient group, which has an inherently poor prognosis. Furthermore, in the severe subgroup of IPF patients heavily burdened by right heart overload, LV pump function (LVEF) becomes an independent, critical determinant of ultimate survival. Therefore, routine measurement and careful monitoring of the universal parameter LVEF are of paramount importance for the risk stratification of high-risk patients under such complex hemodynamics. Full article

Respiratory diseases impose a substantial global burden; however, early diagnosis, disease-activity monitoring, and the clinical translation of nucleic acid therapeutics are constrained by the lack of robust biomarkers and efficient delivery systems. This narrative review focuses on four classes of RNA—messenger RNA (mRNA), circular RNA (circRNA), small interfering RNA (siRNA), and microRNA (miRNA)—using exosomes as a representative subtype of extracellular vesicles (EVs) to discuss EV biogenesis, transport, uptake, and engineered cargo loading. We summarize the diagnostic and therapeutic applications of EV-associated nucleic acids in chronic or non-severe respiratory diseases, including asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and cystic fibrosis, as well as in severe acute conditions such as acute respiratory distress syndrome and severe pneumonia. Biofluid-derived EV-associated RNAs can reflect inflammation, immune dysregulation, epithelial injury, infection, and fibrosis, supporting their potential use in disease classification, monitoring, and prognostic assessment. Natural EVs may modulate inflammation and tissue repair through their endogenous cargo, while engineered EVs can deliver therapeutic nucleic acids to exert anti-inflammatory, anti-infective, antifibrotic, and barrier-restorative effects. However, clinical translation is limited by non-standardized isolation and characterization methods, product heterogeneity, variable cargo loading, and insufficient stability and quality-control frameworks. Continued advances in EV isolation, characterization, nucleic acid loading, potency assessment, and manufacturing control are required to realize the diagnostic and therapeutic potential of EV-associated nucleic acids in respiratory diseases. Full article

Background/Objectives: Distinguishing idiopathic pulmonary fibrosis (IPF) from other interstitial lung diseases is prognostically and therapeutically important. We developed Fibresolve, a machine learning system that analyzes chest computed tomography (CT) to support IPF diagnosis. Fibresolve version 1 (v1) was validated in the PUFAIR study, met its co-primary endpoints, and received U.S. FDA authorization. Fibresolve version 2 (v2) was subsequently developed under the FDA’s Predetermined Change Control Plan (PCCP) framework and, here, is evaluated against the authorized v1 model. Methods: v2 augments the original CT-only v1 classifier by incorporating age, sex, and forced vital capacity into an ensemble, while retaining the v1 CT-only model as a fallback when these variables are unavailable. Both models were evaluated in the same 300-patient PUFAIR cohort (83 IPF, 217 non-IPF) from two U.S. centers. Reference-standard diagnoses were established by institutional multidisciplinary discussion and supported by surgical pathology in 94.7% of cases. McNemar test, Cohen $\kappa$, and bootstrap noninferiority analyses were used for paired model comparisons. Results: In the key thin-slice diagnostic CT subgroup (N = 137), v2 achieved a sensitivity of 57.5% (95% CI, 42.2–71.5) and specificity of 84.5% (95% CI, 76.0–90.4), compared with 55.0% (95% CI, 39.8–69.3) and 82.5% (95% CI, 73.7–88.8) for v1. Performance improvements were directionally consistent across most subgroups, with no evidence of inferior performance. Conclusions: Fibresolve v2 preserved the performance of the FDA-authorized v1 model while providing modest, directionally favorable improvements. These findings support v2 as the primary model, with v1 retained as a robust fallback when clinical variables are unavailable. Full article

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrosing interstitial lung disease characterized by excessive extracellular matrix (ECM) accumulation, disruption of lung architecture, and progressive loss of pulmonary function. IPF is frequently accompanied by comorbid conditions that exacerbate disease progression and negatively impact prognosis. To address the biological complexity of IPF, this study presents a comprehensive molecular systems architecture that enables a system-level understanding of biomolecular interactions within the fibrotic lung microenvironment in response to external and physiological triggers. Methods: A literature search is conducted using the Medical Subject Headings (MeSH) keywords in PubMed and MEDLINE to identify relevant peer-reviewed articles published from April 2008 to June 2025, with Google Scholar used solely to retrieve full-text versions of articles identified through this search. The systems biology tool CytoSolve^® was used to perform the systematic review and to support the curation and development of the molecular systems architecture of IPF pathogenesis. Full-length articles that contained Medical Subject Headings keywords relevant to IPF pathogenesis were selected for a comprehensive review. A total of 150 studies published between April 2008 and June 2025 met the inclusion criteria and were included in the systematic analysis. This systematic review was not registered. Results: Findings were synthesized qualitatively into a multilayered molecular interactome rather than through statistical meta-analysis. The architecture integrates interactions across sixteen lung-associated cell types, including epithelial, endothelial, mesenchymal, immune, and stromal populations. Key external triggers—such as bleomycin (BLM), asbestos, silica, radiation, cigarette smoke, Herpes virus, and genetic mutations (SFTPC I73T), along with hypoxia associated with comorbidities—initiate coordinated cellular responses that converge on three fundamental pathological processes: inflammation, myofibroblast differentiation, and tissue remodeling. These interconnected processes collectively drive the initiation and progression of IPF. Conclusions: This molecular systems architecture unifies triggers, cellular components, molecular pathways, and biological processes into a multilayered framework for identifying therapeutic targets, biomarkers, and rational single- and combination-treatment strategies in IPF. Full article