Tuberc Respir Dis (Seoul). 2025 Jan 6. doi: 10.4046/trd.2024.0168. Online ahead of print.

ABSTRACT

Idiopathic nonspecific interstitial pneumonia (iNSIP) is recognized as a distinct entity among various types of idiopathic interstitial pneumonias (IIP). It is identified histologically by the nonspecific interstitial pneumonia (NSIP) pattern. A diagnosis of iNSIP is feasible once secondary causes or underlying diseases are ruled out. Usually presenting with respiratory symptoms such as shortness of breath and cough, iNSIP has a subacute or chronic course. It predominantly affects females aged 50 to 60 years who are non-smokers. Key imaging findings on chest high-resolution computed tomography (HRCT) include bilateral reticular opacities in lower lungs, traction bronchiectasis, reduced lung volumes and, ground-glass opacities. Abnormalities are typically diffuse across both lungs with subpleural distributions. Treatment often involves systemic steroids, either alone or in combination with other immunosuppressants, although evidence supporting effectiveness of these treatments is limited. Prognosis is generally more favorable for iNSIP than for idiopathic pulmonary fibrosis (IPF), with many studies reporting a 5-year survival rate above 70%. Antifibrotic agents should be considered in a condition, , termed progressive pulmonary fibrosis (PPF), where pulmonary fibrosis progressively worsens.

PMID:39761948 | DOI:10.4046/trd.2024.0168

Front Cell Infect Microbiol. 2024 Dec 20;14:1479801. doi: 10.3389/fcimb.2024.1479801. eCollection 2024.

ABSTRACT

Interstitial lung disease (ILD) is characterized by chronic inflammation and scarring of the lungs, of which idiopathic pulmonary fibrosis (IPF) is the most devastating pathologic form. Idiopathic pulmonary fibrosis pathogenesis leads to loss of lung function and eventual death in 50% of patients, making it the leading cause of ILD-associated mortality worldwide. Persistent and subclinical microbial infections are implicated in the acute exacerbation of chronic lung diseases. However, while epidemiological studies have highlighted pollutants, gastric aspirate, and microbial infections as major causes for the progression and exacerbation of IPF, the role of persistent microbial infections in the pathogenesis of IPF remains unclear. In this review, we have focused on the role of persistent microbial infections, including viral, bacterial, and fungal infections, and their mechanisms of action in the pathogenesis of IPF. In particular, the mechanisms and pathogenesis of the Gram-negative bacteria Non-typeable Haemophilus influenzae (NTHi) in ILDs are discussed, along with growing evidence of its role in IPF, given its unique ability to establish persistent intracellular infections by leveraging its non-capsulated nature to evade host defenses. While antibiotic treatments are presumably beneficial to target the extracellular, interstitial, and systemic burden of pathogens, their effects are significantly reduced in combating pathogens that reside in the intracellular compartments. The review also includes recent clinical trials, which center on combinatorial treatments involving antimicrobials and immunosuppressants, along with antifibrotic drugs that help mitigate disease progression in IPF patients. Finally, future directions focus on mRNA-based therapeutics, given their demonstrated effectiveness across a wide range of clinical applications and feasibility in targeting intracellular pathogens.

PMID:39760094 | PMC:PMC11695292 | DOI:10.3389/fcimb.2024.1479801

Turk J Biol. 2024 Oct 23;48(6):379-389. doi: 10.55730/1300-0152.2713. eCollection 2024.

ABSTRACT

BACKGROUND/AIM: No specific pharmacological treatment regimen for idiopathic pulmonary fibrosis (IPF) exists. Therefore, new antiinflammatory therapeutic strategies are needed. Cannabinoids (CBs), known for their inflammation-modulating and antifibrotic effects, may be potential medication candidates for treating IPF. We aim to evaluate the inflammation-modulating and antifibrotic effects of CB receptor (CBR) agonists and antagonists in lipopolysaccharide-stimulated normal human lung fibroblast, epithelial cells, IPF fibroblast cells, and monocytes.

MATERIALS AND METHODS: We detected CBRs in normal human lung fibroblasts (LL24) and IPF fibroblast cells (LL29), epithelial cells (A549) and monocytes (THP-1) by flow cytometry. We determined TGF-β1, IL-8, and TNF-α inflammatory cytokines in the LL24, LL29, A549, and THP-1 cell culture supernatants on days 1 and 5 by ELISA. We evaluated the cell viability in LL24, LL29, and A549 cells on days 1, 3, and 5 spectrophotometrically and detected collagen Type I (ColI) production in the LL24 and LL29 cell culture supernatants on days 1, 3, and 5 by ELISA.

RESULTS: LL24, LL29, A549, and THP-1 cells exhibited CB1 (CB1R) and CB2 (CB2R) receptors. CB1R and CB2R agonists WIN55,212-2 and JWH015 inhibited fibroblastic and epithelial cell proliferation on day 5. TGF-β1 and TNF-α release increased, while IL-8 release decreased in LL24, LL29, A549, and THP-1 cells in response to the administration of WIN55,212-2 and JWH015 at a 10-2 mM concentration. CB1R and CB2R antagonists AM251 and AM630 did not block agonistic responses, suggesting a nonclassical CBR-mediated pathway. CB2R agonist JWH015 decreased ColI expression in IPF lung fibroblasts LL29 on day 3.

CONCLUSION: These results suggest that CB signaling regulates the progression of pulmonary inflammation and fibrosis via CBR activation. This may offer a potential pharmacological tool for developing antifibrosis therapies.

PMID:39758842 | PMC:PMC11698192 | DOI:10.55730/1300-0152.2713

Health Qual Life Outcomes. 2025 Jan 5;23(1):3. doi: 10.1186/s12955-024-02326-y.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is associated with high mortality, heavy economic burden, limited treatment options and poor prognosis, and seriously affects the health-related quality of life (HRQoL) and life expectancy of patients. This systematic review and meta-analysis of HRQoL and health state utility value (HSUV) in IPF patients and the instruments used in this assessment aimed to provide information sources and data support for the future research on IPF HRQoL and HSUV.

METHODS: We searched the PubMed, EMBASE, Web of Science and Cochrane Library databases for studies reporting the HRQoL or HSUV of IPF patients, with the retrieval time from the establishment of each database to April 2024. After two researchers independently screened the literature, extracted the data, and evaluated the risk of bias in the included studies, pooled analysis was performed on the measurement tools adopted in more than two studies. Subgroup analysis was employed to explore the source of heterogeneity, and sensitivity analysis was used to assess the robustness of the results. Funnel-plot directed evaluation combined with Egger's test quantitative evaluation was conducted to detect publication bias.

RESULTS: Sixty-nine studies were ultimately included, covering eighteen measurement tools. The literature quality was generally excellent. The St. George's Respiratory Questionnaire (SGRQ), EuroQoL Five Dimensions Questionnaire (EQ-5D), Short Form-36 (SF-36) and the King's Brief Interstitial Lung Disease (KBILD) were the most common instruments, among which the EQ-5D included the HSUV and the visual analog scale (VAS). The results of the meta-analysis revealed that the pooled SGRQ total score was 45.28 (95% confidence interval [CI] 41.10-49.47), the mean EQ-5D utility score was 0.75 (95% CI: 0.72-0.79), the total EQ-5D VAS score was 66.88 (95% CI: 63.75-70.01), and the pooled SF-36 physical component summary (PCS) and mental component summary (MCS) score were 36.70 (95% CI: 32.98-40.41) and 48.99 (95% CI: 47.44-50.55), respectively. The total KBILD score was 58.31 (95% CI: 55.43-61.19), the IPF specific version of the SGRQ (SGRQ-I) was 40.38 (95% CI: 28.81-51.96) and the Leicester Cough Questionnaire (LCQ) score was 16.09 (95% CI: 15.45-16.74). The pooled result of the University of California San Diego Shortness of Breath Questionnaire (USCD-SOBQ) was 45.05 (95% CI: 41.56-48.55). The results of other instruments, such as the tool to assess quality of life in IPF (ATAQ-IPF), the World Health Organization Quality of Life assessment 100 (WHOQoL-100) and the 12-item short-form health survey (SF-12) were similar to those of the above measurement tools. Regretfully, subgroup analyses did not identify the source of heterogeneity, but sensitivity analyses demonstrated robustness of our results. Except for the SGRQ total, our results showed little possibility of publication bias.

CONCLUSIONS: HRQoL in IPF patients is generally poor, and all domains are severely affected. With the aggravation of disease, HRQoL and HSUV shows a relatively downward trend, and income level is also an important factor affecting HRQoL and HSUV. At present, the published studies on IPF HRQoL and HSUV have applied many measurement tools with high interstudy heterogeneity, and future research on the optimal disease measurement tools should be strengthened. Our study provides high-quality comprehensive evidence for IPF HRQoL and HSUV, which can be used to guide clinical and economic evaluation in the future.

PMID:39757157 | DOI:10.1186/s12955-024-02326-y

Zhonghua Jie He He Hu Xi Za Zhi. 2025 Jan 12;48(1):66-71. doi: 10.3760/cma.j.cn112147-20241007-00580.

ABSTRACT

The notable advances on interstitial lung disease (ILD) published in Chinese and international authoritative journals from October 2023 to September 2024 were systematically reviewed in this annual review. Advances on pathogenesis, diagnosis, treatment, global and/or Chinese comments and guidelines of idiopathic pulmonary fibrosis, connective tissue disease-associated ILD and sarcoidosis were reviewed in detail in our paper.

PMID:39757099 | DOI:10.3760/cma.j.cn112147-20241007-00580

Biol Pharm Bull. 2024;47(12):2165-2172. doi: 10.1248/bpb.b24-00534.

ABSTRACT

Idiopathic pulmonary fibrosis (PF) is an irreversible and chronic inflammatory condition with limited therapeutic options and a high mortality rate. We aimed to determine the possible role and mechanisms of wogonin (WGN) on PF. A rat model of PF was established with intratracheally administrated with bleomycin (BLM), followed by intravenously injecting with WGN and weekly body weight measurements for four weeks. Hematoxylin-eosin (H&E) and Masson's trichrome staining were implemented for histopathological analysis. In addition, the levels of fibrotic proteins and indicators of the mitogen-activated protein kinase (MAPK) pathway were assessed with Western blot. RT-quantitative (q)PCR experiment was conducted to investigate the fibrotic proteins' mRNA expression. Ultimately, the concentrations of glutathione peroxidase (GSH-PX), malonaldehyde (MDA), and superoxide dismutase (SOD) were ascertained with appropriate kits. The results showed that WGN administration significantly reversed BLM-induced body weight reduction, alleviated pathological fibrosis, and reduced the Ashcroft score and the lung wet-to-dry weight ratio. Additionally, WGN suppressed the rise of fibrotic protein levels in BLM-treated rat's lung tissues. Furthermore, WGN attenuated BLM-stimulated oxidative stress, as evidenced by the increased GSH-PX and SOD levels and decreased MDA levels in vivo. Finally, wogonin supplements significantly lowered the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK phosphorylation levels in the BLM-treated rat's lung tissues. In conclusion, our study proved that PF induced by BLM administration can be mitigated by WGN treatment via suppressing the MAPK pathway, indicating that WGN is a candidate therapeutic agent for managing PF.

PMID:39756931 | DOI:10.1248/bpb.b24-00534

Respir Med. 2025 Jan 2:107939. doi: 10.1016/j.rmed.2025.107939. Online ahead of print.

ABSTRACT

INTRODUCTION: Ca2+ signaling in fibroblasts would be one of the important mediators of lung fibrosis. This study investigated the relationship between calcium channel blocker usage and the risk of developing interstitial lung disease and idiopathic pulmonary fibrosis.

MATERIAL AND METHODS: This cohort study used data from the Korean National Health Screening Cohort spanned from January 1, 2004, to December 31, 2015. The study included 394,142 participants. CCB usage, as a time-dependent variable assessed every two years, was categorized by medication status (ever-users and never-users) and further divided into five groups based on cumulative defined daily dose: <182.5, 182.5-365.0, 365.0-547.5, and ≥547.5. Incidence rates of ILD and IPF among CCB users compared to never-users, analyzed using time-dependent Cox regression models.

RESULTS: The incidence rates were 27.7 per 100,000 person-years for ILD and 15.0 per 100,000 person-years for IPF among never-users, compared to 19.5 per 100,000 person-years for ILD and 13.9 per 100,000 person-years for IPF among ever-users. The adjusted hazard ratios (aHRs) were 0.68 [95% confidence interval (CI), 0.55-0.83] for ILD and 0.69 (95% CI, 0.54-0.88) for IPF. Increasing categories of CCB usage were significantly associated with a lower risk of ILD [aHRs: 1.23 (95% CI, 0.97-1.56), 1.20 (0.85-1.71), 0.49 (0.30-0.81), and 0.27(0.19-0.39)] and IPF [aHRs: 1.21 (95% confidence interval, 0.89-1.64), 1.45 (0.96-2.20), 0.83 (0.52-1.33), and 0.25 (0.16-0.38)], compared to never-users.

CONCLUSIONS: This study found that individuals using CCBs had a significantly lower risk of interstitial lung disease and idiopathic pulmonary fibrosis compared to never-users in a dose-response manner.

PMID:39755283 | DOI:10.1016/j.rmed.2025.107939

Sci Rep. 2025 Jan 3;15(1):610. doi: 10.1038/s41598-024-84820-3.

ABSTRACT

Interstitial lung disease (ILD) is known to be a major complication of systemic sclerosis (SSc) and a leading cause of death in SSc patients. As the most common type of ILD, the pathogenesis of idiopathic pulmonary fibrosis (IPF) has not been fully elucidated. In this study, weighted correlation network analysis (WGCNA), protein‒protein interaction, Kaplan-Meier curve, univariate Cox analysis and machine learning methods were used on datasets from the Gene Expression Omnibus database. CCL2 was identified as a common characteristic gene of IPF and SSc. The genes associated with CCL2 expression in both diseases were enriched mainly in chemokine-related pathways and lipid metabolism-related pathways according to Gene Set Enrichment Analysis. Single-cell RNA sequencing (sc-RNAseq) revealed a significant difference in CCL2 expression in alveolar epithelial type 1/2 cells, mast cells, ciliated cells, club cells, fibroblasts, M1/M2 macrophages, monocytes and plasma cells between IPF patients and healthy donors. Statistical analyses revealed that CCL2 was negatively correlated with lung function in IPF patients and decreased after mycophenolate mofetil (MMF) treatment in SSc patients. Finally, we identified CCL2 as a common biomarker from IPF and SSc, revealing the common mechanism of these two diseases and providing clues for the study of the treatment and mechanism of these two diseases.

PMID:39753882 | DOI:10.1038/s41598-024-84820-3

EBioMedicine. 2025 Jan 2;112:105538. doi: 10.1016/j.ebiom.2024.105538. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia with restrictive ventilation. Recently, the structural and functional defects of small airways have received attention in the early pathogenesis of IPF. This study aimed to elucidate the characteristics of small airway epithelial dysfunction in patients with IPF and explore novel therapeutic interventions to impede IPF progression by targeting the dysfunctional small airways.

METHODS: Airway trees spanning the proximal-distal axis were harvested from control lungs and explanted lungs with end-stage IPF undergoing transplant. Qualified basal cells (BCs, p63/Krt5/ITGA6/NGFR) were expanded, and their cellular functions, feasibility, safety and efficacy for transplantation therapy in IPF were validated with experiments in vitro and mouse model. Single-cell RNA-sequencing was employed to elucidate the underlying mechanisms governing the BCs based therapy. Based upon these evidences, three patients with advanced IPF and small airway dysfunction received autologous-BCs transplantation. Post-transplantation assessments included lung function, exercise capacity and high resolution computed tomography (HRCT) scans were analyzed to quantify the clinical benefits conferred by the BCs transplantation.

FINDINGS: An overall landscape of senescent phenotype in airway epithelial cells and airway stem/progenitor cells along the proximal-distal axis of the airway tree in IPF were outlined. In contrast to the cells situated in distal airways, BCs located in small bronchi in IPF displayed a non-senescent phenotype, with comparable proliferative, differentiative capabilities, and similar transcriptomic profiles to normal controls. In a mouse model of pulmonary fibrosis, BCs exhibited promising protective efficacy and safety for transplantation therapy. Autologous BCs transplantation in three advanced IPF patients with small airway dysfunction yielded significant clinical improvements in pulmonary function, particularly evidence in lung volume and small airway function.

INTERPRETATION: Epithelia of small bronchi in IPF contain functional and expandable basal stem cells, which exert therapeutic benefits via bronchoscopic implantation. Our findings offer a potential for IPF treatment by targeting small airways.

FUNDING: National Natural Science Foundation of China (82430001, 81930001, and 81900059), Shanghai Shenkang Hospital Development Center (SHDC2020CR3063B), Department of Science and Technology of Shandong Province (2024HWYQ-058).

PMID:39753035 | DOI:10.1016/j.ebiom.2024.105538

Lung. 2025 Jan 3;203(1):16. doi: 10.1007/s00408-024-00758-3.

ABSTRACT

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disorder characterized by dry cough, fatigue, and exacerbated dyspnea. The prognosis of IPF is notably unfavorable, becoming extremely poor when the disease advances acutely. Effective therapeutic intervention is essential to mitigate disease progression; hence, early diagnosis and treatment are paramount. When high-resolution computed tomography (HRCT) reveals usual interstitial pneumonia (UIP), a diagnosis of IPF can be established. However, when HRCT fails to conclusively confirm IPF, the diagnostic pathway becomes intricate and necessitates a multidisciplinary approach involving clinicians, radiologists, and pathologists. Consequently, the objective of this study was to investigate new diagnostic approaches through bronchoalveolar lavage (BAL) analysis.

METHODS: BAL is a commonly utilized diagnostic tool for interstitial lung diseases. We review the application of bronchoalveolar lavage (BALF) in idiopathic pulmonary fibrotic disease, emphasizing that the cellular and solute composition of the lower respiratory tract offers valuable insights.

RESULTS: This review delineates the advancements in diagnosing IPF cases that remain indeterminate via HRCT, leveraging BALF analysis. In contrast to surgical lung biopsy, BAL is minimally invasive and offers potential diagnostic utility through the identification of specific BALF biomarkers.

CONCLUSION: Augment the clinical diagnostic armamentarium for IPF, particularly in scenarios where HRCT findings are inconclusive.

PMID:39751999 | DOI:10.1007/s00408-024-00758-3

Eur J Hum Genet. 2025 Jan 2. doi: 10.1038/s41431-024-01772-y. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive, late-onset disease marked by lung scarring and irreversible loss of lung function. Genetic factors significantly contribute to both familial and sporadic cases, yet there are scarce evidence-based studies highlighting the benefits of integrating genetics into the management of IPF patients. In this study, we performed whole-exome sequencing and telomere length (TL) measurements on IPF patients and their relatives. We then identified rare deleterious variants using three virtual gene panels encompassing IPF or TL genes with varying levels of evidence supporting their potential relationship with the disease. We identified 10 candidate variants in well-established disease genes, and these results were validated using two automatic prioritization tools (Exomiser and Franklin). Pathogenic variants were found in two telomere-related genes (RTEL1 and NAF1), and both were associated with severe TL shortening. Our results suggest that this tiered virtual panel strategy is sufficiently robust and serves as a viable solution in clinical practice. It generates valuable genetic data which can be interpreted and validated with the expertise of a multidisciplinary team.

PMID:39748130 | DOI:10.1038/s41431-024-01772-y

Sci Rep. 2025 Jan 2;15(1):143. doi: 10.1038/s41598-024-83787-5.

ABSTRACT

The study investigates the prognostic value of [18F]fluorodeoxyglucose (FDG) PET/CT in patients with idiopathic pulmonary fibrosis (IPF). A total of 346 IPF patients who underwent FDG PET/CT between 2007 and 2020 were analyzed. Pulmonary FDG uptake [target to background ratio (TBR)] was binarized by optimal cut-off value based on survival analysis. The PET-modified GAP (Gender, Age, lung Physiology) score-based staging system included a category for FDG uptake, and its prognostic prediction was compared with the conventional GAP score. Survival analyses were conducted for progression-free, overall, and disease-specific survival. The low FDG uptake group showed a significantly better prognosis than the high uptake group, with cut-off values of 7.26 (p < 0.001), 7.15 (p = 0.04), and 9.23 (p = 0.01) for progression-free, overall, and disease-specific survival, respectively. The PET-modified GAP score-based staging system differentiated better than the conventional GAP system, particularly between stages I and II in overall survival (p = 0.001 vs. p = 0.08). For disease-specific survival, the PET-modified model showed better performance than the original GAP model (p = 0.06 vs. p = 0.33), though neither was statistically significant. Pulmonary FDG uptake in PET/CT is a reliable biomarker for predicting the prognosis of IPF patients and enhances the conventional GAP staging system's predictive value for patient survival.

PMID:39747497 | DOI:10.1038/s41598-024-83787-5

Clin Exp Pharmacol Physiol. 2025 Feb;52(2):e70017. doi: 10.1111/1440-1681.70017.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease characterised by irreversible lung structure and function. Phillygenin (PHI) is a lignan extracted from Forsythiae fructus with the activities of anti-inflammatory and antioxidant. This study aimed to explore the protective effect of PHI on IPF. The mouse model of IPF was established by bleomycin (BLM), and then treated with PHI. After 15 days of administration, the lung index was calculated. H&E staining, Masson staining and immunohistochemical methods were used to detect the effect of PHI on pulmonary fibrosis. MDA and SOD were tested to evaluate the effect of PHI on lung tissue oxidative stress. Western blot was used to detect the effect of PHI on the expressions of α-SMA, p-smad2, TGF- β1, Nrf2, HO-1 and NQO-1. Network pharmacology was used to identify the key signalling pathways for PHI to improve IPF, and Western blot was used to validate the result. The results showed that PHI prevented mice from BLM-induced IPF, manifested by reducing lung index, improving lung tissue pathological damage, inhibiting collagen deposition and expression of fibrosis markers including α-SMA, collagen1, p-smad2 and TGF-β1. PHI inhibited oxidative stress by upregulating the expressions of Nrf2, HO-1 and NQO-1. Network pharmacology revealed that PI3K-Akt-mTOR signalling pathway was the underlying target of PHI for IPF. Molecular docking indicated strong binding of PHI with PIK3CA, AKT1 and RELA. Western blot validated that PHI downregulated the PI3K-Akt-mTOR signalling pathway and stimulated autophagy. This study indicated that PHI prevented BLM-induced pulmonary fibrosis by inhibiting PI3K-Akt-mTOR signalling pathway.

PMID:39746665 | DOI:10.1111/1440-1681.70017

Int Immunopharmacol. 2025 Jan 1;147:113979. doi: 10.1016/j.intimp.2024.113979. Online ahead of print.

ABSTRACT

This review explores the progressive domain of network pharmacology and its potential to revolutionize therapeutic approaches for Interstitial Lung Diseases (ILDs), a collective term encompassing Interstitial Pneumonia, Pneumoconiosis, Connective Tissue Disease-related ILDs, and Sarcoidosis. The exploration focuses on the profound legacy of traditional medicines, particularly Ayurveda and Traditional Chinese Medicines (TCM), and their largely unexplored capacity in ILD treatment. These ancient healing systems, characterized by their holistic methodologies and multifaceted treatment modalities, offer a promising foundation for discovering innovative therapeutic strategies. Moreover, the review underscores the amalgamation of artificial intelligence (AI) and machine learning (ML) methodologies with bioinformatics, creating a computational synergy capable of deciphering the intricate biological networks associated with ILDs. Network pharmacology has tailored the hypothesis from the conventional "one target, one drug" towards a "network target, multi-component therapeutics" approach. The fusion of traditional literature and computational technology can unveil novel drugs, targets, and pathways, augmenting effective therapies and diminishing adverse effects related to current medications. In conclusion, this review provides a comprehensive exposition of how Network Pharmacology tools can leverage the insights of Ayurveda and TCM to craft efficacious therapeutic solutions for ILDs. It sets the stage for future investigations in this captivating interdisciplinary domain, validating the use of traditional medicines worldwide.

PMID:39746273 | DOI:10.1016/j.intimp.2024.113979

Am J Physiol Lung Cell Mol Physiol. 2025 Jan 2. doi: 10.1152/ajplung.00189.2024. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis is a fatal disease characterized by the TGF-β-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive replacement of healthy lung with scar tissue. We and others have shown that TGF-β-mediated activation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and downstream upregulation of Activating Transcription Factor 4 (ATF4) promote metabolic reprogramming in lung fibroblasts characterized by upregulation of the de novo synthesis of glycine, the most abundant amino acid found in collagen protein. Whether mTOR and ATF4 regulate other metabolic pathways in lung fibroblasts has not been explored. Here, we used RNA sequencing to determine how both ATF4 and mTOR regulate gene expression in human lung fibroblasts following TGF-β. We found that ATF4 primarily regulates enzymes and transporters involved in amino acid homeostasis as well as aminoacyl-tRNA synthetases. mTOR inhibition resulted not only in the loss of ATF4 target gene expression, but also in the reduced expression of glycolytic enzymes and mitochondrial electron transport chain subunits. Analysis of TGF-β-induced changes in cellular metabolite levels confirmed that ATF4 regulates amino acid homeostasis in lung fibroblasts while mTOR also regulates glycolytic and TCA cycle metabolites. We further analyzed publicly available single-cell RNA-seq data sets and found increased expression of ATF4 and mTOR-regulated genes in pathologic fibroblast populations from the lungs of IPF patients. Our results provide insight into the mechanisms of metabolic reprogramming in lung fibroblasts and highlight novel ATF4 and mTOR-dependent pathways that may be targeted to inhibit fibrotic processes.

PMID:39745695 | DOI:10.1152/ajplung.00189.2024

Tuberk Toraks. 2024 Dec;72(4):288-294. doi: 10.5578/tt.202404984.

ABSTRACT

INTRODUCTION: Diffuse pulmonary ossification (DPO) refers to the unusual formation of mature bone tissue within the lung parenchyma. It has been shown to be associated with a number of cardiac and chronic lung diseases. The relation between DPO and idiopathic pulmonary fibrosis (IPF) has been shown in the literature. We examined DPO, which is the supporting computed tomography (CT) finding of IPF. In this way, it was aimed to distinguish cases with an IPF-like pattern non-invasively.

MATERIALS AND METHODS: A retrospective analysis included 89 cases exhibiting a CT pattern typical of usual interstitial pneumonia (UIP). The cases were divided into two groups: One with an IPF diagnosis and the other with a nonIPF diagnosis. The presence of DPO was then assessed in each case according to the criteria outlined in the literature. Finally, the occurrence of DPO was compared between the IPF group and the non-IPF group.

RESULT: Forty-seven of 89 cases had a diagnosis of IPF (52.8%). DPO was observed in 31 patients (34.8%). Presence of DPO was detected in 28 (59.6%) patients in the IPF group. The presence of DPO was detected in 3 (7.1%) cases in the non-IPF UIP patient group. A moderate correlation was found between IPF and DPO, and a moderate correlation was found between IPF and the male sex (r= 0.549; r= 0.311, respectively).

CONCLUSIONS: DPO is an important finding to support the diagnosis of IPF.

PMID:39745228 | DOI:10.5578/tt.202404984

Ther Adv Respir Dis. 2025 Jan-Dec;19:17534666241309795. doi: 10.1177/17534666241309795.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is often regarded as the archetypal progressive fibrosing interstitial lung disease (ILD). The term "progressive pulmonary fibrosis" (PPF) generally describes progressive lung fibrosis in an individual with an ILD other than IPF. Both IPF and PPF are associated with loss of lung function, worsening dyspnea and quality of life, and premature death. Current treatments slow the decline in lung function but have side effects that may deter the initiation or continuation of treatment. There remains a high unmet need for additional therapies that can be used alone or in combination with current therapies to preserve lung function in patients with IPF and PPF. Phosphodiesterase-4 (PDE4) is an enzyme involved in the regulation of inflammatory processes. Pre-clinical studies have shown that preferential inhibition of PDE4B has anti-inflammatory and antifibrotic effects and a lower potential for gastrointestinal adverse events than pan-PDE4 inhibition. The preferential PDE4B inhibitor nerandomilast demonstrated efficacy in preserving lung function in a phase II trial in patients with IPF and is under investigation in phase III trials as a treatment for IPF and PPF.

PMID:39745090 | DOI:10.1177/17534666241309795

J Clin Invest. 2025 Jan 2;135(1):e183836. doi: 10.1172/JCI183836.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is etiologically complex, with well-documented genetic and nongenetic origins. In this Review, we speculate that the development of IPF requires two hits: the first establishes a vulnerable bronchoalveolar epithelium, and the second triggers mechanisms that reprogram distal epithelia to initiate and perpetuate a profibrotic phenotype. While vulnerability of the bronchoalveolar epithelia is most often driven by common or rare genetic variants, subsequent injury of the bronchoalveolar epithelia results in persistent changes in cell biology that disrupt tissue homeostasis and activate fibroblasts. The dynamic biology of IPF can best be contextualized etiologically and temporally, including stages of vulnerability, early disease, and persistent and progressive lung fibrosis. These dimensions of IPF highlight critical mechanisms that adversely disrupt epithelial function, activate fibroblasts, and lead to lung remodeling. Together with better recognition of early disease, this conceptual approach should lead to the development of novel therapeutics directed at the etiologic and temporal drivers of lung fibrosis that will ultimately transform the care of patients with IPF from palliative to curative.

PMID:39744946 | DOI:10.1172/JCI183836

Respir Med. 2024 Dec 30:107937. doi: 10.1016/j.rmed.2024.107937. Online ahead of print.

ABSTRACT

BACKGROUND: The relationship between serum lipid with idiopathic pulmonary fibrosis (IPF) required to be explored. We aim to evaluate the association of serum lipid levels with mortality in patients with IPF.

MATERIALS AND METHODS: This retrospective study included IPF patients with more than three years follow-up. We collected baseline demographics information, forced vital capacity (FVC)% predicted, carbon monoxide diffusion capacity (DLCO)% predicted, gender-age-physiology (GAP) index, and serum lipid levels, including Triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C). We evaluate the relationship between the serum lipid levels and the disease severity, and the mortality in IPF.

RESULTS: This study enrolled 146 patients, with the three-year survival rate of 71.23%. The median follow-up time was 46.5 months. There was no significant difference in baseline lipid levels between the survival and non-survival group. TG levels were positively correlated with DLCO% predicted (r = 0.189, p = 0.022) and negatively correlated with GAP index (r=-0.186, p=0.025). After adjusting for GAP index, smoking history, body mass index and the use of antifibrotic and lipid-lowering drug, lower TC levels (HR: 0.74, 95% CI: 0.58-0.94, p=0.013) were identified as an independent risk factor for mortality.

CONCLUSION: This study demonstrated that lower TC levels were associated with increased mortality in IPF. More investigations are required to explore the role of lipid metabolism in the pathogenesis of pulmonary fibrosis.

PMID:39743155 | DOI:10.1016/j.rmed.2024.107937

ACS Nano. 2025 Jan 1. doi: 10.1021/acsnano.4c11113. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterized by persistent tissue injury, dysregulated wound healing, and extracellular matrix (ECM) deposition by myofibroblasts (MFs) through the fibroblast-to-myofibroblast transition (FMT). Implicit in the FMT process are changes in the ECM and cellular topology, but their relationship with the lung fibroblast phenotype has not been explored. We engineered topological mimetics of alignment cues (anisotropy/isotropy) using lung decellularized ECM micropattern arrays and investigated the effects of cellular topology on cellular fates in MRC-5 lung fibroblasts. We found that isotropic MRC-5 cells presented changes of the cytoskeleton, increased cell-cell adhesions and a multicellular architecture with increased overlap, changes in actin-myosin development, and enhanced focal adhesion and cell junction with random alignment. Besides, anisotropic fibroblasts were activated into a regular phenotype with an ECM remodeling profile. In contrast, isotropic fibroblasts developed a highly invasive phenotype expressing molecules, including CD274/programmed death-ligand 1 (PD-L1), cellular communication network factor 2 (CCN2)/connective tissue growth factor (CTGF), hyaluronan synthase 2 (HAS2), and semaphorin 7A (SEMA7A), but with downregulated matrix genes. Moreover, isotropic fibroblasts also showed higher expressions of Ki-67 and cyclin D1 (CCND1), resistance to apoptosis/senescence, and decreased autophagy. The topology regulated the cellular heterogeneity and resulted in positive feedback between changes in the cellular phenotype and the ECM structure, which may aggravate fibrosis and lead to a priming of malignant microenvironment during carcinogenesis. Using the versatile platform of micropattern array, we can not only visualize the interaction mechanism between cells and the ECM but also select potential clinical targets for diagnosis and therapeutics.

PMID:39742460 | DOI:10.1021/acsnano.4c11113