Int J Med Sci. 2025 Jun 12;22(12):2992-3006. doi: 10.7150/ijms.113226. eCollection 2025.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), a chronic progressive fibrosing interstitial lung disease with an unclear etiology, is characterized by progressive respiratory impairment and a median survival of 3-5 years. The pathophysiology associated with genetic factors in IPF remains largely unknown, despite the fact that both familial and sporadic IPF exhibit genetic susceptibility. In this review, we comprehensively examine genetic variations associated with the functional roles of mucin 5B (MUC5B), telomerase complex, surfactant proteins, cytokines, signaling pathways, and epigenetic mechanisms. A multifaceted perspective derived from genetic, epidemiological, and clinical studies demonstrates that genetic variations exert differential impacts on the development, progression, and prognosis of IPF. We advocate for the application of genetic knowledge to facilitate the refinement of diagnostic approaches, enhance the assessment of therapeutic strategies and prognostic outcomes, and underscore the significance of personalized therapy for IPF.

PMID:40657392 | PMC:PMC12244033 | DOI:10.7150/ijms.113226

Front Immunol. 2025 Jun 27;16:1583827. doi: 10.3389/fimmu.2025.1583827. eCollection 2025.

ABSTRACT

BACKGROUND: Neurological symptoms are commonly observed in patients with idiopathic pulmonary fibrosis (IPF). However, the underlying mechanisms remain unclear. Although exercise has been shown to improve pulmonary fibrosis and quality of life in IPF patients, its effects on neurological symptoms in this population are not well understood. Furthermore, a robust animal model linking IPF with comorbid neurological symptoms has not yet been fully developed.

METHODS: Twenty-eight male C57BL/6J mice were divided into four groups: control, bleomycin (BLM), control + exercise, and BLM + exercise. Mice were administered BLM or saline (7.5 mg/kg), and the exercise groups underwent 45 min of treadmill training per day for 28 days. Behavioral tests (open-field test, sucrose preference test, tail suspension test, and forced swimming test) were performed on days 29-33. Histological analysis assessed pulmonary fibrosis, and biomarkers brain-derived neurotrophic factor (BDNF) and c-Fos were detected. Bioinformatics identified genes altered in IPF, exercise, and depression, validated by Western blotting.

RESULTS: BLM induced pulmonary fibrosis and aggravated neurological symptoms. Exercise significantly alleviated these symptoms and reversed the expression of BDNF and c-Fos. Bioinformatics analysis identified 28 genes upregulated in IPF and depression and downregulated by exercise. The S100A12 gene showed reduced expression in both lung and brain tissues in the BLM group and increased expression after exercise. Kyoto Encyclopedia of Genes and Genomes analysis revealed enrichment in the Interleukin 17 (IL-17) and Nucleotide-binding Oligomerization Domain (NOD)-like receptor signaling pathways.

CONCLUSION: This study developed a mouse model and suggests that exercise may offer therapeutic benefits for both pulmonary and neurological symptoms in IPF. Shared molecular pathways may guide future therapies targeting both aspects.

PMID:40655156 | PMC:PMC12245693 | DOI:10.3389/fimmu.2025.1583827

Acta Pharm Sin B. 2025 Jun;15(6):3041-3058. doi: 10.1016/j.apsb.2025.04.017. Epub 2025 Apr 22.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), a chronic interstitial lung disease, is characterized by aberrant wound healing, excessive scarring and the formation of myofibroblastic foci. Although the role of alternative splicing (AS) in the pathogenesis of organ fibrosis has garnered increasing attention, its specific contribution to pulmonary fibrosis remains incompletely understood. In this study, we identified an up-regulation of serine/arginine-rich splicing factor 7 (SRSF7) in lung fibroblasts derived from IPF patients and a bleomycin (BLM)-induced mouse model, and further characterized its functional role in both human fetal lung fibroblasts and mice. We demonstrated that enhanced expression of Srsf7 in mice spontaneously induced alveolar collagen accumulation. Mechanistically, we investigated alternative splicing events and revealed that SRSF7 modulates the alternative splicing of pyruvate kinase (PKM), leading to metabolic dysregulation and fibroblast activation. In vivo studies showed that fibroblast-specific knockout of Srsf7 in conditional knockout mice conferred resistance to bleomycin-induced pulmonary fibrosis. Importantly, through drug screening, we identified lomitapide as a novel modulator of SRSF7, which effectively mitigated experimental pulmonary fibrosis. Collectively, our findings elucidate a molecular pathway by which SRSF7 drives fibroblast metabolic dysregulation and propose a potential therapeutic strategy for pulmonary fibrosis.

PMID:40654335 | PMC:PMC12254822 | DOI:10.1016/j.apsb.2025.04.017

Int J Mol Sci. 2025 Jul 7;26(13):6538. doi: 10.3390/ijms26136538.

ABSTRACT

Emerging evidence suggests a significant association between monocytes and the pathophysiology and prognosis of idiopathic pulmonary fibrosis (IPF). This review aims to systematically evaluate current knowledge regarding blood monocyte counts and their relationship with the etiology, progression, and prognosis of IPF. We conducted a systematic search in the PubMed database for articles published through 17 February 2025, using the MeSH terms "lung diseases, interstitial" and "monocytes," which yielded 314 results. After filtering for full-text articles in English (n = 242), we included only studies focusing on blood monocyte counts with clinical implications in IPF. Articles relating to other cell types or non-IPF lung diseases were excluded. Our systematic search identified 12 relevant articles. Monocytes play an essential role in regulating inflammatory responses and resolution across multiple diseases, with established but incompletely understood contributions to lung fibrosis development in IPF. Correlations have been demonstrated between elevated blood monocyte counts and the following: (1) the presence and progression of interstitial lung abnormalities, (2) the progression from an indeterminate usual interstitial pneumonia (UIP) pattern on CT scans to definitive IPF, and (3) worse lung function parameters, an increased risk of acute exacerbations, and reduced overall survival in IPF patients. Monocytes serve as critical orchestrators throughout IPF's natural history-from early interstitial changes to disease progression and acute exacerbations. Targeting monocyte recruitment pathways and reprogramming their differentiation represents a promising therapeutic approach, while circulating monocyte counts offer potential as accessible biomarkers for disease progression and treatment response. Future research should characterize stage-specific monocyte phenotypes to enable precision-targeted interventions.

PMID:40650314 | DOI:10.3390/ijms26136538

Int J Mol Sci. 2025 Jun 27;26(13):6202. doi: 10.3390/ijms26136202.

ABSTRACT

The uncontrolled fibrosis of lung tissue can lead to premature death in patients suffering from idiopathic pulmonary fibrosis (IPF), and it complicates the course of chronic obstructive pulmonary disease (COPD) and emphysema. It is also a risk factor for developing lung cancer. Antifibrotic drugs, such as nantedanib and pirfenidone, are able to slow down the progression of pulmonary fibrosis, but more effective treatment is still needed to reverse it. Studies on the pathogenesis of tissue fibrosis have demonstrated that integrins play a crucial role affecting the development of pulmonary fibrosis, for example, by activating transforming growth factor-β (TGF-β). Taking the above into consideration, targeting specific integrins could offer promising opportunities for managing fibroplastic changes in lung tissue. Integrins are a type of transmembrane molecule that mediate interactions between cells and extracellular matrix (ECM) molecules. This review discusses the role of integrins in the pathogeneses of respiratory diseases and carcinogenesis, as well as presents promising approaches to the drug therapy of pulmonary fibrosis of various etiologies based on integrin inhibition.

PMID:40649983 | DOI:10.3390/ijms26136202

Toxicology. 2025 Jul 9:154233. doi: 10.1016/j.tox.2025.154233. Online ahead of print.

ABSTRACT

Pulmonary fibrosis, a progressive and debilitating disease, presents a significant global health challenge. Even though often idiopathic, drug-induced fibrosis is increasing its incidence. Traditional chemical safety assessments, relying on apical endpoints from in-vivo models, are limited in capturing the early molecular events initiating fibrosis, consequently limiting the potential for early diagnosis and mechanism-driven treatment. This study employed a toxicogenomic approach on in-vitro MRC-5 fibroblasts, a crucial cell type involved in fibrosis, to dissect the initiating profibrotic mechanisms of Bleomycin (1, 1.5, 2 ug/mL), a profibrotic triggering stimulus, comparing it with TGFβ-1(5, 10, 15ng/mL), a known sustaining mediator of fibrosis over 24, 48, and 72hours. Our analysis reveals that while both agents alter matrix-related processes, their initiation mechanisms diverge. Specifically, TGFβ-1 directly induces myofibroblast transition, whereas Bleomycin potentially induces an indirect transition through the establishment of a senescence-associated secretory phenotype (SASP). By capturing the early SASP signature, we identified a critical driver of Bleomycin-induced fibroblast fibrosis, relevant to drug-induced fibrosis where antineoplastic agents are a major concern. This study underscores the critical importance of integrating mechanistic understanding into chemical safety assessment, thereby facilitating the development and implementation of safer, more sustainable chemical development.

PMID:40645554 | DOI:10.1016/j.tox.2025.154233

Int Immunopharmacol. 2025 Jul 10;162:115182. doi: 10.1016/j.intimp.2025.115182. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by excessive extracellular matrix (ECM) accumulation, fibroblast activation, and chronic inflammation. This study examined the antifibrotic effects of naltrexone (NTX), an opioid receptor antagonist, in a bleomycin (BLM)-induced pulmonary fibrosis model in Wistar rats. Daily administration of NTX significantly reduced alveolar wall thickening, collagen deposition, and histopathological injury scores. At higher doses, NTX markedly decreased levels of pro-inflammatory cytokines (TNF-α, IL-6, TGF-β), oxidative stress markers (MPO, NO), and key fibrotic markers including α-SMA and delta opioid receptor (DOR). Additionally, NTX restored antioxidant defenses (GSH, TAC) and enhanced GSK-3β phosphorylation, thereby modulating the Wnt/β-catenin and NF-κB signaling pathways. To further investigate the cellular mechanisms underlying NTX's antifibrotic activity, in vitro experiments were conducted using BLM-stimulated NIH-3 T3 fibroblasts. NTX inhibited the production of collagen type I and III, tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2), and matrix metalloproteinases (MMP-2 and MMP-9) in a dose- and time-dependent manner. This dual regulation of ECM synthesis and degradation suggests a more balanced therapeutic strategy compared to merely inhibiting collagen accumulation. Molecular docking analyses revealed strong interactions between NTX and key proteins involved in inflammatory and fibrotic signaling cascades. Notably, NTX at a dose of 20 mg/kg demonstrated antifibrotic efficacy comparable to that of pirfenidone. Collectively, these findings suggest that NTX exerts protective effects in pulmonary fibrosis by simultaneously targeting inflammation, oxidative stress, and ECM remodeling. Given its favorable tolerability and potential cost-effectiveness, NTX emerges as a promising candidate for IPF therapy. Further clinical investigations are warranted to evaluate its translational potential.

PMID:40644860 | DOI:10.1016/j.intimp.2025.115182

Tissue Barriers. 2025 Jul 11:2532160. doi: 10.1080/21688370.2025.2532160. Online ahead of print.

ABSTRACT

This review describes similarities between the biological actions of cell adhesion molecule antagonists and pan-growth factor receptor tyrosine kinase (GF-RTK) antagonists. In particular, the biological consequences of the interaction between the cell adhesion molecule, neural (N)-cadherin (CDH2) and the fibroblast GF-RTK (FGF-RTK) are discussed. Intercellular adhesion mediated by N-cadherin stimulates FGF-RTK activity triggering intracellular signaling pathways (e.g. PI3/Akt/mTOR pathway) that regulate various morphogenetic processes (e.g. apoptosis). Antagonists of either N-cadherin or GF-RTKs modulate these processes. N-cadherin antagonists can be regarded as a previously unappreciated class of FGF-RTK inhibitors. These antagonists, similar to GF-RTK antagonists should be capable of serving as therapeutics for treating a variety of fibrotic diseases and cancers.

PMID:40642775 | DOI:10.1080/21688370.2025.2532160

Front Mol Biosci. 2025 Jun 26;12:1596364. doi: 10.3389/fmolb.2025.1596364. eCollection 2025.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease that worsens over time, culminating in respiratory failure. Emerging evidence implicates dysregulated energy metabolism in driving fibroblast activation and extracellular matrix remodeling during IPF pathogenesis. To systematically investigate metabolic reprogramming mechanisms, we performed integrated bioinformatics analyses focusing on energy metabolism-related differentially expressed genes (EMRDEGs) and their regulatory networks in fibrotic remodeling.

METHODS: Differentially Expressed Genes (DEGs) were identified by accessing datasets GSE242063 and GSE110147 from the GEO database. Energy metabolism-related genes (EMRGs) were extracted from GeneCards, followed by Venn diagram analysis to obtain EMRDEGs. Subsequent analyses included functional enrichment (GO/KEGG), protein-protein interaction network, and mRNA-miRNA, mRNA-transcription factor interaction networks. Immune infiltration analyses, including the CIBERSORT algorithm, and single-sample gene set enrichment analysis (ssGSEA), were subsequently conducted.

RESULTS: We identified 12 EMRDEGs and eight hub genes (ACSL1, CEBPD, CFH, HMGCS1, IL6, SOCS3, TLR2, and UCP2). Regulatory network analysis revealed HMGCS1 as a novel IPF-associated gene interacting with PPARα signaling, while SOCS3 coordinated multiple hub genes (IL6, CEBPD, UCP2, and CFH) through FOXA1/2-mediated transcriptional regulation alongside JAK/STAT3 pathway suppression. Immune profiling demonstrated significant hub gene-immune cell correlations, particularly neutrophil-mediated differential gene expression and microenvironment remodeling.

CONCLUSION: The core EMRDEGs (HMGCS1 and SOCS3) and prioritized pathways (PPARα signaling, FOXA networks, JAK/STAT3 suppression) elucidate metabolic reprogramming mechanisms in fibrotic progression. These molecular signatures provide novel clinical biomarkers for IPF diagnosis.

PMID:40642530 | PMC:PMC12241802 | DOI:10.3389/fmolb.2025.1596364

Respirol Case Rep. 2025 Jul 9;13(7):e70270. doi: 10.1002/rcr2.70270. eCollection 2025 Jul.

ABSTRACT

Hypereosinophilic Syndrome (HES) represents a heterogeneous and complex group of disorders characterised by persistent blood and tissue eosinophilia, leading to progressive tissue damage and organ dysfunction. This spectrum includes both hematologic variants and non-hematologic forms, either secondary to identifiable causes or idiopathic in nature. In this article, we describe a rare clinical presentation of HES manifesting primarily with pulmonary involvement, diagnosed as Non-Specific Interstitial Pneumonia (NSIP). Remarkably, the interstitial lung disease showed near-complete reversibility following targeted inhibition of the IL-5 pathway with mepolizumab, highlighting the potential role of Th2-driven eosinophilic inflammation in the pathogenesis of certain forms of interstitial lung disease.

PMID:40641495 | PMC:PMC12241705 | DOI:10.1002/rcr2.70270

Future Cardiol. 2025 Jul 11:1-12. doi: 10.1080/14796678.2025.2529696. Online ahead of print.

ABSTRACT

Right ventricular (RV) function is the primary determinant of survival in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH). A "double hit" hypothesis suggests that RV suffers not only from pressure overload common to all PAH but also from direct insults related to the underlying systemic autoimmunity and inflammation. This likely drives distinct maladaptive remodeling (fibrosis, inflammation) and contributes to the poorer prognosis observed in CTD-PAH compared to idiopathic PAH (IPAH).Comprehensive, multi-modal RV assessment - integrating clinical evaluation, biomarkers, echocardiography, cardiac MRI, and right heart catheterization - is crucial for prognosis and monitoring therapy. RV size, function, and tissue characteristics are key indicators.Current management involves PAH-targeted therapies to reduce RV afterload, optimal CTD control, and supportive care. However, CTD-PAH often shows attenuated treatment responses and worse outcomes, emphasizing the need for therapies directly addressing RV maladaptation. Future research priorities include understanding specific RV injury mechanisms in CTD, refining assessment tools, and developing novel RV-directed strategies. Optimizing outcomes requires a deep understanding of RV pathobiology within the CTD context and integrated, multidisciplinary care.

PMID:40641351 | DOI:10.1080/14796678.2025.2529696

Orphanet J Rare Dis. 2025 Jul 10;20(1):354. doi: 10.1186/s13023-025-03876-0.

ABSTRACT

OBJECTIVE: Emerging evidence suggests a potential relationship between lipid metabolism and idiopathic pulmonary fibrosis (IPF). This study aimed to identify lipid-related genes implicated in IPF pathogenesis.

METHODS: Lipid-associated genes were retrieved from the GeneCards database and analyzed using unsupervised consensus clustering to classify IPF samples. Weighted gene co-expression network analysis (WGCNA) was performed on the identified clusters to determine core modules and hub genes associated with IPF. Machine learning algorithms were applied to these hub genes to construct diagnostic and prognostic models, which were validated across multiple datasets. Single-cell sequencing was used to investigate the distribution of potential pathogenic genes, and their functional roles were further validated through cellular experiments.

RESULTS: Two distinct clusters were identified, showing significant differences in lung function parameters and fibrosis-related gene expression. WGCNA revealed that the blue module was strongly associated with IPF and served as the core module. Genes from this module were used to construct diagnostic and prognostic models, which demonstrated strong predictive performance across multiple validation datasets. Single-cell sequencing revealed that KLF4 was highly expressed in lung epithelial cells. Functional assays indicated that knockdown of KLF4 did not affect the proliferation of human alveolar type II epithelial cells but significantly enhanced their migratory capacity, thereby promoting the fibrotic process.

CONCLUSION: This study successfully constructed lipid-related diagnostic and prognostic models for IPF and identified KLF4 as a potential causative gene. These findings provide a foundation for further exploration of lipid metabolism in IPF pathogenesis and potential therapeutic strategies targeting KLF4.

PMID:40640934 | DOI:10.1186/s13023-025-03876-0

Eur Respir J. 2025 Jul 10:2402250. doi: 10.1183/13993003.02250-2024. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is marked by progressive lung scarring with no existing cure, emphasizing the need for new therapeutic targets. Current evidence suggests that cyclic adenosine monophosphate (cAMP) mitigates lung fibroblast proliferation via the PKA pathway, but the impact of Epac1, a cAMP-activated protein, on IPF remains unexplored.

OBJECTIVE: To investigate the role of Epac1 in IPF progression.

METHODS: We examined lung samples from IPF patients and controls, and from a bleomycin-induced mouse model of pulmonary fibrosis (PF). Epac1's effects were analysed in knock-out mice and through modulation using viral vectors. The Epac1-specific small compound inhibitor AM-001 was evaluated in vitro using lung fibroblasts from patients with IPF, in vivo in bleomycin mice, and ex vivo in IPF precision cut lung slices.

RESULTS: Increased Epac1 expression was observed in lung tissues from IPF patients, fibrotic fibroblasts, and bleomycin-challenged mice. Genetic or pharmacological inhibition of Epac1 with AM-001 decreased proliferation in normal and IPF fibroblasts, and reduced expression of pro-fibrotic markers such as α-SMA, TGF-β/SMAD2/3, and IL-6/STAT3 pathways. Epac1-specific inhibition consistently protected against bleomycin-induced lung injury and fibrosis, suggesting a significant therapeutic potential. Global gene expression profiling indicated reduced pro-fibrotic gene signature and neddylation pathway components in Epac1-deficient fibroblasts and human-derived lung cells. Mechanistically, the protective effects may involve inhibiting the neddylation pathway and preventing NEDD8 activation, which in turn reduces the degradation of FoxO3a by NEDD8. Additionally, these effects may be enhanced while also limiting the proliferation of lung-infiltrating monocytes.

CONCLUSIONS: Our findings demonstrate that Epac1 regulates fibroblast activity in pulmonary fibrosis, and that targeting Epac1 with the pharmacological specific inhibitor AM-001 offers a promising therapeutic approach for treating IPF disease.

PMID:40639873 | DOI:10.1183/13993003.02250-2024

Clin Chim Acta. 2025 Jul 8:120473. doi: 10.1016/j.cca.2025.120473. Online ahead of print.

ABSTRACT

BACKGROUND: High-resolution CT and pulmonary function tests remain the standard for diagnosing fibrotic interstitial lung diseases (ILDs) butare limited by radiation exposure, access, and inter-observer variability. Blood-based biomarkers could enable earlier, less invasive diagnosis and monitoring. We therefore evaluated the diagnostic accuracy of biomarkers, specifically Krebs von den Lungen-6 (KL-6), surfactant protein A (SP-A), and surfactant protein D (SP-D), in distinguishing fibrotic ILDs from healthy individuals or non-fibrotic respiratory conditions.

METHODS: A systematic review and bivariate random-effects meta-analysis were conducted, comparing serum or bronchoalveolar lavage fluid levels of KL-6, SP-A, or SP-D against histopathology or high-resolution computed tomography (HRCT). Diagnostic accuracy was assessed using sensitivity, specificity, and heterogeneity (I2). Subgroup analyses examined disease subtypes, control groups, and biomarker cutoffs.

RESULTS: Nineteen studies involving 3,320 participants were included. KL-6 (16 studies, 3,006 participants) had a pooled sensitivity of 0.74 (95 % CI: 0.67-0.80) and specificity of 0.90 (95 % CI: 0.85-0.93). SP-D (11 studies, 1,167 participants) showed a sensitivity of 0.73 (95 % CI: 0.66-0.79) and specificity of 0.78 (95 % CI: 0.69-0.86). SP-A (five studies, 671 participants) had a sensitivity of 0.71 (95 % CI: 0.51-0.85) and specificity of 0.91 (95 % CI: 0.67-0.98). Subgroup analysis showed significantly reduced diagnostic performance in autoimmune-associated ILDs versus idiopathic interstitial pneumonia (e.g., KL-6 specificity 0.87 vs. 0.98; P = 0.015).

CONCLUSION: KL-6 and SP-A demonstrated high specificity and moderate sensitivity, supporting their use to rule in fibrotic ILDs. Diagnostic accuracy was lower in autoimmune interstitial lung diseases (ILDs), suggesting that tailored thresholds or combined testing may be necessary.

PMID:40639593 | DOI:10.1016/j.cca.2025.120473

Int Immunopharmacol. 2025 Jul 9;162:115169. doi: 10.1016/j.intimp.2025.115169. Online ahead of print.

ABSTRACT

Senescent alveolar epithelial cells (AEC) play a pivotal role in the progression of idiopathic pulmonary fibrosis (IPF), attracting increasing attention from researchers. Central to the pathogenesis of pulmonary fibrosis (PF) is the excessive deposition of extracellular matrix (ECM). However, there remains a significant gap in understanding how the ECM microenvironment influences senescence in type II alveolar epithelial cells (AEC II). This study investigates the activation of the integrin-β1/FAK/YAP signaling pathway and its role in inducing cellular senescence in both in vivo and in vitro models of bleomycin (BLM)-induced PF. We employed decellularized lung scaffolds (DLS) to replicate the natural ECM microenvironment, aiming to elucidate whether the fibrotic ECM promotes AEC II senescence through the integrin-β1/FAK/YAP pathway. Notably, our findings indicate that exogenous integrin-β1 does not induce AEC II senescence. This suggests that the fibrotic ECM microenvironment regulates AEC II senescence via the integrin-β1/FAK/YAP pathway independently of exogenous integrin-β1. Therefore, targeting alterations in the fibrotic ECM microenvironment may represent a promising therapeutic strategy for IPF by modulating AEC II senescence.

PMID:40639050 | DOI:10.1016/j.intimp.2025.115169

Expert Rev Respir Med. 2025 Jul 10. doi: 10.1080/17476348.2025.2528947. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by relentless parenchymal scarring, deteriorating pulmonary function, and unpredictable exacerbations. The prognosis remains poor, despite antifibrotic and other therapies. Patients with IPF experience a high symptom burden, frequent hospitalizations, and uncertainty regarding disease progression. Advance care planning (ACP), the process of defining patients' preferences for medical care, is inconsistently implemented in IPF care. This often leads to end-of-life care unaligned with the patient's wishes and increased distress amongst patients and their care partners.

AREAS COVERED: In this perspective, we argue for the early and routine integration of ACP into IPF management. We review the multifaceted patient-, provider-, and system-level barriers to ACP and propose actionable strategies to normalize, document, and operationalize patient-centered ACP across the IPF disease trajectory. We highlight the critical need for an interdisciplinary team to best address ACP.

EXPERT OPINION: While IPF research has resulted in huge progress in the understanding of disease pathobiology and the expansion of treatment options, perhaps the most patient-centered portion of care remains under-studied. We must prioritize research to better understand an interdisciplinary system of iterative ACP that gives IPF patients a clear voice until the last moment of life.

PMID:40638442 | DOI:10.1080/17476348.2025.2528947

Naunyn Schmiedebergs Arch Pharmacol. 2025 Jul 10. doi: 10.1007/s00210-025-04410-6. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an irreversible and progressive interstitial lung disease that results from excessive tissue repair. Production of excessive extracellular matrix (ECM) by myofibroblasts has been known as an important pathological feature in IPF. Connective tissue growth factor (CTGF) is a secreted matricellular protein modulating myofibroblast activation and ECM deposition, leading to fibrosis and tissue remodeling. Protocatechuic acid is extensively distributed in many edible nuts, vegetables, and fruits and is readily absorbed by both animals and humans. Numerous biological actions of protocatechuic acid (PCA) have been observed, including antibacterial, antidiabetic, antioxidant, and anti-inflammatory characteristics. The purpose of this study is to investigate the protective effect of PCA on bleomycin-induced pulmonary fibrosis in rats. The pathological changes of the lung and levels of malondialdehyde (MDA) and glutathione (GSH) were measured. Our results revealed that PCA decreased the oxidative production of lipid MDA and increased GSH content. Moreover, PCA suppressed the expression of inflammatory biomarkers transforming growth factor β (TGF-β) and tumor necrosis factor α (TNF-α), as well as decreased collagen deposition and ECM markers alpha-smooth muscle actin (α-SMA), matrix metalloproteinase-2 (MMP-2), and metallopeptidase inhibitor 1 (TIMP-1). PCA has an anti-fibrotic effect against pulmonary fibrosis by downregulation of the CTGF/NOX4/ET-1 gene expression. Also, PCA treatment ameliorated BLM-induced lung damage by improving alveolar sac structure, reducing inflammatory cell infiltration, and preserving bronchiolar epithelial integrity, suggesting that PCA may serve as a potential treatment option for PF.

PMID:40637744 | DOI:10.1007/s00210-025-04410-6

Clin Respir J. 2025 Jul;19(7):e70111. doi: 10.1111/crj.70111.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) leads to irreversible scarring of lung tissue, resulting in deteriorating respiratory function, particularly in older adults. We aimed to explore the causative link between hypothyroidism and IPF, particularly focusing on immune cell phenotypes as mediating factors.

METHODS: A two-sample Mendelian randomization (MR) approach was utilized to investigate the influence of hypothyroidism on IPF and the role of 731 distinct immune cell phenotypes as mediators. The mediating effects were quantified using the coefficient product method. Various sensitivity analyses, including Cochran's Q test for heterogeneity, MR-Egger for pleiotropy, and the "leave-one-out" method, were conducted to verify the robustness of single-nucleotide polymorphism-derived casual estimates. Statistical analyses were carried out using the R software (Version 4.3.1).

RESULTS: Hypothyroidism was significantly associated with increased IPF risk (odds ratio [OR] = 1.13, 95% confidence interval [CI] = 1.06-1.21, p = 1.34 × 10-4). Of the 36 immune cell phenotypes associated with IPF, those related to the mean fluorescence intensity of B cells were the most prevalent. Mediation analysis showed that CD19 on IgD- CD27- accounted for approximately 3.68% of the effect of hypothyroidism on IPF, whereas herpesvirus entry mediator (HVEM) on T cells accounted for approximately 3.83% of this effect.

CONCLUSION: We identified a marked association between hypothyroidism and IPF. Specific immune cell phenotypes may partially mediate this relationship, although the observed effect sizes were modest. Further research is needed to validate these results in diverse populations and larger clinical trials.

PMID:40635577 | DOI:10.1111/crj.70111

Korean J Intern Med. 2025 Jul;40(4):634-644. doi: 10.3904/kjim.2024.388. Epub 2025 Jul 1.

ABSTRACT

BACKGROUND/AIMS: The impact of coronavirus disease 2019 (COVID-19) on severe exacerbation and mortality in interstitial lung disease (ILD) is unclear. In this study, we evaluate the risk of severe exacerbation and mortality in individuals with ILD following COVID-19.

METHODS: Using the Korean National Health Insurance claim-based database, we compared the incidence and risk of severe exacerbation and mortality in individuals with ILD who survived at least one month after COVID-19 (COVID-19 cohort, n = 359) and 1:3 age, sex, and body mass index-matched individuals with ILD who did not have COVID-19 (controls, n = 1,077) between October 8, 2020, and August 30, 2021.

RESULTS: During a mean follow-up of 7.4 months, the COVID-19 cohort had a higher risk of severe exacerbation compared to controls (aHR 2.26, 95% CI 1.38-3.69). During a mean follow-up of 19.6 months, the COVID-19 cohort had a higher risk of death (aHR 2.79, 95% CI 1.63-4.79) compared to controls. When considering COVID-19 severity, the severe COVID-19 group had a higher risk of severe exacerbation and death compared to controls, while the non-severe COVID-19 group did not show increased risk of severe exacerbation or death. In analyses based on ILD subtype, individuals with idiopathic pulmonary fibrosis in the COVID-19 cohort had the highest risk of severe exacerbation and death.

CONCLUSION: Previous severe COVID-19 was associated with worse clinical outcomes in individuals with ILD, especially in patients with idiopathic pulmonary fibrosis.

PMID:40635490 | DOI:10.3904/kjim.2024.388

Intern Med. 2025 Jul 10. doi: 10.2169/internalmedicine.5537-25. Online ahead of print.

ABSTRACT

Established fibrosis in pulmonary sarcoidosis is typically not progressive. However, progressive fibrosis similar to interstitial pneumonia occasionally occurs. We herein report a 49-year-old woman who was histologically diagnosed with sarcoidosis. She also had honeycomb-like manifestations in the lower lobes that resembled idiopathic pulmonary fibrosis on computed tomography, whereas pathological findings of a surgical lung biopsy suggested interstitial lung disease associated with rheumatoid arthritis. However, the patient did not develop clinical rheumatoid arthritis even after 17 years of follow-up. Notably, she showed progressive fibrosis and was treated with anti-fibrotic therapy. It is thus important to recognize progressive fibrosis in pulmonary sarcoidosis, although it is rare.

PMID:40634093 | DOI:10.2169/internalmedicine.5537-25