Mol Pharm. 2024 Aug 26. doi: 10.1021/acs.molpharmaceut.4c00571. Online ahead of print.

ABSTRACT

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.

PMID:39186477 | DOI:10.1021/acs.molpharmaceut.4c00571

Chron Respir Dis. 2024 Jan-Dec;21:14799731241274785. doi: 10.1177/14799731241274785.

ABSTRACT

INTRODUCTION: Multiple studies focusing on chronic lung diseases (i.e. COPD), have indicated that the quality of life (QoL) can be impacted by disease-related fears. In the context of Interstitial Lung Diseases (ILD), however, these have never been systematically examined. Therefore, the aim of the present study was to develop and evaluate an appropriate measuring tool, and to investigate the influence of disease-related anxieties on QoL in ILD.

METHOD: N = 166 ILD patients participated in the study and completed an itempool on disease-related fears, based on the COPD-Anxiety-Questionnaire (CAF-R) and expert assessments. Further, demographic and psychological variables were assessed (anxiety: GAD-7, QoL: K-BILD; Beliefs about Health: KKG). Psychometric properties were analyzed (factor structure, reliability, validity). Regression analyses were used to calculate the differential predictive power of disease-related anxieties on QoL.

RESULTS: The factor structure was confirmed (Scales: Fear-of-Dependence-and-Progression, Fear-of-Social-Exclusion-and-Isolation, Fear-of-Physical-Activity, Fear-of-Dyspnea, and Sleep-related- Complaints). The Scales showed satisfying reliabilities (α = 0.68 to 0.89) and good validity. Disease-related anxieties proved to be differential predictors for different scales of the K-BILD (ß = -0.15 to ß = -0.58, all ps < .01).

CONCLUSIONS: The ILD-Anxiety-Questionnaire (IAQ) is an easy-to-use, valid measurement tool for assessing disease-related anxieties. These vary in their impact on different aspects of QoL. Therefore, it might aid in specifying the indication for potential psychological supplementary interventions. Additional long-term studies are required to investigate how specific anxieties affect both overall and condition-specific QoL in diverse situations.

PMID:39186048 | DOI:10.1177/14799731241274785

Front Immunol. 2024 Aug 9;15:1379480. doi: 10.3389/fimmu.2024.1379480. eCollection 2024.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease characterized by progressive fibrosis, leading to impaired gas exchange and high mortality. The etiology of IPF is complex, with potential links to autoimmune disorders such as hypothyroidism. This study explores the relationship between hypothyroidism and IPF, focusing on the mediating role of plasma proteins.

METHODS: A two-sample Mendelian randomization (MR) approach was employed to determine the impact of hypothyroidism on IPF and the mediating role of 4,907 plasma proteins, all in individuals of European ancestry. Sensitivity analyses, external validation, and reverse causality tests were conducted to ensure the robustness of the findings. Additionally, the function of causal SNPs was evaluated through gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses.

CONCLUSION: The findings suggest that hypothyroidism, through altered plasma protein expression, particularly CXCL10, may contribute to the pathogenesis of IPF. This novel insight highlights the potential of CXCL10 as a therapeutic target in IPF, especially in patients with hypothyroidism. The study emphasizes the need for further research into the complex interplay between autoimmune disorders and IPF, with a view towards developing targeted interventions for IPF management.

PMID:39185418 | PMC:PMC11341476 | DOI:10.3389/fimmu.2024.1379480

Front Pharmacol. 2024 Aug 9;15:1451447. doi: 10.3389/fphar.2024.1451447. eCollection 2024.

ABSTRACT

BACKGROUND: Pirfenidone is an antifibrotic medication approved for idiopathic pulmonary fibrosis (IPF). Fybro®, a generic version of pirfenidone developed in South Korea, gained approval and is available in 200 mg and in higher-dose formulations of 400 and 600 mg. This real-world prospective cohort study investigated the safety and effectiveness of Fybro®.

METHODS: A nationwide observational study was conducted in patients with IPF. Patients were followed up for 6 months, with a subset of patients being followed up for 12 months. Data on lung function and adverse events were collected. Patient adherence to fewer-pill (400 and/or 600 mg tablets) and multiple-pill (200 mg tablets) regimens were compared.

RESULTS: Of the 359 enrolled patients, 352 received pirfenidone (Fybro®) at least once and were included in the analysis. The mean age was 69.0 years and 82.4% of patients were male. The median treatment duration was 186.0 days. A total of 253 patients (71.9%) experienced adverse events, with decreased appetite being the most common (16.5%). The adjusted decline rates in lung function were -1.5% and -2.2% predicted per year for forced vital capacity and diffusing capacity, respectively. No significant differences were observed based on the pirfenidone dose. For a daily intake of 1,200 or 1800 mg of pirfenidone, a significantly longer duration of drug administration was observed with the fewer-pill regimen than with multiple-pill regimen.

CONCLUSION: The safety and effectiveness of Fybro® observed in this real-world cohort study are consistent with previous studies. Using higher-strength tablets to reduce pill burden may improve medication adherence.

PMID:39185314 | PMC:PMC11341391 | DOI:10.3389/fphar.2024.1451447

J Thorac Imaging. 2024 Aug 26. doi: 10.1097/RTI.0000000000000803. Online ahead of print.

ABSTRACT

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease, with a median survival time of 2 to 5 years. The focus of this study is to establish a novel imaging biomarker.

MATERIALS AND METHODS: In this study, 79 patients (19% female) with a median age of 70 years were studied retrospectively. Fully automated body composition analysis (BCA) features (bone, muscle, total adipose tissue, intermuscular, and intramuscular adipose tissue) were combined into Sarcopenia, Fat, and Myosteatosis indices and compared between patients with a survival of more or less than 2 years. In addition, we divided the cohort at the median (high=≥ median, low=<median) of the respective BCA index and tested the impact on the overall survival using the Kaplan-Meier methodology, a log-rank test, and adjusted multivariate Cox-regression analysis.

RESULTS: A high Sarcopenia and Fat index and low Myosteatosis index were associated with longer median survival (35 vs. 16 mo for high vs. low Sarcopenia index, P=0.066; 44 vs. 14 mo for high vs. low Fat index, P<0.001; and 33 vs. 14 mo for low vs. high Myosteatosis index, P=0.0056) and better 5-year survival rates (34.0% vs. 23.6% for high vs. low Sarcopenia index; 47.3% vs. 9.2% for high vs. low Fat index; and 11.2% vs. 42.7% for high vs. low Myosteatosis index). Adjusted multivariate Cox regression showed a significant impact of the Fat (HR=0.71, P=0.01) and Myosteatosis (HR=1.12, P=0.005) on overall survival.

CONCLUSION: The fully automated BCA provides biomarkers with a predictive value for the overall survival in patients with IPF.

PMID:39183570 | DOI:10.1097/RTI.0000000000000803

Am J Physiol Cell Physiol. 2024 Aug 26. doi: 10.1152/ajpcell.00675.2023. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a devastating condition characterized by progressive lung scarring and uncontrolled fibroblast proliferation, inevitably leading to organ dysfunction and mortality. While elevated iron levels have been observed in patients and animal models of lung fibrosis, the mechanisms linking iron dysregulation to lung fibrosis pathogenesis, particularly the role of macrophages in orchestrating this process, remain poorly elucidated. Here we evaluate iron metabolism in macrophages during pulmonary fibrosis using both in vivo and in vitro approaches. In murine bleomycin- and amiodarone-induced pulmonary fibrosis models, we observed significant iron deposition and lipid peroxidation in pulmonary macrophages. Intriguingly, the ferroptosis regulator glutathione peroxidase 4 (GPX4) was upregulated in pulmonary macrophages following bleomycin instillation, a finding corroborated by single-cell RNA sequencing analysis. Moreover, macrophages isolated from fibrotic mouse lungs exhibited increased transforming growth factor (TGF)-β1 expression that correlated with lipid peroxidation. In vitro, iron overload in bone marrow-derived macrophages triggered lipid peroxidation and TGF-β1 upregulation, which was effectively suppressed by ferroptosis inhibitors. When co-cultured with iron-overloaded macrophages, lung fibroblasts exhibited heightened activation, evidenced by increased α-smooth muscle actin and fibronectin expression. Importantly, this pro-fibrotic effect was attenuated by treating macrophages with a ferroptosis inhibitor or blocking TGF-β receptor signaling in fibroblasts. Collectively, our study elucidates a novel mechanistic paradigm in which the accumulation of iron within macrophages initiates lipid peroxidation, thereby amplifying TGF-β1 production, subsequently instigating fibroblast activation through paracrine signaling. Thus, inhibiting iron overload and lipid peroxidation warrants further exploration as a strategy to suppress fibrotic stimulation by disease-associated macrophages.

PMID:39183565 | DOI:10.1152/ajpcell.00675.2023

Br J Pharmacol. 2024 Aug 25. doi: 10.1111/bph.17303. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: The PDE4 family is considered a prime target for therapeutic intervention in several fibro-inflammatory diseases. We have investigated the molecular mechanisms of nerandomilast (BI 1015550), a preferential PDE4B inhibitor.

EXPERIMENTAL APPROACH: In addition to clinically relevant parameters of idiopathic pulmonary fibrosis (IPF; lung function measurement/high-resolution computed tomography scan/AI-Ashcroft score), whole-lung homogenates from a therapeutic male Wistar rat model of pulmonary fibrosis were analysed by next-generation sequencing (NGS). Data were matched with public domain data derived from human IPF samples to investigate how well the rat model reflected human IPF. We scored the top counter-regulated genes following treatment with nerandomilast in human single cells and validated disease markers discovered in the rat model using a human disease-relevant in vitro assay of IPF.

KEY RESULTS: Nerandomilast improved the decline of lung function parameters in bleomycin-treated animals. In the NGS study, most transcripts deregulated by bleomycin treatment were normalised by nerandomilast treatment. Most notably, a significant number of deregulated transcripts that were identified in human IPF disease were also found in the animal model and reversed by nerandomilast. Mapping to single-cell data revealed the strongest effects on mesenchymal, epithelial and endothelial cell populations. In a primary human epithelial cell culture system, several disease-related (bio)markers were inhibited by nerandomilast in a concentration-dependent manner.

CONCLUSIONS AND IMPLICATIONS: This study further supports the available knowledge about the anti-inflammatory/antifibrotic mechanisms of nerandomilast and provides novel insights into the mode of action and signalling pathways influenced by nerandomilast treatment of lung fibrosis.

PMID:39183442 | DOI:10.1111/bph.17303

Respir Med Res. 2024 Jul 30;86:101126. doi: 10.1016/j.resmer.2024.101126. Online ahead of print.

ABSTRACT

INTRODUCTION: Interstitial lung disease (ILD) is a known risk factor for lung cancer (LC). However, the surgical risk of LC in patients with ILD remains unclear. Therefore, we conducted a single-center retrospective study to assess clinical features and outcomes of LC population who underwent surgery with or without ILD.

METHODS: Patients who underwent surgery for LC between January 2006 and June 2023 in our center were assessed using data extracted from the nationwide EPITHOR thoracic surgery database. Suspicion of ILD was based on patients' records. Confirmation of ILD was then made on the patient's medical and radiological history. Patients were classified according to the pattern of ILD. The study aimed to describe the outcomes after lung cancer resection in patients with confirmed LC-ILD group compared to those without ILD (LC-non-ILD): post-operative complications, disease-free survival (DFS) and overall survival (OS). A subgroup analysis was also performed on patients with idiopathic pulmonary fibrosis and lung cancer (LC-IPF).

RESULTS: 4073 patients underwent surgery for LC at Assistance Publique des Hôpitaux de Marseille between January 2006 and June 2023. Of these, 4030 were in the LC-non-ILD group and 30 were LC-ILD patients. In the LC-ILD group, the predominant CT scan pattern was probable UIP (50 %). OS was not significantly lower in the LC-ILD group (45 months versus 84 months, p = 0.068). Dyspnea and tumor size were identified as potential univariate predictors of OS. No significant differences were observed on post-operative complications or their severity. The most common post-operative complications in the LC-ILD group were prolonged air leak, respiratory failure, or pneumonia. 13 patients had cancer recurrence in the LC-ILD group.

CONCLUSION: Our study provides a comprehensive analysis of a LC-ILD population features and outcome when undergoing surgery for LC. Patients with LC-ILD appeared to have a reduced OS compared with LC-non-ILD. Further investigations with larger prospective studies could be useful to confirm and develop these preliminary findings.

PMID:39182360 | DOI:10.1016/j.resmer.2024.101126

Immunobiology. 2024 Feb 14;229(5):152791. doi: 10.1016/j.imbio.2024.152791. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial pneumonia with a poor prognosis and a pathogenesis that has not been fully elucidated. Oxidative stress is closely associated with IPF. In this research, we aimed to identify reliable diagnostic biomarkers associated with the oxidative stress through bioinformatics techniques. The gene expression profile data from the GSE70866 dataset was retrieved from the gene expression omnibus (GEO) database. We extracted 437 oxidative stress-related genes (ORGs) from gene set enrichment analysis (GSEA). The GSE141939 dataset was used for single-cell RNA-seq analysis to identify the expression of diagnostic genes in different cell clusters. A total of 10 differentially expressed oxidative stress-related genes (DE-ORGs) were screened. Subsequently, SOD3, CD36, ACOX2, RBM11, CYP1B1, SNCA, and MPO from the 10 DE-ORGs were identified as diagnostic genes based on random forest algorithm with randomized least absolute shrinkage and selection operator (LASSO) regression. A nomogram was constructed to evaluate the risk of disease. The decision curve analysis (DCA) and clinical impact curves indicated that the nomogram based on these seven biomarkers had extraordinary predictive power. Immune cell infiltration analysis results revealed that DE-ORGs were closely related to various immune cells, especially CYP1B1 was in positive correlation with monocytes and negative correlation with macrophages M1. Single-cell RNA-seq analysis showed that CYP1B1 was mainly associated with macrophages, and SNCA was mainly associated with basal cells. CYP1B1 and SNCA were diagnostic genes associated with oxidative stress in IPF.

PMID:39180853 | DOI:10.1016/j.imbio.2024.152791

BMC Pulm Med. 2024 Aug 23;24(1):405. doi: 10.1186/s12890-024-03214-3.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF), an interstitial lung disease, is characterized by the exacerbation of progressive pulmonary fibrosis (PF). IPF primarily affects older individuals and can lead to respiratory failure. This study aimed to assess the effects of triiodothyronine (T3) treatment on the lung microbiome of mice with PF.

METHODS: Mice were perfused with bleomycin (BLM) to establish a PF model. Using a randomized design, 40 female specific pathogen-free (SPF) C57BL6/N mice were divided into four groups: saline, saline + T3, BLM, and BLM + T3. Histological morphology was assessed through Hematoxylin and Eosin staining as well as Masson's Trichrome staining. For the identification of lung bacteria, 16S rRNA gene sequencing was employed. An Enzyme-Linked Immunosorbent Assay was used to measure total T3 (TT3), free T3 (FT3, and reverse T3 (rT3) levels in the peripheral serum.

RESULTS: T3 treatment ameliorated BLM-induced lung fibrosis and structural damage. The microbiome experienced a decrease in the abundance of Proteobacteria, Bacteroides, and Actinomycetes and an increase in the abundance of Firmicutes when exposed to BLM; however, T3 treatment reversed this effect. The four groups showed no significant difference in alpha microbiome diversity (P > 0.05). Serum concentrations of TT3 and FT3 were positively correlated with microbiome abundance (P < 0.05). Administration of T3 enhanced the microbiota in PF without affecting the diversity and biological functions of the microbiome (P > 0.05).

CONCLUSION: The administration of T3 demonstrated a favorable impact on the lung microbiota of mice afflicted with PF, thereby partially substantiating the potential role of T3 as a therapeutic agent in the management of PF.

PMID:39180004 | DOI:10.1186/s12890-024-03214-3

Chest. 2024 Aug 21:S0012-3692(24)04930-4. doi: 10.1016/j.chest.2024.07.166. Online ahead of print.

ABSTRACT

BACKGROUND: Bronchoalveolar lavage (BAL) cellular analysis is often recommended during the initial diagnostic evaluation of fibrotic ILD. Despite recommendation for its use, between-center heterogeneity exists and supportive data concerning the clinical utility and correlation of BAL findings with radiologic features or patterns remains sparse.

RESEARCH QUESTION: In patients with fibrotic ILD, are BAL findings associated with radiologic features, patterns, and clinical diagnoses?

METHODS: Patients with fibrotic ILD who underwent BAL for diagnostic evaluation and enrolled in the prospective Canadian Registry for Pulmonary Fibrosis were re-reviewed in a standardized multidisciplinary discussion (MDD). BAL was categorized according to guideline-recommended thresholds, and also using thresholds of lymphocytosis>20% and neutrophils>4.5%. High-resolution computed tomography (HRCT) scans were scored (blinded to clinical data) for specific features and percentage lung involvement. Radiologists classified HRCTs according to guideline-defined patterns for idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (fHP), then MDD diagnoses were assigned, considering all available data.

RESULTS: Bronchoscopy with cellular analysis was performed in 209/1593 (13%) patients. Lymphocyte% was weakly negatively correlated with total fibrosis% (r=-0.16, p=0.023) but not statistically significantly correlated with ground glass opacity% (r=0.01, p=0.94). A mixed BAL pattern was the most frequent in all radiologic patterns (range 45% to 69%), with a minority classifiable according to BAL guidelines. BAL lymphocytosis appeared with similar frequency across HRCT patterns of fHP (21%) and UIP (18%). Only 5% of patients with MDD-based fHP had a guideline defined isolated lymphocytosis >15%.

INTERPRETATION: BAL cellular analyses did not significantly correlate with radiologic features, guideline patterns, or MDD-based diagnoses. Ground glass opacities are often interpreted to represent pulmonary inflammation, but were not associated with BAL lymphocytosis in this cohort.

PMID:39179174 | DOI:10.1016/j.chest.2024.07.166

Sci Adv. 2024 Aug 23;10(34):eadk2524. doi: 10.1126/sciadv.adk2524. Epub 2024 Aug 23.

ABSTRACT

Idiopathic pulmonary fibrosis is a major cause of death with few treatment options. Here, we demonstrate the therapeutic efficacy for lung fibrosis of adult lung cell transplantation using a single-cell suspension of the entire lung in two distinct mouse systems: bleomycin treatment and mice lacking telomeric repeat-binding factor 1 expression in alveolar type 2 (AT2) cells (SPC-Cre TRF1fl/fl), spontaneously developing fibrosis. In both models, the progression of fibrosis was associated with reduced levels of host lung progenitors, enabling engraftment of donor progenitors without any additional conditioning, in contrast to our previous studies. Two months after transplantation, engrafted progenitors expanded to form numerous donor-derived patches comprising AT1 and AT2 alveolar cells, as well as donor-derived mesenchymal and endothelial cells. This lung chimerism was associated with attenuation of fibrosis, as demonstrated histologically, biochemically, by computed tomography imaging, and by lung function measurements. Our study provides a strong rationale for the treatment of lung fibrosis using lung cell transplantation.

PMID:39178253 | DOI:10.1126/sciadv.adk2524

Cureus. 2024 Jul 22;16(7):e65146. doi: 10.7759/cureus.65146. eCollection 2024 Jul.

ABSTRACT

Systemic sclerosis (SSc) is one of the chronic autoimmune diseases characterized by the infiltration of excess collagen in various organs, especially the skin. It is found to be associated with a higher prevalence of internal malignancies, particularly lung carcinoma. Herein, we report a case of adenosquamous carcinoma confining within the lung in a patient who had long-standing SSc. She was a 55-year-old female patient presenting with progressive dry cough and breathlessness for six months. She had been a known case of diffuse cutaneous SSc for over a decade, based on 2013 American College of Rheumatology (ACR) criteria. The diagnosis is made based on her findings of bilateral thickening of the fingers on both hands, extending up to the metacarpophalangeal joints. Furthermore, she had telangiectasia at the upper chest wall and neck, multiple pitting scars at the toes, Raynaud's esophageal dilatation, and interstitial lung disease (ILD). She had been treated on Mycophenolate Mofetil 500 mg twice daily and low-dose prednisolone 5 mg once daily for 10 years. The patient's high-resolution computed tomography (HRCT) of the chest revealed a subpleural nodule in the posterior basal segment of the left lower lobe with areas of reticular opacities and interlobular septal thickening on bilateral lung fields six months earlier. The current computed tomography of the lung revealed a new 2.6 x 2.5 cm ill-defined lesion with irregular margins at the left lower lobe. A CT-guided biopsy was done for the lesion, which revealed adenosquamous carcinoma. Immunohistochemistry was consistent with a diagnosis of primary pulmonary adenosquamous carcinoma. The patient did not accept any further investigations and/or treatment. Herein, we present a rare lung malignancy, adenosquamous carcinoma of the lung with an underlying long-term diffuse cutaneous SSc in a nonsmoking female, which highlights the importance of lung cancer screening in individuals with SSc complicated with ILD and supports the fact that there is an increased prevalence of lung cancer among SSc-ILD patients than that of the regular population.

PMID:39176361 | PMC:PMC11341069 | DOI:10.7759/cureus.65146

Front Med (Lausanne). 2024 Aug 7;11:1410051. doi: 10.3389/fmed.2024.1410051. eCollection 2024.

ABSTRACT

BACKGROUND: Alterations in metabolites and metabolic pathways are thought to be important triggers of idiopathic pulmonary fibrosis (IPF), but our lack of a comprehensive understanding of this process has hampered the development of IPF-targeted drugs.

METHODS: To fully understand the metabolic profile of IPF, C57BL/6 J male mice were injected intratracheally with bleomycin so that it could be used to construct a mouse model of IPF, and lung tissues from 28-day and control IPF mice were analyzed by pathology and immunohistochemistry. In addition, serum metabolites from IPF mice were examined using LC-ESI-MS/MS, and the differential metabolites were analyzed for KEGG metabolic pathways and screened for biomarkers using machine learning algorithms.

RESULTS: In total, the levels of 1465 metabolites were detected, of which 104 metabolites were significantly altered after IPF formation. In IPF mouse serum, 52% of metabolite expression was downregulated, with lipids (e.g., GP, FA) and organic acids and their derivatives together accounting for more than 70% of the downregulated differentially expressed metabolites. In contrast, FA and oxidised lipids together accounted for 60% of the up-regulated differentially expressed metabolites. KEGG pathway enrichment analyses of differential metabolites were mainly enriched in the biosynthesis of unsaturated fatty acids, pentose phosphate pathway, and alanine, aspartate, and glutamate metabolism. Seven metabolites were screened by machine learning LASSO models and evaluated as ideal diagnostic tools by receiver operating characteristic curves (ROCs).

DISCUSSION: In conclusion, the serum metabolic disorders found to be associated with pulmonary fibrosis formation will help to deepen our understanding of the pathogenesis of pulmonary fibrosis.

PMID:39175820 | PMC:PMC11340507 | DOI:10.3389/fmed.2024.1410051

Ther Adv Respir Dis. 2024 Jan-Dec;18:17534666241275329. doi: 10.1177/17534666241275329.

ABSTRACT

BACKGROUND: A six-minute walk test (6MWT) is a reproducible, easily performed test, and is widely used to determine functional exercise capacity in patients with idiopathic pulmonary fibrosis (IPF). However, there is currently a paucity of data on the clinical significance of baseline and serial 6-minute walk tests in patients with IPF, especially in Asian patients.

OBJECTIVES: We aimed to investigate the clinical significance of serial 6MWT in patients with IPF, especially in Asian patients.

DESIGN: This is a single-center retrospective cohort study.

METHODS: Clinical data of patients diagnosed with IPF at a tertiary center in Korea were retrospectively analyzed. IPF diagnosis was defined according to the clinical guidelines of the American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society/Latin American Thoracic Association.

RESULTS: There were 216 patients diagnosed with IPF from December 2012 to January 2022, of whom 198 had a baseline of 6MWT data. The mean age of the cohort was 66.9 ± 8.6, and 89% were male. The non-survivors showed significantly lower six-minute walk distance (6MWD), minimum saturation of peripheral oxygen (SpO2) during 6MWT, forced vital capacity, and diffusing capacity of the lung for carbon monoxide than survivors at baseline. A multivariate Cox analysis demonstrated that lower minimum SpO2 was independently associated with increased mortality rates (Hazard ratio (HR): 1.081, 95% confidence interval (CI): 1.024-1.142, p = 0.005). Higher mortality rates were also associated with echocardiographic-determined pulmonary hypertension (HR: 2.466, 95% CI: 1.149-5.296, p = 0.021) at diagnosis. Among 144 patients with 6MWT results at 12 months, patients with a decline of 50 m or more in the 6MWD showed poorer overall survival than others (median survival: 45.0 months vs 58.0 months, p < 0.001).

CONCLUSIONS: Baseline lower minimum SpO2 during 6MWT was an independent prognostic factor in patients with IPF, and a decline in 6MWD in serial follow-up was also associated with a poorer prognosis. These findings suggest that both baseline 6MWT and follow-up data are important in the prognostication of patients with IPF.

PMID:39175212 | DOI:10.1177/17534666241275329

Eur Respir J. 2024 Aug 22;64(2):2401305. doi: 10.1183/13993003.01305-2024. Print 2024 Aug.

NO ABSTRACT

PMID:39174288 | DOI:10.1183/13993003.01305-2024

BMC Pulm Med. 2024 Aug 22;24(1):404. doi: 10.1186/s12890-024-03224-1.

ABSTRACT

BACKGROUND: The serum markers Krebs von den Lungen-6 (KL-6), surfactant protein A (SP-A), and surfactant protein D (SP-D) have been used for the diagnosis, differential diagnosis, and prognosis prediction of interstitial pneumonia. However, the significance of measuring the serum and bronchoalveolar lavage fluid (BALF) KL-6, SP-D, and SP-A levels in predicting the prognosis of chronic fibrosing interstitial pneumonia (CFIP), idiopathic pulmonary fibrosis, and idiopathic nonspecific interstitial pneumonia remains unclear. We aimed to clarify the significance of measuring the serum and BALF KL-6, SP-A, and SP-D levels in predicting the prognosis of patients with CFIP.

METHODS: Among 173 patients who were diagnosed with CFIP between September 2008 and February 2021, 39 who underwent bronchoalveolar lavage were included in this study. Among these, patients experiencing an annual decrease in forced vital capacity (FVC) of ≥10% or those facing challenges in undergoing follow-up pulmonary function tests owing to significant deterioration in pulmonary function were categorized as the rapidly progress group. Conversely, individuals with an annual decrease in the FVC of <10% were classified into the slowly progress group. The serum and BALF KL-6, SP-D, and SP-A levels, as well as BALF/serum SP-D and SP-A ratios were compared between the two groups.

RESULTS: Among the patients with CFIP, the BALF SP-D level (p=0.0111), BALF SP-A level (p<0.0010), BALF/serum SP-D ratio (p=0.0051), and BALF/serum SP-A ratio (p<0.0010) were significantly lower in the rapidly than in the slowly progress group (p<0.0010). The receiver operating characteristics analysis results demonstrated excellent performance for diagnosing patients with CFIP, with the BALF SP-D level (area under the curve [AUC], 0.7424), BALF SP-A level (AUC, 0.8842), BALF/serum SP-D ratio (AUC, 0.7673), and BALF/serum SP-A ratio (AUC, 0.8556). Moreover, the BALF SP-A level showed a notably superior CFIP diagnostic capability. Survival analysis using the Kaplan-Meier method revealed that patients with a BALF SP-A level of <1500 ng/mL and BALF/serum SP-A ratio of <15.0 had poor prognoses.

CONCLUSIONS: Our results suggest that BALF SP-A measurement may be useful for predicting the prognosis in patients with CFIP.

PMID:39174992 | DOI:10.1186/s12890-024-03224-1

Genes Immun. 2024 Aug 22. doi: 10.1038/s41435-024-00292-5. Online ahead of print.

ABSTRACT

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.

PMID:39174688 | DOI:10.1038/s41435-024-00292-5

Curr Opin Rheumatol. 2024 Aug 23. doi: 10.1097/BOR.0000000000001047. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Scleroderma and other fibrotic diseases have been investigated using single-cell RNA sequencing (scRNA-Seq), which has demonstrated enrichment in myeloid cell populations in multiple tissues. However, scRNA-Seq studies are inconsistent in their nomenclature of myeloid cell types, including dendritic cells, monocytes, and macrophages. Using cell type-defining gene signatures, I propose a unified nomenclature through analysis of myeloid cell enrichment across fibrotic tissues.

RECENT FINDINGS: scRNA-Seq of human blood and skin identified a new subset of dendritic cells called DC3. DC3 express similar inflammatory genes to monocytes, including FCN1, IL1B, VCAN, S100A8, S100A9, and S100A12. DC3 can be distinguished from monocytes by expression of EREG and Fc receptor genes such as FCER1A and FCGR2B. scRNA-Seq analyses of scleroderma skin and lung, idiopathic pulmonary fibrosis (IPF), COVID-19 lung fibrosis, myelofibrosis, and liver, kidney, and cardiac fibrosis all showed enrichment in myeloid cell types. Although they were called different names, studies of scleroderma skin and lung as well as liver cirrhosis datasets demonstrated enrichment in DC3. By contrast, lung, heart, and kidney fibrosis were enriched in SPP1 macrophages. High numbers of DC3 in the skin was associated with worse SSc skin and lung fibrosis severity.

SUMMARY: scRNA-Seq of multiple diseases showed enrichment of DC3 in fibrotic skin, lung, and liver, whereas SPP1 macrophages occurred in fibrotic lung, heart, and kidney. Because DC3 and SPP1 macrophages showed organ-specific enrichment, understanding their signaling mechanisms across tissues will be important for future investigation.

PMID:39171604 | DOI:10.1097/BOR.0000000000001047

BMC Pulm Med. 2024 Aug 22;24(1):403. doi: 10.1186/s12890-024-03226-z.

ABSTRACT

BACKGROUND: Progressive pulmonary fibrosis is the symptomatic, physiological, and radiological progression of interstitial lung diseases. The aim of this study was to examine the relationship between progressive pulmonary fibrosis and demographic characteristics and to evaluate the effect on clinical outcomes and mortality.

METHODS: This cross-sectional study included 221 patients diagnosed with non-idiopathic pulmonary fibrosis interstitial lung diseases who were followed in the last 5 years. Patient symptoms, clinical, radiological, and demographic data were examined. Risk factors for the development of progressive pulmonary fibrosis and the relationship with clinical outcomes and mortality were examined.

RESULTS: Of the patients, 33.0% (n = 73) had fibrotic idiopathic nonspecific interstitial pneumonia (iNSIP), 35.7% (n = 79) had fibrotic hypersensitivity pneumonia (HP), 18.1% (n = 40) had fibrotic connective tissue disease (CTD) interstitial lung diseases (ILD), and 13.1% (n = 29) had postinfectious fibrotic ILD. The progressive pulmonary fibrosis development rates of the subtypes were 46.5% iNSIP (n = 34), 86.0% fibrotic HP (n = 68), 42.5% fibrotic CTD-ILD (n = 17), and 20.7% postinfectious ILD (n = 6). The presence of progressive pulmonary fibrosis was associated with the development of respiratory failure and mortality (odds ratio [OR]: 2.70, 95% CI: 1.04-7.05 and OR: 2.13, 95% CI: 1.23-3.69). Progressive pulmonary fibrosis development was higher in hypersensitivity pneumonia patients with farmer's lung (OR: 5.06, 95% CI: 1.02-25.18).

CONCLUSION: Progressive pulmonary fibrosis was more prevalent in older patients. Farming was an important risk factor in the development of hypersensitivity pneumonia-progressive pulmonary fibrosis. Respiratory failure and mortality were higher in those who developed progressive pulmonary fibrosis.

PMID:39169372 | DOI:10.1186/s12890-024-03226-z