Idiopathic Pulmonary Fibrosis Patients Research Articles

Pirfenidone as a Cornerstone in the Management of Fibrotic Interstitial Lung Diseases and Its Emerging Applications: A Comprehensive Review.

Pirfenidone is a groundbreaking antifibrotic agent that has become a cornerstone in managing fibrotic interstitial lung diseases (ILDs), particularly idiopathic pulmonary fibrosis (IPF). This review comprehensively analyzes pirfenidone's mechanisms of action, clinical efficacy, safety profile, and emerging applications beyond IPF. Pirfenidone exerts its therapeutic effects by inhibiting key pathways involved in fibrosis, including transforming growth factor-beta (TGF-β) and other pro-fibrotic cytokines. It also reduces oxidative stress and inflammation. Clinical trials have consistently demonstrated pirfenidone's ability to slow the decline in lung function, reduce disease progression, and improve survival rates in IPF patients. Furthermore, emerging evidence supports its potential use in other fibrotic ILDs and non-pulmonary fibrotic conditions, such as liver and kidney fibrosis. Despite its proven benefits, pirfenidone's safety and tolerability profiles require careful monitoring, with gastrointestinal and photosensitivity reactions being the most common adverse effects. Future research is poised to explore combination therapies, personalized treatment approaches, and novel applications of pirfenidone in a broader range of fibrotic disorders. As the field of antifibrotic therapy advances, pirfenidone remains a pivotal agent with the potential to significantly impact the management of fibrotic diseases across multiple organ systems. This review aims to provide clinicians and researchers with a detailed understanding of pirfenidone's current role and prospects in treating fibrosis.

Regenerative capacity of alveolar type 2 cells is proportionally reduced following disease progression in idiopathic pulmonary fibrosis-derived organoid cultures.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease that leads to respiratory failure and death due to irreversible scarring of the distal lung. While historically considered a chronic inflammatory disorder, the aberrant function of the alveolar epithelium is now recognized to play a central role in IPF pathophysiology. This study aimed to investigate the regenerative capacity of AT2 cells using IPF-derived alveolar organoids and to examine the effects of disease progression on this capacity. Lung tissues from 3 pneumothorax patients and 6 IPF patients (early and advanced stages) were obtained by VATS and lung transplantation. HTII-280+ cells were isolated from CD31-CD45-EpCAM+ cells in the distal lungs of IPF and pneumothorax patients using fluorescence-activated cell sorting (FACS) and resuspended in 48-well plates to establish IPF-derived alveolar organoids. Immuno-staining was used to confirm the presence of AT2 cells. FACS sorting yielded approximately 1% AT2 cells of the total cells in early IPF tissue, and the number decreased as the disease progressed, compared with 2.7% in pneumothorax. Additionally, the cultured organoids in the IPF groups were smaller in size and fewer in number compared to those from pneumothorax patients. The colony-forming efficiency decreased as the disease progressed. In immuno-staining results, the IPF organoids showed lower expression of SFTPC compared to the pneumothorax group and contained KRT5+ cells. This study confirmed that the regenerative capacity of AT2 cells in IPF decreases as the disease progresses, and IPF AT2 cells inherently exhibit functional abnormalities and altered differentiation plasticity.

Identification of immune patterns in idiopathic pulmonary fibrosis patients driven by PLA2G7-positive macrophages using an integrated machine learning survival framework

Patients with advanced idiopathic pulmonary fibrosis (IPF), a complex and incurable lung disease with an elusive pathology, are nearly exclusive candidates for lung transplantation. Improved identification of patient subtypes can enhance early diagnosis and intervention, ultimately leading to better prognostic outcomes for patients. The goal of this study is to identify new immune patterns and biomarkers in patients. Immune subtypes in IPF patients were identified using single-sample gene set enrichment analysis, and immune subtype-related genes were explored using the weighted correlation network analysis algorithm. A machine learning integration framework was used to establish the optimal prognostic model, known as the immune-related risk score (IRS). Single-cell sequencing was conducted to investigate the major role of macrophage-derived PLA2G7 in the immune microenvironment. We assessed the stability of celecoxib in targeting PLA2G7 through molecular docking and surface plasmon resonance. IPF patients present two distinct immune subtypes, one characterized by immune activation and inflammation, and the other by immune suppression. IRS can predict the immune status and prognosis of IPF patients. Furthermore, multi-cohort analysis and single-cell sequencing analysis demonstrated the diagnostic and prognostic value of PLA2G7 derived from macrophages and its role in shaping the inflammatory immune microenvironment in IPF patients. Celecoxib could effectively and stably bind with PLA2G7. PLA2G7, as identified through IRS, demonstrates marked stability in diagnosing and predicting the prognosis of IPF patients as well as predicting their immune status. It can serve as a novel biomarker for IPF patients.

GTSE1-driven ZEB1 stabilization promotes pulmonary fibrosis through the epithelial-to-mesenchymal transition

G2 and S phase-expressed protein 1 (GTSE1) has been implicated in the development of pulmonary fibrosis (PF); however, its biological function, molecular mechanism, and potential clinical implications remain unknown. Here, we explored the genomic data of patients with idiopathic PF (IPF) and found that GTSE1 expression is elevated in their lung tissues, but rarely expressed in normal lung tissues. Thus, we explored the biological role and downstream events of GTSE1 using IPF patient tissues and PF mouse models. The comprehensive bioinformatics analyses suggested that the increase of GTSE1 in IPF is linked to the enhanced gene signature for the epithelial-to-mesenchymal transition (EMT), leading us to investigate the potential interaction between GTSE1 and EMT transcription factors. GTSE1 preferentially binds to the less stable form of zinc-finger E-box-binding homeobox 1 (ZEB1), the unphosphorylated form at Ser585, inhibiting ZEB1 degradation. Consistently, the ZEB1 protein level in IPF patient and PF mouse tissues correlates with the GTSE1 protein level and the amount of collagen accumulation, representing fibrosis severity. Collectively, our findings highlight the GTSE1–ZEB1 axis as a novel driver of the pathological EMT characteristic during PF development and progression, supporting further investigation into GTSE1-targeting approaches for PF treatment.

Diagnostic Performance of CLEIA Versus FEIA for KL-6 Peripheral and Alveolar Concentrations in Fibrotic Interstitial Lung Diseases: A Multicentre Study.

Interstitial lung diseases (ILD) is a group of lung disorders characterized by interstitial lung thickening due to inflammatory and fibrotic processes. Krebs von den Lungen-6 (KL-6) is a molecule secreted by damaged type II alveolar pneumocytes in the alveolar space. The goal of the present study was to compare two detection methods of KL-6 in both bronchoalveolar lavage (BAL) and serum from ILD patients at the moment of diagnosis. Patients with suspicious of ILD and followed at two Italian referral centres for rare lung diseases were included in the study. BAL fluid and serum were collected and analysed by chemiluminescent enzyme immunoassay (CLEIA) and fluorescent enzyme immunoassay (FEIA) methods provided by Tosoh Biosciences. A total of 158 (mean age ± standard deviation, 61.5 ± 13.7, 65 females) patients were enrolled. A total of, 36 had diagnosis of idiopathic pulmonary fibrosis (IPF), 74 sarcoidosis, 15 connective tissue disease-ILD (CTD-ILD) and 33 other ILD. Diagnostic agreement between two methods was demonstrated for both BAL (r = 0.707, p < 0.0001) and serum (r = 0.816, p < 0.0001). BAL KL-6 values were lower than serum (p < 0.0001). IPF patients had higher serum KL-6 concentration than other ILDs (p = 0.0294), while BAL KL-6 values were lower in IPF than in non-IPF (p = 0.0023). This study explored KL-6 concentrations through the CLEIA method in serum and BAL of patients with various ILDs, showing significant differences of biomarkers concentrations between IPF and other non-IPF ILDs. Our findings are promising as they provided further knowledge concerning KL-6 expression across different ILDs and may suggest its utility in differential diagnosis.

MEOX1 triggers myofibroblast apoptosis resistance, contributing to pulmonary fibrosis in mice.

The apoptosis resistance of myofibroblasts is a hallmark in the irreversible progression of pulmonary fibrosis (PF). While the underlying molecular mechanism remains elusive. In this study, we unveiled a previously unrecognized mechanism underlying myofibroblast apoptosis resistance during PF. Our investigation revealed heightened expression of mesenchyme homeobox 1 (MEOX1) in the lungs of idiopathic pulmonary fibrosis (IPF) patients and bleomycin-induced PF mice. Silencing MEOX1 significantly attenuated PF progression in mice. In vitro, we found a notable increase in MEOX1 expression in transforming growth factor-β1 (TGF-β1)-induced myofibroblasts. Silencing MEOX1 enhanced apoptosis of myofibroblasts. Mechanistically, we identified G-protein signaling pathway regulatory factor 4 (RGS4) as a critical downstream target of MEOX1, as predicted by bioinformatics analysis. MEOX1 enhanced apoptosis resistance by upregulating RGS4 expression in myofibroblasts. In conclusion, our study highlights MEOX1 as a promising therapeutic target for protecting against PF by modulating myofibroblast apoptosis resistance.

Correlation of serum Krebs von den Lungen-6 levels with fibrosis score on high resolution chest tomography and pulmonary function parameters in treatment naïve Idiopathic Pulmonary Fibrosis.

While serum Krebs von den Lungen-6 (KL-6) has been found to be a helpful biomarker in interstitial lung diseases for evaluating disease severity and progression, especially in connective tissue disease-associated interstitial lung disease (CTD ILD) and idiopathic non-specific interstitial pneumonia (NSIP), data on correlation of serum KL-6 levels with radiological fibrosis and pulmonary function parameters is lacking in treatment naïve Idiopathic Pulmonary Fibrosis (IPF) patients. Serum KL-6 levels were measured in thirty-nine treatment naïve newly detected IPF patients using automated immunofluorescence enzyme assay (AIA) by Tosoh Corporation, bioscience division, Tokyo, Japan. Fibrosis score was calculated by independent visual assessment of the pattern and severity of abnormalities on high resolution computed tomography (HRCT) thorax. HRCT fibrosis scores were correlated with serum KL-6 levels and pulmonary function parameters like forced vital capacity (FVC), diffusion capacity of lung for carbon monoxide (DLco). Median value of serum KL-6 levels was 1519 U/ml (range 199.41-6055 U/ml). There was positive correlation of serum KL-6 with HRCT fibrosis score (r=0.692, p<0.001) and negative correlation with FVC (r=-0.511, p=0.001) and DLco (r=-0.354, p=0.043). In the HRCT fibrosis score pattern subset analysis, the presence of reticulation revealed weak negative and statistically insignificant correlation (r=-0.116, p=0.481) while traction bronchiectasis and honeycombing exhibited statistically significant positive correlation (r=0.425, p=0.007; r=0.584, p<0.001 respectively) with serum KL-6 levels. Serum KL-6 levels showed a positive correlation with the degree of fibrotic abnormalities on HRCT thorax and pulmonary function parameters, indicating a potential use of serum KL-6 in monitoring of parenchymal fibrosis in Idiopathic Pulmonary fibrosis.

The transcriptome of CD14 + CD163 - HLA-DR low monocytes predicts mortality in Idiopathic Pulmonary Fibrosis.

The association between immune-cell-specific transcriptomic profiles and Idiopathic Pulmonary Fibrosis (IPF) mortality is unknown. To determine immune-cell-specific transcriptomic profiles associated with IPF mortality. We profiled peripheral blood mononuclear cells (PBMC) in 18 participants [University of South Florida: IPF, COVID-19, post-COVID-19 Interstitial Lung Disease (Post-COVID-19 ILD), controls] by single-cell RNA sequencing (scRNA-seq) and identified 16 immune-cell-specific transcriptomic profiles. The Scoring Algorithm of Molecular Subphenotypes (SAMS) was used to calculate Up-scores based on these 16 gene profiles. Their association with outcomes was investigated in peripheral blood, Bronchoalveolar Lavage (BAL) and lung tissue of N=416 IPF patients from six cohorts. Findings were validated in an independent IPF, PBMC scRNA-seq dataset (N=38). Cox-regression models demonstrated that 230 genes from CD14 + CD163 - HLA-DR low circulating monocytes predicted IPF mortality [Pittsburgh (p=0.02), Chicago (p=0.003)]. PBMC proportions of CD14 + CD163 - HLA-DR low monocytes were higher in progressive versus stable IPF (Yale, 0.13±0.05 versus 0.09±0.05, p=0.034). Receiving operating characteristic identified a 230 gene, Up-score >41.84 (Pittsburgh) predictive of mortality in Chicago (HR: 6.58, 95%CI: 2.15-20.13, p=0.001) and in pooled analysis of BAL cohorts (HR: 2.20, 95%CI: 1.44-3.37, p=0.0003). High-risk patients had decreased expression of the T-cell co-stimulatory genes CD28 , ICOS , ITK and LCK (Pittsburgh and Chicago, p<0.01). 230 gene-up-scores negatively correlated with Forced Vital Capacity (FVC) in IPF lung tissues (LGRC, rho=-0.2, p=0.02). Results were replicated using a subset of 13 genes from the 230-gene signature (pooled PBMC cohorts - HR: 5.34, 95%CI: 2.83-10.06, p<0.0001). The transcriptome of CD14 + CD163 - HLA-DR low monocytes is associated with increased IPF mortality.

The incidence of acute exacerbation of idiopathic pulmonary fibrosis: a systematic review and meta-analysis

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with a high incidence of acute exacerbation and an increasing mortality rate. Currently, treatment methods and effects are limited. Therefore, we conducted a meta-analysis of the incidence of acute exacerbation in patients with IPF, hoping to provide reference for the prevention and management of IPF. We systematically searched the PubMed, Embase, Cochrane Library and Web of Science databases. From the creation of the database to the cohort study on April 3, 2023, we collected studies on the incidence of acute exacerbation of IPF patients, and used Stata software (version 16.0) for meta analysis. We used the Newcastle Ottawa Quality Assessment Scale (NOS) to assess the risk of bias for each study. We calculated the incidence of acute exacerbation in IPF patients and analyzed the risk factors for acute exacerbation in IPF patients and prognostic factors for overall survival from the initial IPF diagnosis. A total of ten cohort studies on the incidence of AE-IPF were included, including 11,855 IPF patients. The results showed that the incidence of acute exacerbation within one year was 9%; the incidence of acute exacerbation within 2 years is 13%; the incidence of acute exacerbation within 3 years is 19%; the incidence of acute exacerbation within 4 years is 11%. In addition, one study reported an acute exacerbation rate of 1.9% within 30 days. The incidence of acute exacerbation within ten years reported in one study was 9.8%. Mura et al.'s article included a retrospective cohort study and a prospective cohort study. The prospective cohort study showed that the incidence of acute exacerbation within 3 years was 18.6%, similar to the results of the retrospective cohort study meta-analysis. Our system evaluation and meta-analysis results show that the incidence of AE-IPF is relatively high. Therefore, sufficient attention should be paid to the research results, including the management and prevention of the disease, in order to reduce the risk of AE.Trial registration: PROSPERO, identifier CRD42022341323.

CD8+ tissue-resident memory T cells are essential in bleomycin-induced pulmonary fibrosis.

Human tissue-resident memory T (TRM) cells play a crucial role in protecting the body from infections and cancers. Recent research observed increased numbers of TRM cells in the lung tissues of idiopathic pulmonary fibrosis patients. However, the functional consequences of TRM cells in pulmonary fibrosis remain unclear. Here, we found that the numbers of TRM cells, especially the CD8+ subset, were increased in the mouse lung with bleomycin-induced pulmonary fibrosis. Increasing or decreasing CD8+ TRM cells in mouse lungs accordingly altered the severity of fibrosis. In addition, the adoptive transfer of CD8+ T cells containing a large number of CD8+ TRM cells from fibrotic lungs was sufficient to induce pulmonary fibrosis in control mice. Treatment with chemokine CC-motif ligand (CCL18) induced CD8+ TRM cell expansion and exacerbated fibrosis, whereas blocking C-C chemokine receptor 8 (CCR8) prevented CD8+ TRM recruitment and inhibited pulmonary fibrosis. In conclusion, CD8+ TRM cells are essential for bleomycin-induced pulmonary fibrosis, and targeting CCL18/CCR8/CD8+ TRM cells may be a potential therapeutic approach. NEW & NOTEWORTHY The role of CD8+ TRM cells in the development of pulmonary fibrosis was validated and studied in the classic model of pulmonary fibrosis. It was proposed for the first time that CCL18 has a chemotactic effect on CD8+ TRM cells, thereby exacerbating pulmonary fibrosis.

Short- and long-term clinical outcomes of nintedanib therapy in IPF patients with different phenotypes: A retrospective registry-based study

BackgroundThere is a lack of data on the long-term effect of nintedanib on survival in specific groups of idiopathic pulmonary fibrosis (IPF) patients with different phenotypes. We investigated the outcomes of nintedanib therapy in an observational study of a large multicentre real-world cohort of IPF patients with various initial characteristics. MethodsThe analysis included IPF patients treated with nintedanib (NIN) and IPF patients not receiving antifibrotic treatment (NAF) enrolled for the EMPIRE registry in 2015–2020. The patients were stratified according to their initial FVC predicted, dyspnoea, UIP pattern and age. All-cause mortality and annual rate of FVC decline were the main endpoints. Cox proportional hazards model for survival assessment and linear mixed-effects model for FVC decline modelling were used. ResultsA total of 869 NIN patients and 691 NAF patients were eligible for the analysis. The annual FVC decline rate was significantly different (adjusted values −0.053 l/yr vs −0.122 l/yr; p = 0.001). The adjusted hazard ratio (HR) for mortality was 0.40 (95 % CI 0.3 to 0.53, p < 0.001). The most significant effect of nintedanib was demonstrated in patients with impaired lung function, i.e., with an FVC predicted to be less than 80 % and a NYHA II to IV. Nintedanib therapy also reduced the difference in survival between men and women. ConclusionsModelling confirmed that NIN therapy reduced differences in OS between patients with better and worse initial conditions and prognosis. Our results indicate that NIN is particularly beneficial for patients with advanced IPF and more severe phenotypes. Trial registrationEMPIRE was registered as a non-interventional post-registration study at the State Institute for Drug Control of the Czech Republic under ID 1412080000 on December 8, 2014.

A Pilot HRCT Follow-Up Study to Test the Feasibility of Predictive Efficacy of Serum Periostin in Idiopathic Pulmonary Fibrosis.

While serum periostin and Krebs von den Lungen-6 (KL-6) have been acknowledged as independent markers in idiopathic pulmonary fibrosis (IPF) diagnosis, the clinical combinatory potential of these biomarkers combined with high-resolution computed tomography (HRCT) has yet to be fully explored. This retrospective study involved 78 participants, comprising 51 UIP-IPF patients and 27healthy controls. All subjects underwent clinical and laboratory examinations, particularly the detection of periostin and KL-6 using ELISA with innovative HRCT fibrosis score evaluations at admission and discharge during hospitalization in UIP-IPF patients. In our cohort of patients with IPF, predominantly male, over an average follow-up period of 195.27 days. Serum levels of periostin and KL-6 were significantly elevated in IPF patients compared to healthy controls (*p < 0.05). Post-treatment, KL-6 levels decreased significantly, while periostin levels increased. Notably, periostin exhibited superior prognostic accuracy over KL-6, with a higher AUC of 0.875 than 0.639 in ROC analysis. An increase in periostin levels correlated with disease progression, as evidenced by worsened HRCT fibrotic scores and decreased survival probability. These findings underscore periostin's potential as a reliable biomarker for assessing IPF severity and therapeutic response. Our findings underscore the preeminence of serum periostin over KL-6 in UIP-IPF diagnosis, particularly when conjoined with HRCT fibrosis score.

Shared and unique transcriptomic signature genes and pathways among biopsy, peripheral blood mononuclear cells and bronchoalveolar lavage samples in IPF patients revealed using comparative meta-transcriptome analysis.

Idiopathic pulmonary fibrosis (IPF) affects the tissue surrounding the alveoli and occurs when the lung tissue becomes thick and stiff for unknown reasons. Clinical findings are fairly well settled, but the molecular mechanisms of IPF are still poorly known. To further our understanding, we collected publicly available transcriptome dataset from IPF cohorts, grouped them according to sampling method [bronchoalveolar lavage (BAL), biopsy, blood], and performed comparative meta-transcriptome study to (I) unravel key pathways (II), set out differences in discovered genes, pathways, and functional annotation with respect to the sampling method, and (III) find biomarkers for early diagnosis. The resulting lists are also compared with DisGeNet reported genes, earlier work, and Kyoto encyclopedia of genes and genomes (KEGG) pathways. Several pathways are shared among BAL and biopsy samples while blood samples point to alternative pathways, indicating the noise in information obtained from these samples. Common to all sampling methods, interleukin-10 pathway and extracellular signaling pathways are pointed as further targets.

IA-Body Composition CT at T12 in Idiopathic Pulmonary Fibrosis: Diagnosing Sarcopenia and Correlating with Other Morphofunctional Assessment Techniques.

Body composition (BC) techniques, including bioelectrical impedance analysis (BIVA), nutritional ultrasound® (NU), and computed tomography (CT), can detect nutritional diagnoses such as sarcopenia (Sc). Sc in idiopathic pulmonary fibrosis (IPF) is associated with greater severity and lower survival. Our aim was to explore the correlation of BIVA, NU and functional parameters with BC at T12 level CT scans in patients with IPF but also its relationship with degree of Sc, malnutrition and mortality. This bicentric cross-sectional study included 60 IPF patients (85.2% male, 70.9 ± 7.8 years). Morphofunctional assessment (MFA) techniques included BIVA, NU, CT at T12 level (T12-CT), handgrip strength, and timed up and go. CT data were obtained using FocusedON®. Statistical analysis was conducted using JAMOVI version 2.3.22 to determine the cutoff points for Sc in T12-CT and to analyze correlations with other MFA techniques. the cutoff for muscle area in T12-CT was ≤77.44 cm2 (area under the curve (AUC) = 0.734, sensitivity = 41.7%, specificity = 100%). The skeletal muscle index (SMI_T12CT) cutoff was ≤24.5 cm2/m2 (AUC = 0.689, sensitivity = 66.7%, specificity = 66.7%). Low SMI_T12CT exhibited significantly reduced median survival and higher risk of mortality compared to those with normal muscle mass (SMI cut off ≥ 28.8 cm/m2). SMI_T12CT was highly correlated with body cell mass from BIVA (r = 0.681) and rectus femoris cross-sectional area (RF-CSA) from NU (r = 0.599). Cronbach's α for muscle parameters across different MFA techniques and CT was 0.735, confirming their validity for evaluating muscle composition. T12-CT scan is a reliable technique for measuring low muscle mass in patients with IPF, specifically when the L3 vertebrae are not captured. An SMI value of <28.8 is a good predictor of low lean mass and 12-month mortality in IPF patients.

Chlorquinaldol Alleviates Lung Fibrosis in Mice by Inhibiting Fibroblast Activation through Targeting Methionine Synthase Reductase.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited treatment options. Thus, it is essential to investigate potential druggable targets to improve IPF treatment outcomes. By screening a curated library of 201 small molecules, we have identified chlorquinaldol, a known antimicrobial drug, as a potential antifibrotic agent. Functional analyses have demonstrated that chlorquinaldol effectively inhibits the transition of fibroblasts to myofibroblasts in vitro and mitigates bleomycin-induced pulmonary fibrosis in mice. Using a mass spectrometry-based drug affinity responsive target stability strategy, we revealed that chlorquinaldol inhibited fibroblast activation by directly targeting methionine synthase reductase (MTRR). Decreased MTRR expression was associated with IPF patients, and its reduced expression in vitro promoted extracellular matrix deposition. Mechanistically, chlorquinaldol bound to the valine residue (Val-467) in MTRR, activating the MTRR-mediated methionine cycle. This led to increased production of methionine and s-adenosylmethionine, counteracting the fibrotic effect. In conclusion, our findings suggest that chlorquinaldol may serve as a novel antifibrotic medication, with MTRR-mediated methionine metabolism playing a critical role in IPF development. Therefore, targeting MTRR holds promise as a therapeutic strategy for pulmonary fibrosis.

Imaging Pulmonary Fibrosis and Treatment Efficacy In Vivo with Autotaxin-Specific PET Ligand [18F]ATX-1905.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by unpredictable progression and limited therapeutic options. Current diagnosis relies on high resolution computed tomography (HRCT), which may not adequately capture early signs of deterioration. The enzyme autotaxin (ATX) emerges as a prominently expressed extracellular secretory enzyme in the lungs of IPF patients. The objective of this study was to evaluate the effectiveness of 18F-labeled ATX-targeted tracer [18F]ATX-1905, in comparison with [18F]FDG, for early fibrosis diagnosis, disease evolution monitoring, and treatment efficacy assessment in bleomycin-induced pulmonary fibrosis (BPF) models. To assess treatment efficacy, mice were treated with two commonly used drugs for IPF, pirfenidone or nintedanib, from Day 9 to Day 23 postbleomycin administration. Lung tissue assessments encompassed inflammation severity via H&E staining, and Ashcroft scoring via Masson staining, alongside quantification of ATX expression through ELISA. Positron emission tomography (PET) imaging employing [18F]FDG and [18F]ATX-1905 tracked disease progression pre- and post-treatment. The extent of pulmonary fibrosis corresponded to changes in ATX expression levels in the BPF mouse model. Notably, [18F]ATX-1905 exhibited elevated uptake in BPF lungs during the progression of the disease, particularly evident at the early stage (Day 9). This uptake was inhibited by an ATX inhibitor, PF-8380, underscoring the specificity of the radiotracer. Conversely, [18F]FDG uptake, peaking at Day 15, decreased subsequently, likely reflective of diminished inflammation. A 2-week treatment regimen using either pirfenidone or nintedanib resulted in notable reductions of ATX expression levels and fibrosis degrees within lung tissues, based on ELISA and Masson staining, as evidenced by PET imaging with [18F]ATX-1905. [18F]FDG uptake also decreased following the treatment period. Additionally, PET/CT imaging extended to a nonhuman primate (NHP) BPF model. The uptake of [18F]ATX-1905 (SUVmax = 2.2) was significantly higher than that of [18F]FDG (SUVmax = 0.7) in fibrotic lung tissue. Using our novel ATX-specific radiotracer [18F]ATX-1905 and PET/CT imaging, we demonstrated excellent ability in early fibrosis detection, disease monitoring, and treatment assessment within lungs of the BPF mouse models. [18F]ATX-1905 displayed remarkable specificity for ATX expression and high sensitivity for ATX alterations, suggesting its potential for monitoring varying ATX expression in lungs of IPF patients.

Deciphering the role of oxidative stress genes in idiopathic pulmonary fibrosis: a multi-omics mendelian randomization approach.

Oxidative stress (OS) is crucial in idiopathic pulmonary fibrosis (IPF) pathogenesis, with its genes potentially acting as both causes and consequences of the disease. We identified OS-related genes from GeneCards and performed a meta-analysis on pulmonary transcriptome datasets to discover differentially expressed genes (DEGs) related to OS in IPF. We integrated this data with the largest available IPF GWAS summaries, expression quantitative trait loci (eQTLs), and DNA methylation QTLs (mQTLs) from blood. This approach aimed to identify blood OS genes and regulatory elements linked to IPF risk, incorporating the latest pulmonary eQTLs and bronchoalveolar lavage fluid microbial QTLs (bmQTLs) for a comprehensive view of gene-lung microbiota interactions through SMR and colocalization analyses. Sensitivity analyses were conducted using two additional mendelian randomization (MR) methods. Meta-analysis revealed 1090 differentially expressed OS genes between IPF patients and controls. Integration with IPF GWAS, eQTL, and mQTL data identified key genes and regulatory elements involved in IPF pathogenesis, highlighting the role of specific genes such as KCNMA1 and SLC22A5 in modulating IPF risk through epigenetic mechanisms. Colocalization analysis further identified potential interactions between gene expression and lung microbiota. Our findings elucidate the complex interplay between OS genes and IPF, suggesting potential therapeutic targets and highlighting the importance of considering epigenetic and microbial interactions in the disease's etiology and progression.

RIOK2 transcriptionally regulates TRiC and dyskerin complexes to prevent telomere shortening

Telomere shortening is a prominent hallmark of aging and is emerging as a characteristic feature of Myelodysplastic Syndromes (MDS) and Idiopathic Pulmonary Fibrosis (IPF). Optimal telomerase activity prevents progressive shortening of telomeres that triggers DNA damage responses. However, the upstream regulation of telomerase holoenzyme components remains poorly defined. Here, we identify RIOK2, a master regulator of human blood cell development, as a critical transcription factor for telomere maintenance. Mechanistically, loss of RIOK2 or its DNA-binding/transactivation properties downregulates mRNA expression of both TRiC and dyskerin complex subunits that impairs telomerase activity, thereby causing telomere shortening. We further show that RIOK2 expression is diminished in aged individuals and IPF patients, and it strongly correlates with shortened telomeres in MDS patient-derived bone marrow cells. Importantly, ectopic expression of RIOK2 alleviates telomere shortening in IPF patient-derived primary lung fibroblasts. Hence, increasing RIOK2 levels prevents telomere shortening, thus offering therapeutic strategies for telomere biology disorders.

Idiopathic Pulmonary Fibrosis in Type 2 Diabetes Mellitus

Type 2 Diabetes Mellitus (T2DM) is a chronic condition that afflicts millions of people worldwide. T2DM correlates with increased levels of pro-inflammatory and pro-fibrotic molecules and respiratory cell injury leading to Idiopathic Pulmonary Fibrosis (IPF) development. Idiopathic pulmonary fibrosis patients with T2DM have a higher rate of progression and worse prognosis, including higher hospital stay length and mortality rate. On High-resolution Computed Tomography (HRCT), IPF patients with T2DM are more likely to exhibit the Usual Interstitial Pneumonia (UIP) pattern (reticular and honeycomb patterns) than those without T2DM. Interventions for IPF include non-pharmacological interventions, i.e., oxygen supplementation and pulmonary rehabilitation, and pharmacological interventions, including nintedanib and pirfenidone. Antidiabetic agents, such as metformin, thiazolidinediones, and glucagon-like peptide 1, have shown anti-pulmonary fibrotic effects and to be associated with better clinical outcomes.

Reply to Yu et al.: Elevated Suicide Risk in Idiopathic Pulmonary Fibrosis Patients.

Reply to Yu et al.: Elevated Suicide Risk in Idiopathic Pulmonary Fibrosis Patients.