Biomater Sci. 2025 Feb 19. doi: 10.1039/d4bm00906a. Online ahead of print.

ABSTRACT

Fibrosis, a pathological hallmark of various chronic diseases, involves the excessive accumulation of extracellular matrix (ECM) components leading to tissue scarring and functional impairment. Understanding how cells interact with the ECM in fibrotic diseases such as idiopathic pulmonary fibrosis (IPF), is crucial for developing effective therapeutic strategies. This study explores the effects of decellularized extracellular matrix (dECM) coatings derived from non-IPF and IPF donor lung tissue samples on the behavior of primary human lung fibroblasts (HLFs). Utilizing a substrate coating method that preserves the diversity of in situ ECM, we studied both the concentration-dependent effects and the intrinsic biochemical cues of ECM on cell morphology, protein expression, mechanobiology biomarkers, and gene expression. Morphological analysis revealed that HLFs displayed altered spreading, shape, and nuclear characteristics in response to dECM coatings relative to control plastic, indicating a response to the physical and biochemical cues. Protein expression studies showed an upregulation of α-smooth muscle actin (α-SMA) in cells interacting with both non-IPF and IPF dECM coatings, that was more prominent at IPF dECM-coated surface. In addition, YAP localization, a marker of mechanotransduction, was also dysregulated on dECM coatings, reflecting changes in mechanical signaling pathways. Gene expression profiles were differentially regulated by the different dECM coatings. The developed dECM coating strategy in this work facilitates the integration of tissue-specific biochemical cues onto standard cell culture platforms, which is ideal for high-throughput screening. Importantly, it minimizes the requirement for human tissue samples, especially when compared to more sample-intensive 3D models like dECM-based hydrogels.

PMID:39968884 | DOI:10.1039/d4bm00906a

Front Oncol. 2025 Feb 4;15:1487334. doi: 10.3389/fonc.2025.1487334. eCollection 2025.

ABSTRACT

BACKGROUND: Alpha-fetoprotein (AFP)-producing hepatoid adenocarcinoma of lung (HAL) is a rare type of lung cancer, with its characteristics being not yet fully clarified. We recently encountered a case of HAL combined with idiopathic pulmonary fibrosis (IPF), which has never been reported.

CASE PRESENTATION: A 66-year-old man consulted our hospital with a chief complaint of cough. Chest computed tomography (CT) revealed multiple nodules measuring from 8mm to 20mm in diameter located in bilateral lung, along with an enlarged left hilar lymph node. CT-guided percutaneous lung biopsy confirmed the diagnosis of AFP-producing primary HAL combined with IPF. Systemic treatment according to guidelines for advanced non-small cell lung cancer resulted in a long-term survival.

CONCLUSIONS: This case report documents the first occurrence and prognosis of AFP-producing HAL in a patient with IPF. The long-term survival brought by the diagnosis and treatment model in our case may provide significant prognostic value for this rare condition.

PMID:39968074 | PMC:PMC11832387 | DOI:10.3389/fonc.2025.1487334

ACS Med Chem Lett. 2025 Jan 23;16(2):317-326. doi: 10.1021/acsmedchemlett.4c00559. eCollection 2025 Feb 13.

ABSTRACT

Lysophosphatidic acid (LPA) is a phospholipid activating different biological functions by binding to G protein-coupled receptors (LPA1-6). Among these, the role of the LPA1 receptor in modulating fibrotic processes is well-known, making it a therapeutic target for pulmonary fibrosis and other fibrotic disorders. Herein we report the search for a new class of LPA1 antagonists for the oral treatment of idiopathic pulmonary fibrosis with a focus on hepatobiliary safety. Compound 7 excelled in in vitro and in vivo efficacy, showing significant efficacy both in PD studies and in a rodent lung fibrosis model, with a promising in vitro hepatic safety profile. However, in a dose range finding (DRF) toxicity study, compound 7 did not ensure safety regarding potential hepatobiliary toxicity, leading to its development being halted.

PMID:39967626 | PMC:PMC11831564 | DOI:10.1021/acsmedchemlett.4c00559

Small. 2025 Feb 19:e2409126. doi: 10.1002/smll.202409126. Online ahead of print.

ABSTRACT

This study advances sustainable pharmaceutical research for endometriosis by developing in vitro 3D cell culture models of endometriotic pathophysiology that allow antifibrotic drug candidates to be tested. Fibrosis is a key aspect of endometriosis, yet current cell models to study it remain limited. This work aims to bridge the translational gap between in vitro fibrosis research and preclinical testing of non-hormonal drug candidates. When grown in a 3D matrix of sustainably produced silk protein functionalized with a fibronectin-derived cell adhesion motif (FN-silk), endometrial stromal and epithelial cells respond to transforming growth factor beta-1 (TGF-β1) in a physiological manner as probed at the messenger RNA (mRNA) level. For stromal cells, this response to TGF-β1 is not observed in spheroids, while epithelial cell spheroids behave similarly to epithelial cell FN-silk networks. Pirfenidone, an antifibrotic drug approved for the treatment of idiopathic pulmonary fibrosis, reverses TGF-β1-induced upregulation of mRNA transcripts involved in fibroblast-to-myofibroblast transdifferentiation of endometrial stromal cells in FN-silk networks, supporting pirfenidone's potential as a repurposed non-hormonal endometriosis therapy. Overall, endometrial stromal cells cultured in FN-silk networks-which are composed of a sustainably produced, fully defined FN-silk protein-recapitulate fibrotic cellular behavior with high fidelity and enable antifibrotic drug testing.

PMID:39967482 | DOI:10.1002/smll.202409126

Sci Rep. 2025 Feb 18;15(1):5954. doi: 10.1038/s41598-025-89770-y.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an age-related interstitial lung disease of unknown cause. Oxidative stress, an imbalance between oxidants and antioxidants, is implicated in IPF pathogenesis and prognosis but needs further study. We used transcriptome sequencing data (GSE70866) and oxidative stress-related genes from GeneCards. A prognostic risk model for IPF patients was constructed using LASSO. Functional and pathway differences were analyzed between risk score groups, along with comparisons of immune cells and functions. An IPF rat model with vitamin D3 (VD3) intervention was also established. Finally, we used IL-4 to induce M2 macrophages to explore the mechanism of action of CCL2. We identified 483 DEGs and 50 oxidative stress-related DEGs (OSDEGs). Single-factor COX regression identified 34 prognostic OSDEGs, and LASSO identified an 8-gene signature for the risk model. The high-risk group had more CD8 + T cells, macrophages, APC costimulation, and cytokine-cytokine receptor activity. CCL2 was significantly correlated with macrophages in IPF. VD3 inhibited the TGF-β signaling pathway and reduced macrophage M2 infiltration in the rat model. In the IL-4 induced M2 macrophage model, we found that M2 macrophages produced more CCL2, and the production of CCL2 was significantly reduced after VD3 intervention. We established prognostic markers of eight oxidative stress-related genes. The risk score effectively predicts adverse outcomes in IPF. VD3 may alleviate IPF by reducing macrophage infiltration and inhibiting the TGF-β signaling pathway.

PMID:39966531 | DOI:10.1038/s41598-025-89770-y

Cell Biochem Biophys. 2025 Feb 19. doi: 10.1007/s12013-025-01696-4. Online ahead of print.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a severe, rapidly advancing disease that drastically diminishes life expectancy. Without treatment, it can progress to lung cancer. The precise etiology of IPF remains unknown, but inflammation and damage to the alveolar epithelium are widely thought to be pivotal in its development. Research has indicated that activating the NLRP3 inflammasome is a crucial mechanism in IPF pathogenesis, as it triggers the release of pro-inflammatory cytokines such as IL-1β, IL-18, and TGF-β. These cytokines contribute to the myofibroblast differentiation and extracellular matrix (ECM) accumulation. Currently, treatment options for IPF are limited. Only two FDA-approved medications, pirfenidone and nintedanib, are available. While these drugs can decelerate disease progression, they come with a range of side effects and do not cure the disease. Additional treatment strategies primarily involve supportive care and therapy. Emerging research has highlighted that numerous flavonoids derived from traditional medicines can inhibit the critical regulators responsible for activating the NLRP3 inflammasome. These flavonoids show promise as potential therapeutic agents for managing IPF, offering a new avenue for treatment that targets the core inflammatory processes of this debilitating condition.

PMID:39966334 | DOI:10.1007/s12013-025-01696-4

JCI Insight. 2025 Feb 18:e177072. doi: 10.1172/jci.insight.177072. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring and loss of lung function. With limited treatment options, patients succumb to the disease within 2 to 5 years. The molecular pathogenesis of IPF regarding the immunologic changes that occur is poorly understood. We characterize a role for non-canonical aryl-hydrocarbon receptor signaling (ncAHR) in dendritic cells (DCs) that leads to production of IL-6 and increased IL-17+ cells, promoting fibrosis. TLR9 signaling in myofibroblasts is shown to regulate production of TDO2 which converts tryptophan into the endogenous AHR ligand kynurenine. Mice with augmented ncAHR signaling were created by crossing floxed AHR exon-2 deletion mice (AHRΔex2) with mice harboring a CD11c-Cre. Bleomycin (blm) was used to study fibrotic pathogenesis. Isolated CD11c+ cells and primary fibroblasts were treated ex-vivo with relevant TLR agonists and AHR modulating compounds to study how AHR signaling influenced inflammatory cytokine production. Human datasets were also interrogated. Inhibition of all AHR signaling rescued fibrosis, however, AHRΔex2 mice treated with blm developed more fibrosis and DCs from these mice were hyperinflammatory and profibrotic upon adoptive transfer. Treatment of fibrotic fibroblasts with TLR9 agonist increased expression of TDO2 and fibrotic fibroblasts activated IL-6 production in CD103+ DCs. Study of human samples corroborates the relevance of these findings in IPF patients. We also, for the first time, identify that AHR exon-2 floxed mice retain capacity for ncAHR signaling.

PMID:39964756 | DOI:10.1172/jci.insight.177072

Drug Dev Ind Pharm. 2025 Feb 18:1-18. doi: 10.1080/03639045.2025.2468811. Online ahead of print.

ABSTRACT

OBJECTIVE: This review aims to explore innovative therapeutic strategies, with a particular focus on recent advancements in drug delivery systems using bioinspired nanomaterials such as solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) for the Idiopathic pulmonary fibrosis (IPF).

SIGNIFICANCE OF THE REVIEW: Current treatments for IPF, including the FDA-approved anti-fibrotic agents pirfenidone and nintedanib, primarily aim to slow disease progression rather than reverse fibrosis. Bioinspired nanomaterials like SLNs and NLCs have shown promise in enhancing the efficacy of anti-fibrotic agents by improving drug solubility, stability, and targeted delivery. These systems not only minimize systemic side effects but also maximize therapeutic impact in lung tissues, offering a new hope for improved patient management and outcomes in this debilitating disease.

KEY FINDINGS: SLNs facilitate sustained drug release and have demonstrated potential in delivering phosphodiesterase type 5 inhibitors effectively to lung cells. NLCs, on the other hand, exhibit superior biocompatibility and controlled release properties, making them suitable for pulmonary applications. Studies indicate that both SLNs and NLCs can enhance the bioavailability of drugs like ciprofloxacin and montelukast, thereby improving treatment outcomes in pulmonary conditions.

CONCLUSIONS: The integration of nanotechnology into anti-fibrotic therapy represents a significant advancement in addressing the challenges posed by IPF. By leveraging the unique properties of SLNs and NLCs, there is potential to overcome the limitations of current treatments and provide new therapeutic options that offer better management and improved outcomes for patients suffering from this debilitating disease.

PMID:39963904 | DOI:10.1080/03639045.2025.2468811

Minerva Med. 2025 Feb 17. doi: 10.23736/S0026-4806.25.09643-0. Online ahead of print.

ABSTRACT

BACKGROUND: Early diagnosis of idiopathic pulmonary fibrosis (IPF) is fundamental to slow disease progression; multidisciplinary teams (MDTs) play a central role in posing the final diagnosis of IPF, thus aiming to improve patient outcomes. However, the practical implementation of MDTs in clinical real-life settings may be hindered by the lack of local expertise or time constraints, with the diagnosis being made without the support of complementary professional health care figures. This study aims to evaluate the impact of MDT meetings on the latency between the symptom onset and the final diagnosis of IPF.

METHODS: Patients referred to a regional center for IPF between January 2019 and August 2019 were included. The length of time to pose a definite diagnosis by means of MDT evaluation was compared with that of patients diagnosed elsewhere (no MDT evaluation) in an observational case-control investigation.

RESULTS: Among 24 IPF patients, those evaluated by MDT (M/F: 14/2, age: 69.8±8.2 yrs) showed a time interval from the first outpatient visit to the definite diagnosis of 3±2.3 months; on the other hand, patients in the control group (M/F: 7/1, age: 76.9±7.7 yrs) showed a time interval of 12.8±9.4 months (P=0.02). The time elapsed between the onset of symptoms and the definite diagnosis was 11.1±5.3 months for patients evaluated within the MDT, compared to 33.8±21.5 months for the control group (P=0.02).

CONCLUSIONS: These exploratory findings confirm the essential role of the MDT in the early diagnosis of IPF, thus discouraging the acquisition of diagnosis solely on individual basis. The current findings highlight the need for the implementation of MDTs in clinical practice to optimize patient care.

PMID:39960753 | DOI:10.23736/S0026-4806.25.09643-0

J Inflamm Res. 2025 Feb 11;18:1993-2009. doi: 10.2147/JIR.S489210. eCollection 2025.

ABSTRACT

BACKGROUND: Studies suggest that immune and inflammation processes may be involved in the development of idiopathic pulmonary fibrosis (IPF); however, their roles remain unclear. This study aims to identify key genes associated with immune response and inflammation in IPF using bioinformatics.

METHODS: We identified differentially expressed genes (DEGs) in the GSE93606 dataset and GSE28042 dataset, then obtained differentially expressed immune- and inflammation-related genes (DE-IFRGs) by overlapping DEGs. Two machine learning algorithms were used to further screen key genes. Genes with an area under curve (AUC) of > 0.7 in receiver operating characteristic (ROC) curves, significant expression and consistent trends across datasets were considered key genes. Based on these key genes, we carried out nomogram construction, enrichment and immune analyses, regulatory network mapping, drug prediction, and expression verification.

RESULTS: 27 DE-IFRGs were identified by intersecting 256 DEGs, 1793 immune-related genes, and 1019 inflammation-related genes. Three genes (RNASE3, S100A12, S100A8) were obtained by crossing two machine algorithms (Boruta and LASSO),which had good diagnostic performance with AUC values. These key genes were all enriched in the same pathways, such as GOCC_azurophil_granule, IL-12 signalling and production in macrophages is the pathway with the strongest role for key genes. Six distinct immune cells, including naive CD4 T cells, T cells CD4 memory resting, T cells regulatory (Tregs), Monocytes, Macrophages M2, Neutrophils were identified. Real-time quantitative polymerase chain reaction (RT-qPCR) results were consistent with the training and validation sets, and the expression of these key genes was significantly upregulated in the IPF samples.

CONCLUSION: This study identified three key genes (RNASE3, S100A12 and S100A8) associated with immune response and inflammation in IPF, providing valuable insights into the diagnosis and treatment of IPF.

PMID:39959639 | PMC:PMC11829586 | DOI:10.2147/JIR.S489210

Cureus. 2025 Jan 16;17(1):e77522. doi: 10.7759/cureus.77522. eCollection 2025 Jan.

ABSTRACT

Bird fancier's lung (BFL) is a subtype of hypersensitivity pneumonitis (HP), an immune-mediated interstitial lung disease (ILD) resulting from the repeated inhalation of avian proteins found in bird droppings, feathers, and serum. Diagnosing BFL is challenging due to nonspecific symptoms that overlap with other ILDs like idiopathic pulmonary fibrosis and sarcoidosis. This complexity is heightened during pandemics such as coronavirus disease 2019 (COVID-19), where respiratory symptoms may be misattributed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, leading to diagnostic anchoring and delays in appropriate management. High-resolution computed tomography (HRCT) is pivotal in detecting subtle pulmonary changes, characteristic of HP, surpassing standard chest radiographs. We present the case of a 43-year-old male pigeon keeper with an eight-week history of progressive dyspnea on exertion and intermittent chest pain. Despite unremarkable chest X-rays, HRCT revealed bilateral diffuse centrilobular nodules, patchy ground-glass opacities, and a mosaic attenuation pattern without fibrosis, consistent with acute HP. A thorough occupational history uncovered significant avian antigen exposure, and a family history suggested genetic susceptibility. The patient was diagnosed with BFL and treated with a tapering regimen of oral corticosteroids, starting at 40 mg/day. He was advised to cease pigeon keeping and avoid future avian exposure. Significant symptomatic improvement occurred within three months. Follow-up imaging over one year confirmed stable lung parenchyma with no disease progression or recurrence. This case underscores the importance of incorporating detailed occupational histories and utilizing advanced imaging modalities like HRCT when standard imaging is inconclusive. Early identification and intervention are crucial to prevent progression to chronic HP and irreversible fibrosis. Management should focus on reducing inflammation with corticosteroids and implementing strict environmental controls to prevent re-exposure. Long-term follow-up is essential to monitor for recurrence and maintain remission. Clinicians should remain vigilant for alternative diagnoses during pandemics to avoid diagnostic anchoring. This case contributes to the evidence supporting HRCT's critical role in early HP detection and emphasizes heightened clinical awareness of occupational lung diseases. A multidisciplinary approach involving pulmonologists, radiologists, and occupational medicine specialists is key to optimizing outcomes in HP and other ILDs.

PMID:39958101 | PMC:PMC11830419 | DOI:10.7759/cureus.77522

Biomed Pharmacother. 2025 Feb 15;184:117891. doi: 10.1016/j.biopha.2025.117891. Online ahead of print.

ABSTRACT

Cyclin-dependent kinase 8 (CDK8) plays a crucial role in the transforming growth factor beta (TGF-β) signaling pathway, which is critical to the pathology of idiopathic pulmonary fibrosis (IPF). CDK8 promotes the epithelial-mesenchymal transition (EMT) and excessive extracellular matrix (ECM) deposition, making it a promising target for IPF treatment. This study focused on optimizing F059-1017, a previously identified CDK8 inhibitor, to enhance its potency. Through integrated structure-based modifications, a series of compounds was synthesized, and their inhibitory effects on CDK8 were tested. Results indicated that substituting with cyclopentanone significantly improved the inhibitory activity, and compound 4j demonstrated the best potency (IC50 = 16 nM). Notably, compared to F059-1017, its potency increased 35-fold, and kinase profiling revealed that the compound was selective for CDK8. Compound 4j inhibited the TGF-β1-induced EMT, cell migration, and morphological changes in A549 cells at a concentration of 0.1 μM and inhibited ECM and EMT protein expressions. In addition, the compound blocked TGF-β1-induced transcriptional changes and inhibited Smad3 and RNA polymerase II phosphorylation. These results highlight the potential of the optimized CDK8 inhibitor as a prospective drug for IPF treatment.

PMID:39955852 | DOI:10.1016/j.biopha.2025.117891

Eur J Pharmacol. 2025 Feb 13:177381. doi: 10.1016/j.ejphar.2025.177381. Online ahead of print.

ABSTRACT

Bicyclol, a drug stemmed from the traditional Chinese medicine Schisandra chinensis, has been widely utilized in clinical practice due to its efficacy and safety to manage hepatopathy. Its diverse biological properties-including antiviral, anti-inflammatory, antifibrotic, immunomodulatory, antioxidative, antisteatotic, and antitumor effects-underscore its significant medicinal effects in versatile hepatic disorders, incorporating viral hepatitis, non-alcoholic fatty liver disease, hepatocellular carcinoma, acute hepatic failure, hepatic fibrosis as well as drug-induced liver injury. Furthermore, ongoing researches into the molecular mechanisms, biological activities and mode of actions concerning bicyclol have uncovered its potential therapeutic implications in other multiple diseases/conditions. Studies have indicated promising efficacy pertaining to bicyclol to treat idiopathic pulmonary fibrosis, acute lung injury, cerebral ischemia/reperfusion injury, renal dysfunction, renal cell carcinoma, and cardiovascular diseases. Accordingly, this narrative review article summarizes the current understanding of diverse biological activities and underpinning mechanisms of bicyclol across a range of diseases, as well as its pharmacokinetics, toxicity profile and shed light on future perspectives.

PMID:39954842 | DOI:10.1016/j.ejphar.2025.177381

Transl Res. 2025 Feb 12:S1931-5244(25)00023-4. doi: 10.1016/j.trsl.2025.02.002. Online ahead of print.

ABSTRACT

Mitochondrial dysfunction is closely associated with idiopathic pulmonary fibrosis (IPF). However, the causal association between mitochondria-related genes and IPF remains to be determined. We obtained gene expression, protein abundance, and methylation quantitative trait locus data for mitochondria-related genes from previous studies. Genome-wide association study data for patients with IPF were obtained from the FinnGen study. A two-sample Mendelian randomisation analysis was conducted to assess the association between mitochondria-related genes and IPF. Furthermore, we conducted validation of expression differences utilizing transcriptome data derived from the BLM-induced pulmonary fibrosis mouse model (n=15). Concurrently, multiphoton imaging was utilized to quantify collagen contents and structural assessment. The direction of causality was verified using the Steiger test, and colocalisation analysis was used to better validate causality. Single-cell data were used to explore the localisation and expression of positive genes across different cell types. The study identified significant associations between mitochondria-related genes and IPF, with POLG and NDUFB10 classified as Grade 1; LYRM4, NBR1, and ACSF3 as Grade 2; MCL1, GFER, MFN2, IVD, and SLC25A35 as Grade 3; and METAP1D and MTX1 as Grade 4. Single-cell analysis showed elevated expression of NBR1, MCL1, and MTX1 in pulmonary myofibroblasts of IPF. This study elucidated the causal effects of mitochondria-related genes on IPF, underscoring their significance in pathogenesis. These findings contribute to an improved understanding of the mechanisms underlying IPF, offering new potential therapeutic targets for interventions.

PMID:39952317 | DOI:10.1016/j.trsl.2025.02.002

Aging Cell. 2025 Feb 13:e14503. doi: 10.1111/acel.14503. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an age-associated disease characterized by the irreversible accumulation of excessive extracellular matrix components by activated myofibroblasts (aMYFs). Following bleomycin administration in young mice, fibrosis formation associated with efficient resolution takes place limiting the clinical relevance of this model for IPF. In this study, we used aged mice in combination with bleomycin administration to trigger enhanced fibrosis formation and delayed resolution as a more relevant model for IPF. Alveolosphere assays were carried out to compare the alveolar resident mesenchymal niche activity for AT2 stem cells in young versus old mice. Lineage tracing of the Acta2+ aMYFs in old mice exposed to bleomycin followed by scRNAseq of the lineage-traced cells isolated during fibrosis formation and resolution was performed to delineate the heterogeneity of aMYFs during fibrosis formation and their fate during resolution. Integration of previously published similar scRNAseq results using young mice was carried out. Our results show that alveolar resident mesenchymal cells from old mice display decreased supporting activity for AT2 stem cells. Our findings suggest that the cellular and molecular mechanisms underlying the aMYFs formation and differentiation towards the Lipofibroblast phenotype are mostly conserved between young and old mice. In addition to persistent fibrotic signaling in aMYF from old mice during resolution, we also identified differences linked to interleukin signaling in old versus young alveolar fibroblast populations before and during bleomycin injury. Importantly, our work confirms the relevance of a subcluster of aMYFs in old mice that is potentially relevant for future management of IPF.

PMID:39945330 | DOI:10.1111/acel.14503

Front Genet. 2025 Jan 29;15:1496462. doi: 10.3389/fgene.2024.1496462. eCollection 2024.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a rare but debilitating lung disease characterized by excessive fibrotic tissue accumulation, primarily affecting individuals over 50 years of age. Early diagnosis is challenging, and without intervention, the prognosis remains poor. Understanding the molecular mechanisms underlying IPF pathogenesis is crucial for identifying diagnostic markers and therapeutic targets.

METHODS: We analyzed transcriptomic data from lung tissues of IPF patients using two independent datasets. Differentially expressed genes (DEGs) were identified, and their functional roles were assessed through pathway enrichment and tissue-specific expression analysis. Protein-protein interaction (PPI) networks and co-expression modules were constructed to identify hub genes and their associations with disease severity. Machine learning approaches were applied to identify genes capable of differentiating IPF patients from healthy individuals. Regulatory signatures, including transcription factor and microRNA interactions, were also explored, alongside the identification of potential drug targets.

RESULTS: A total of 275 and 167 DEGs were identified across two datasets, with 67 DEGs common to both. These genes exhibited distinct expression patterns across tissues and were associated with pathways such as extracellular matrix organization, collagen fibril formation, and cell adhesion. Co-expression analysis revealed DEG modules correlated with varying IPF severity phenotypes. Machine learning analysis pinpointed a subset of genes with high discriminatory power between IPF and healthy individuals. PPI network analysis identified hub proteins involved in key biological processes, while functional enrichment reinforced their roles in extracellular matrix regulation. Regulatory analysis highlighted interactions with transcription factors and microRNAs, suggesting potential mechanisms driving IPF pathogenesis. Potential drug targets among the DEGs were also identified.

DISCUSSION: This study provides a comprehensive transcriptomic overview of IPF, uncovering DEGs, hub proteins, and regulatory signatures implicated in disease progression. Validation in independent datasets confirmed the relevance of these findings. The insights gained here lay the groundwork for developing diagnostic tools and novel therapeutic strategies for IPF.

PMID:39944354 | PMC:PMC11813903 | DOI:10.3389/fgene.2024.1496462

Expert Rev Respir Med. 2025 Feb 13. doi: 10.1080/17476348.2025.2467341. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) isa chronic, progressive lung disease characterized by distorted alveolar structureand reduced lung compliance, and impaired ventilation-perfusion. Small airwaydisease (SAD) is often termed a 'quietzone' due to its asymptomatic nature. Around 30-40% of IPF patients exhibit SAD,which is associated with worse prognosis, higher fibrosis and emphysema scores,and elevated mortality risk. We used PubMed and Google Scholar for literaturesearch.

AREAS COVERED: This review explores thepathophysiology of small airways in IPF, focusing on 1. risk factors, includingage, gender, smoking and occupational dust exposure, and ozone. 2. Diagnosticchallenges: SAD is difficult to detect through traditional spirometry or high-resolutioncomputed tomography imaging due to resolutionlimitations. 3. Early physiologicalchanges of small airways include airway wall thickening, lumen distortion, andreduced terminal bronchioles, preceding microscopic fibrosis, occurs in the earlyprocess of IPF. 4. Pathological mechanisms: The review examines the underlyingmechanisms driving small airway disease in IPF.

EXPERT OPINION: A comprehensive approach is essential to improve the understanding andmanagement of SAD in IPF. Priorities include identifying therapeutic targets,advanced imaging and functional assessments. Forced oscillation technique should be introduced for early detection for smallairway abnormalities in IPF.

PMID:39943815 | DOI:10.1080/17476348.2025.2467341

J Clin Med. 2025 Jan 23;14(3):731. doi: 10.3390/jcm14030731.

ABSTRACT

Background: Transbronchial lung cryobiopsy (TBLC) has a high incidence of adverse events. This study aimed to investigate the relationship between the occurrence of these events and the condition of the pathology samples or pathological diagnosis in TBLC. Methods: We studied 102 patients who underwent TBLC for the diagnosis of interstitial lung disease. We analyzed the association between the condition or diagnosis of pathology samples and the occurrence of TBLC-related adverse events, including hemorrhage, pneumothorax, and acute exacerbation of interstitial lung disease. Results: The adverse events occurred in 19 patients (18.6%), of which hemorrhage was the most common (14 patients, 13.7%). The patients who experienced adverse events, especially hemorrhage, were less likely to have successful sampling with TBLC and showed lower diagnostic confidence in the pathology results. The diagnostic confidence was level A in 50 cases (49.0%) and level C in 23 cases (22.6%). TBLC-related adverse events, including hemorrhage, were significantly more common in patients with lower pathological confidence levels. Conclusions: TBLC-related adverse events, particularly hemorrhage, can lead to fewer successful samples and lower levels of diagnostic confidence.

PMID:39941401 | DOI:10.3390/jcm14030731

J Clin Med. 2025 Jan 22;14(3):714. doi: 10.3390/jcm14030714.

ABSTRACT

Background: Over the last few years, a few imaging studies have performed conventional transthoracic echocardiography (TTE) implemented with speckle tracking echocardiography (STE) for the assessment of biventricular mechanics in patients with non-advanced idiopathic pulmonary fibrosis (IPF). This systematic review and meta-analysis aimed at evaluating the overall effect of mild-to-moderate IPF on the main indices of biventricular systolic function assessed by TTE and STE. Methods: All imaging studies assessing right ventricular (RV)-global longitudinal strain (GLS), left ventricular (LV)-GLS, tricuspid annular plane systolic excursion (TAPSE), and left ventricular ejection fraction (LVEF) in IPF patients vs. healthy controls, selected from PubMed, Scopus, and EMBASE databases, were included. Continuous data (RV-GLS, LV-GLS, TAPSE, and LVEF) were pooled as standardized mean differences (SMDs) comparing the IPF group with healthy controls. The SMD of RV-GLS was calculated using the random-effect model, whereas the SMDs of LV-GLS, TAPSE, and LVEF were calculated using the fixed-effect model. Results: The full texts of 6 studies with 255 IPF patients and 195 healthy controls were analyzed. Despite preserved TAPSE and LVEF, both RV-GLS and LV-GLS were significantly, although modestly, reduced in the IPF patients vs. the controls. The SMD was large (-1.01, 95% CI -1.47, -0.54, p < 0.001) for RV-GLS, medium (-0.62, 95% CI -0.82, -0.42, p < 0.001) for LV-GLS, small (-0.42, 95% CI -0.61, -0.23, p < 0.001) for TAPSE, and small and not statistically significant (-0.20, 95% CI -0.42, 0.03, p = 0.09) for LVEF assessment. Between-study heterogeneity was high for the studies assessing RV-GLS (I2 = 80.5%), low-to-moderate for those evaluating LV-GLS (I2 = 41.7%), and low for those measuring TAPSE (I2 = 16.4%) and LVEF (I2 = 7.63%). The Egger's test yielded a p-value of 0.60, 0.11, 0.31, and 0.68 for the RV-GLS, LV-GLS, TAPSE, and LVEF assessment, respectively, indicating no publication bias. On meta-regression analysis, none of the moderators was significantly associated with effect modification for RV-GLS (all p > 0.05). The sensitivity analysis supported the robustness of the results. Conclusions: RV-GLS impairment is an early marker of subclinical myocardial dysfunction in mild-to-moderate IPF. STE should be considered for implementation in clinical practice for early detection of RV dysfunction in IPF patients without advanced lung disease.

PMID:39941384 | DOI:10.3390/jcm14030714

Int J Mol Sci. 2025 Feb 6;26(3):1378. doi: 10.3390/ijms26031378.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) has been associated with mitochondrial dysfunction. We investigated whether mitochondrial DNA variants in peripheral blood leukocytes (PBLs), which affect proteins of the respiratory chain and mitochondrial function, could be associated with an increased risk and poor prognosis of IPF. From 2020 to 2022, we recruited 36 patients (age: 75.3 ± 8.5; female: 19%) with IPF, and 80 control subjects (age: 72.3 ± 9.0; female: 27%). The mitochondrial genome of peripheral blood leukocytes was determined using next-generation sequencing. During a 45-month follow-up, 10 (28%) patients with IPF remained stable and the other 26 (72%) progressed, with 12 (33%) mortalities. IPF patients had more non-synonymous (NS) variants (substitution/deletion/insertion) in mitochondrial COX3 gene (coding for subunit 3 of complex IV of the respiratory chain), and more mitochondrial tRNA variants located in the anticodon (AC) stem, AC loop, variable loop, T-arm, and T-loop of the tRNA clover-leaf structure in PBLs than the control group. The succumbed IPF patients were older, had lower initial diffusion capacity, and higher initial fibrosis score on high-resolution computerized tomography (HRCT) than the alive group. NS variants in mitochondrial COX3 gene and tRNA variants in PBLs were associated with shorter survival. Our study shows that (1) leukocyte mitochondrial COX3 NS variants are associated with risk and prognosis of IPF; (2) leukocyte mitochondrial tRNA variants located in the AC stem, AC loop, variable loop, T-arm, and T-loop of the tRNA clover-leaf structure are associated with risk, and the presence of tRNA variants is associated with poor prognosis of IPF.

PMID:39941146 | DOI:10.3390/ijms26031378