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Background: Growing evidence indicates an association between circulating immune cell phenotypes and idiopathic pulmonary fibrosis (IPF). Although studies have attempted to elucidate the causal relationship between the two, further clarification of the specific mechanisms and causal linkages is warranted. Objective: We aimed to conduct a two-sample Mendelian randomization (MR) analysis with transcriptomics data analysis to elucidate the causal relationship between circulating immune cells and IPF and to explore potential biomarkers. Methods: We first explored the bidirectional causal association between IPF and immune cell phenotypes using two-sample MR analysis. Genome-wide association studies data for immune cell phenotype and IPF were obtained from publicly available databases. A standardized instrumental variable screening process was used to select single nucleotide polymorphisms (SNPs) for inclusion in the MR. Five methods represented by IVW were used to assess causal effects. Subsequently, SNP-nearest genes combined with the transcriptomics data of IPF were subjected to multiple bioinformatics analyses such as TIMER, WGCNA, functional enrichment analysis, protein-protein interaction analysis, and ROC to identify IPF biomarkers. Finally, the single-cell RNA sequencing (scRNA-seq) data was used to validate our findings by single-cell analysis. Results: The MR study identified 27 immune cell phenotypes causally associated with IPF, of which 20 were associated with a decreased risk of developing IPF and 7 were associated with an increased risk. CTSB (AUC=0.98), IL10 (AUC=0.83), and AGER (AUC=0.87) were identified as promising biomarkers of IPF. Single cell analysis showed differences in CD14+ CD16+ monocytes, CD16+ monocytes and Granulocyte-monocyte progenito between the IPF group and the healthy control group. The three hub genes were highly expressed in three immune cell subsets of IPF patients. It underscores the potential feasibility of three genes as biomarkers. Conclusions: Our study demonstrates the causal associations of specific immune cell phenotypes with IPF through genetic methods and identifies CTSB , IL10 , and AGER as biomarkers of IPF through bioinformatics analysis. These findings provide guidance for future clinical and basic research. [ABSTRACT FROM AUTHOR]

Background: Pulmonary fibrosis is characterized by the destruction of normal lung tissue and then replacement by abnormal fibrous tissue, leading to an overall decrease in gas exchange function. The effective treatment for pulmonary fibrosis remains unknown. The upstream pathogenesis of pulmonary fibrosis may involve cellular senescence of the lung tissue. Previously, a new gene therapy technology using Box A of the HMGB1 plasmid (Box A) was used to reverse cellular senescence and cure liver fibrosis in aged rats. Methods: Here, we show that Box A is a promising medicine for the treatment of lung fibrosis. In a bleomycin-induced pulmonary fibrosis model in the male Wistar rats, Student's t-test and one-way ANOVA were used to compare groups of samples. Results: Box A effectively lowered fibrous tissue deposits (from 18.74 ± 0.62 to 3.45 ± 1.19%) and senescent cells (from 3.74 ± 0.40% to 0.89 ± 0.18%) to levels comparable to those of the negative control group. Moreover, after eight weeks, Box A also increased the production of the surfactant protein C (from 3.60 ± 1.68% to 6.82 ± 0.65%). Conclusions: Our results demonstrate that Box A is a promising therapeutic approach for pulmonary fibrosis and other senescence-promoted fibrotic lesions. [ABSTRACT FROM AUTHOR]

Background and aims: Predicting progression and prognosis in Interstitial Lung Diseases (ILD), especially Idiopathic Pulmonary Fibrosis (IPF) and Progressive Pulmonary Fibrosis (PPF), remains a challenge. Integrating patient-centered measurements is essential for earlier and safer detection of disease progression. Home monitoring through e-health technologies, such as spirometry and oximetry connected to smartphone applications, holds promise for early detection of ILD progression or acute exacerbations, enabling timely therapeutic interventions. Methods: The European ILD Registry Algorithm for Self-Assessment in ILD (eurILDreg ASA-ILD), developed by all eurILDreg principal investigators, includes questionnaires on symptom burden, respiratory infections, and quality of life (EQ5D VAS, K-BILD, LCQ). The algorithm also incorporates spirometry and oxygen saturation measurements, both at rest and during exercise (one-minute sit-to-stand test, 1STST). This ASA-ILD algorithm is integrated into the patientMpower Ltd. smartphone application, used for patient-led monitoring, research, and clinical care since 2016, and available on both Apple and Android platforms. Discussion: For patient-centered measurements, participants in the multicenter eurILDreg study will receive a patientMpower account, a handheld clinical-grade spirometer (Spirobank Smart, MIR, Italy), and a pulse oximeter (Nonin Medical, Inc. Plymouth, MN, USA), along with usage instructions. Artificial intelligence software (ArtiQ) will analyze spirometry maneuvers in real-time, ensuring compliance with recent ERS/ATS criteria and providing automated feedback. Pulse oximetry is integrated into the exercise testing within the application, following an automated in-app protocol developed with clinician involvement for safety and accuracy. The application will send reminders to participants to complete patient-reported outcome measures (PROMs) according to the study protocol. Conclusion: This study is designed to explore the potential of e-Health technologies, such as home monitoring via spirometry and oximetry, integrated with the eurILDreg ASA-ILD algorithm and patientMpower app, to improve early detection and management of ILD. A pilot trial showed promising adherence to spirometry, indicating that digital health interventions could enhance patient care and outcomes in ILD. Trial registration: The ethics committee of the Justus-Liebig-University of Giessen has approved the eurILDreg and this substudy with the protocol reference number 111/08. The research was conducted strictly according to the principles of the Declaration of Helsinki. Patients were included into the registry upon having signed the informed consent. The eurIPFreg and eurIPFbank are listed in ClinicalTrials.gov (NCT02951416). EurILDreg is registered in German Clinical Trials Register, DRKS 00028968. [ABSTRACT FROM AUTHOR]

Background: Fibrotic types of interstitial lung abnormalities seen on high-resolution computed tomography scans, characterised by traction bronchiolectasis/bronchiectasis with or without honeycombing, are predictors of progression and poor prognostic factors of interstitial lung abnormalities. There are no reports on the clinical characteristics of fibrotic interstitial lung abnormalities on high-resolution computed tomography scans. Therefore, we aimed to examine these clinical characteristics and clarify the predictive factors of fibrotic interstitial lung abnormalities on high-resolution computed tomography scans. Methods: Clinical and paraclinical data of 164 patients enrolled in the initial year of a multicentre prospective observational study (Kumamoto interstitial lung abnormalities study in Japan) involving over 62,000 examinees during routine health examinations were analysed. Clinical laboratory evaluations are expressed as medians and interquartile ranges for each evaluation time point, and boxplots were created for graphical representation. The percentages of abnormal clinical laboratory results were compared between the groups using chi-square or Fisher's exact tests. Univariate or multivariate logistic regression analyses were performed to analyse the relationship between fibrotic interstitial lung abnormalities and other clinical factors. Results: Fibrotic interstitial lung abnormalities were observed on high-resolution computed tomography scans in 135 (82%) patients at the time of diagnosis. Multivariate analysis showed that older age (Odds ratio, 1.06; 95% confidence interval, 1.01–1.12; p = 0.021), auscultatory fine crackles (Odds ratio, 3.39; 95% confidence interval, 1.33–8.65; p < 0.01), and elevated serum surfactant protein-D (Odds ratio, 2.68; 95% confidence interval, 1.02–8.64; p = 0.045) were independent predictive factors of fibrotic interstitial lung abnormalities. The predicted area under the curve of the fibrotic interstitial lung abnormalities based on these three factors was 0.77 (95% confidence interval, 0.68–0.86). The proportion of undecided diagnoses in the fibrotic interstitial lung abnormalities group (14%) was significantly lower than that in the non-fibrotic interstitial lung abnormalities group (41%) (p = 0.0027). Conclusions: Fine crackles on auscultation and elevated serum surfactant protein-D levels are predictors of fibrotic interstitial lung abnormalities in older patients with interstitial lung abnormalities. These findings may assist non-radiological physicians in referring patients to specialists for early intervention in progressive fibrotic interstitial lung diseases. Trial registration number/date: UMIN000045149/2021.12.1. [ABSTRACT FROM AUTHOR]

Introduction: Diffuse parenchymal lung diseases (DPLD) cover heterogeneous types of lung disorders. Among many pathological phenotypes, pulmonary fibrosis is the most devastating and represents a characteristic sign of idiopathic pulmonary fibrosis (IPF). Despite a poor prognosis brought by pulmonary fibrosis, there are no specific diagnostic biomarkers for the initial development of this fatal condition. The major hallmark of lung fibrosis is uncontrolled activation of lung fibroblasts to myofibroblasts associated with extracellular matrix deposition and the loss of both lung structure and function. Methods: Here, we used this peculiar feature in order to identify specific biomarkers of pulmonary fibrosis in bronchoalveolar lavage fluids (BALF). The primary MRC-5 human fibroblasts were activated with BALF collected from patients with clinically diagnosed lung fibrosis; the activated fibroblasts were then washed rigorously, and further incubated to allow secretion. Afterwards, the secretomes were analysed by mass spectrometry. Results: In this way, the CD44 protein was identified; consequently, BALF of all DPLD patients were positively tested for the presence of CD44 by ELISA. Finally, biochemical and biophysical characterizations revealed an exosomal origin of CD44. Receiver operating characteristics curve analysis confirmed CD44 in BALF as a specific and reliable biomarker of IPF and other types of DPLD accompanied with pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Background: A growing body of evidence suggests that prolonged use of inhaled corticosteroids (ICS) and proton pump inhibitors (PPIs) is associated with increased risks of pneumonia. A substantial proportion of people with idiopathic pulmonary fibrosis (IPF) are prescribed PPIs or ICS to treat common comorbidities, giving rise to concerns that use of these medications may be associated with potential harms in this patient population. Methods: We used UK Clinical Practice Research Datalink (CPRD) Aurum primary care data linked to national mortality and hospital admissions data to create a cohort of people diagnosed with IPF on or after 1 January 2010. Patients were assigned to one of three exposure categories according to their prescribing history in the 12 months prior to IPF diagnosis as follows: "regular" users (≥ 4 prescriptions), "irregular" users (1–3 prescriptions) and "non-users" (no prescriptions). We explored the association between PPI/ICS prescription and pneumonia hospitalisation and all-cause mortality using multinomial Cox regression models. Results: A total of 17,105 people met our study inclusion criteria; 62.6% were male and 15.9% were current smokers. Median age at IPF diagnosis was 76.7 years (IQR: 69.6–82.7). 19.9% were regularly prescribed PPIs, and 16.0% ICS, prior to IPF diagnosis. Regular prescribing of PPIs and ICS was positively associated with hospitalisation for pneumonia; the adjusted HR for pneumonia hospitalisation comparing regular PPI users with non-users was 1.14 (95%CI: 1.04–1.24); for regular ICS users the corresponding HR was 1.40 (95%CI: 1.25–1.55). We also observed a small increased risk for all-cause mortality in the "regular ICS user" group compared with the "non-user" control group (HRadj = 1.19, 1.06–1.33). We found no evidence of an association between PPI prescribing and all-cause mortality. Conclusion: Prolonged prescription of medications used to treat common comorbidities in IPF may be associated with increased risks for severe respiratory infections. These findings point to a need to adopt an adequate risk–benefit balance approach to the prescribing of ICS-containing inhalers and PPIs in people with IPF without evidence of comorbidities, especially older patients and/or those with more advanced disease in whom respiratory infections are more likely to result in poorer outcomes. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal disease of the lungs. It is characterized by pulmonary and extrapulmonary comorbidities. So far, little is known as regards the prevalence of cardiovascular comorbidities in IPF patients. This study aims to investigate the prevalence of cardiovascular comorbidities in patients with IPF and correlate it with different radiological and laboratory indices of disease severity. Methods: This prospective case–control study was performed on 134 IPF patients above 18 years. Diagnosis of IPF was based on diagnostic radiologic criteria addressed by ATS guidelines. Patients were recruited from the Pulmonology Department, Assiut University Hospitals, from June 2023 to June 2024. Cardiac comorbidities were assessed by ECG and echocardiography. All patients had C-reactive protein (CRP), Krebs von den Lungen-6 (KL-6), and lipid profile including cholesterol level, triglyceride level, HDL-cholesterol level, and LDL-cholesterol level measured. Patients were divided into two groups: IPF patients with cardiovascular comorbidities and IPF patients without cardiovascular comorbidities. Comparison between both groups as regards clinical, radiological, and laboratory criteria was carried out. Results: The studied group consists predominantly of females (65%). Sixty out of the 134 documented IPF patients had cardiovascular comorbidities (44.7%), cardiomyopathy (mean ± SD: 43.63 ± 10.56), pulmonary hypertension (mean ± SD: 41.67 ± 15.32), ECG-ischemic changes (40.0%), and atrial fibrillation (13.3%). IPF patients with cardiovascular comorbidities vs. patients without had higher radiological HRCT total fibrosis score TFS (P value < 0.001). As regards laboratory serum biomarkers, the group with comorbidities showed significantly higher CRP, KL-6, cholesterol level, triglyceride level, and LDL-cholesterol level (P value < 0.001). Box plot analysis demonstrated significantly higher KL-6 serum level among IPF patients with cardiovascular comorbidities. Sensitivity 90.0%, specificity 94.6%, and accuracy 92.5% were associated with a cutoff value of KL-6 ≥ 299 for prediction of associated cardiovascular comorbidities among the studied IPF group. Conclusions: Dyslipidemia and cardiovascular comorbidities were detected in a large group of IPF patients. These comorbidities were associated with a high HRCT TFS score. High serum levels of CRP and KL-6 were predictors of associated cardiovascular comorbidities in IPF. Trial registration: ClinicalTrials.gov. NCT06539962. [ABSTRACT FROM AUTHOR]

Invasive lung myofibroblasts are the main cause of tissue remodeling in idiopathic pulmonary fibrosis (IPF). A key mechanism contributing to this important feature is aberrant crosstalk between the abnormal/injured lung epithelium and pulmonary fibroblasts. Here, we demonstrate that lungs from patients with IPF and from mice with bleomycin (BLM)-induced pulmonary fibrosis (PF) are characterized by the induction of human epididymis protein 4 (HE4) overexpression in epithelial cells. HE4 knockdown primarily in epithelial cells attenuates BLM-induced PF in mice, whereas the administration of recombinant mouse HE4 exacerbates fibrosis after BLM stimulation. Mechanistic analysis shows that HE4 and annexin II (ANXA2) specific binding enhances the profibrotic phenotype in epithelial cells, and directly promotes lung fibroblast activation, leading to aberrant epithelial-fibroblast crosstalk and the persistent myofibroblast phenotype. The HE4 and ANXA2 binding site is located after the 30th amino acid at the N terminus of the HE4 molecule. Finally, intratracheal administration of HE4 shRNA lentivirus protects mice against BLM-induced PF. These data suggest that HE4 can serve as a potential therapeutic target in the treatment of IPF. HE4 and ANXA2 specific binding enhances the profibrotic phenotype in epithelial cells, and directly promotes lung fibroblast activation, leading to aberrant epithelial-fibroblast crosstalk in pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Background: Current research underscores the need to better understand the pathogenic mechanisms and treatment strategies for idiopathic pulmonary fibrosis (IPF). This study aimed to identify key targets involved in the progression of IPF. Methods: We employed Mendelian randomization (MR) with three genome-wide association studies and four quantitative trait loci datasets to identify key driver genes for IPF. Prioritized targets were evaluated for respiratory insufficiency and transplant-free survival. The therapeutic efficacy of the core gene was validated in cellular and animal models. Additionally, we conducted a comprehensive evaluation of therapeutic value, pathogenic mechanisms, and safety through phenome-wide association study (PheWAS), mediation analysis, transcriptomic analyses, shared causal variant exploration, DNA methylation MR, and protein interactions. Results: Multiple MR results revealed that BRSK2 has a significant pathogenic impact on IPF at both transcriptional and translational levels, with a lung tissue-specific association (OR = 1.596; CI, 1.300–1.961; Pval = 8.290 × 10 − 6). BRSK2 was associated with IPF progression driven by high-risk factors, with mediation effects ranging from 34.452 to 69.665%. Elevated BRSK2 expression in peripheral blood mononuclear cells correlated with reduced pulmonary function, while increased circulating BRSK2 levels suggested respiratory failure and shorter transplant-free survival in IPF patients. BRSK2 silencing attenuated lung fibrosis progression in cellular and animal models. Transcriptomic integration identified PSMB1, CTSD, and CTSH as significant downstream effectors of BRSK2, with PSMB1 showing robust shared causal variant support (PPH4 = 0.800). Colocalization analysis and phenotype scan deepened the pathogenic association of BRSK2 with IPF, while methylation MR analysis highlighted the critical role of epigenetic regulation in BRSK2-driven IPF pathogenesis. PheWAS revealed no significant drug-related toxicities for BRSK2, and its therapeutic potential was further underscored by protein interaction analyses. Conclusions: BRSK2 is identified as a critical pathogenic factor in IPF, with strong potential as a therapeutic target. Future studies should focus on its translational implications and the development of targeted therapies to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is the most common Interstitial Lung Disease (ILD). It is characterized by dyspnoea and a progressive decline in lung function, which negatively affects life. This study aimed to evaluate Health-Related Quality of Life (HRQoL) in IPF patients in Latin American countries. Methods: Six countries (Argentina, Bolivia, Colombia, Chile, Mexico, and the Dominican Republic) enrolled patients with IPF. They answered the Saint George's Respiratory Questionnaire for Idiopathic Pulmonary Fibrosis (SGRQ-I) and the Hospital Anxiety and Depression Scale (HADS). Demographic characteristics, the Torvan index, and a lung function test were also assessed. IPF was diagnosed according to the ATS/ERS/JRS/ALAT 2018 criteria. Results: We enlisted 75 patients diagnosed with IPF; 81% were male, with an average age of 74 ± 7. The total SGRQ-I score was 49 ± 23, with a higher score in the activity domain of 70 ± 23. Torvan index average was 17 ± 6. We found that 28% presented anxiety and 35% depression. Besides, we observed that patients requiring oxygen had a worse quality of life (total SGRQ-I 62 ± 22 vs. 45 ± 22, p = 0.003) without finding differences in antifibrotic therapy. We did not find differences in HRQoL when dividing groups according to their altitude above sea level, except for a higher frequency of anxiety in patients living at sea level. Conclusions: We found similar data compared to those reported in real-life European populations. We also found that anxiety and depression are prevalent. However, they are often underdiagnosed and, therefore, left untreated. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease, characterized by impaired wound repair, tissue remodeling and fibrosis. Immune system may participate in the development and progression of the disease as indicated by altered activity in IPF sufferers. This study investigates the immune response to the BNT162b2 COVID-19 vaccine in patients with IPF compared to healthy controls, with a particular focus on evaluation of antibody responses, interferon-gamma release, cytokine profiling and a broad panel of immune cell subpopulations. IPF patients without prior exposure to SARS-CoV-2 had undetectable levels of anti-N IgG antibodies, highlighting their lack of previous infection. After vaccination, IPF patients showed a significant increase in anti-S1 IgG and IgA antibodies, though their levels were lower compared to healthy controls and convalescent IPF patients. Additionally, IPF patients exhibited altered proportions of regulatory T cells (Tregs) and effector T lymphocytes (Teffs) before and after vaccination. Specifically, IPF patients had higher percentages of Tregs with a Th2 phenotype and Th17 Tregs, along with reduced proportions of Th1/17 Tregs. Teffs in IPF patients showed a decrease in Th1-like and Th2-like populations after vaccination. Moreover, IPF patients demonstrated elevated populations of cytotoxic T lymphocytes (Tc) before vaccination and increased levels of γδ Tc cells throughout the study. Alterations in cytokine profiles were also observed, IPF patients showed higher levels of IL-6 and IL-22 compared to healthy controls. These findings suggest a distinct immune response in IPF patients to the COVID-19 vaccine, characterized by differences in antibody production, T cell differentiation and cytokine secretion compared to healthy individuals. [ABSTRACT FROM AUTHOR]

Collagen-I fibrillogenesis is crucial to health and development, where dysregulation is a hallmark of fibroproliferative diseases. Here, we show that collagen-I fibril assembly required a functional endocytic system that recycles collagen-I to assemble new fibrils. Endogenous collagen production was not required for fibrillogenesis if exogenous collagen was available, but the circadian-regulated vacuolar protein sorting (VPS) 33b and collagen-binding integrin α11 subunit were crucial to fibrillogenesis. Cells lacking VPS33B secrete soluble collagen-I protomers but were deficient in fibril formation, thus secretion and assembly are separately controlled. Overexpression of VPS33B led to loss of fibril rhythmicity and overabundance of fibrils, which was mediated through integrin α11β1. Endocytic recycling of collagen-I was enhanced in human fibroblasts isolated from idiopathic pulmonary fibrosis, where VPS33B and integrin α11 subunit were overexpressed at the fibrogenic front; this correlation between VPS33B, integrin α11 subunit, and abnormal collagen deposition was also observed in samples from patients with chronic skin wounds. In conclusion, our study showed that circadian-regulated endocytic recycling is central to homeostatic assembly of collagen fibrils and is disrupted in diseases. [ABSTRACT FROM AUTHOR]

Aim: Transbronchial cryobiopsies are increasingly used for the diagnosis of interstitial lung disease (ILD), but there is a lack of published information on the features of specific ILD in cryobiopsies. Here we attempt to provide pathological guidelines for separating usual interstitial pneumonia (UIP) of idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis (FHP) and connective tissue disease‐associated ILD (CTD–ILD) in cryobiopsies. Methods: We examined 120 cryobiopsies from patients with multidisciplinary discussion (MDD)‐established CTD–ILD and compared them to a prior series of 121 biopsies from patients with MDD‐established IPF or FHP. Results: A non‐specific interstitial pneumonia (NSIP) pattern alone was seen in 36 of 120 (30%) CTD–ILD, three of 83 (3.6%) FHP and two of 38 (5.2%) IPF cases, statistically favouring a diagnosis of CTD–ILD. The combination of NSIP + OP was present in 29 of 120 (24%) CTD–ILD, two of 83 (2.4%) FHP and none of 38 (0%) IPF cases, favouring a diagnosis of CTD–ILD. A UIP pattern, defined as fibroblast foci plus any of patchy old fibrosis/fibrosis with architectural distortion/honeycombing, was identified in 28 of 120 (23%) CTD–ILD, 45 of 83 (54%) FHP and 27 of 38 (71%) IPF cases and supported a diagnosis of FHP or IPF. The number of lymphoid aggregates/mm2 and fibroblast foci/mm2 was not different in IPF, CTD–ILD or FHP cases with a UIP pattern. Interstitial giant cells supported a diagnosis of FHP or CTD–ILD over IPF, but were infrequent. Conclusions: In the correct clinical/radiological context the pathological findings of NSIP, and particularly NSIP plus OP, favour a diagnosis of CTD–ILD in a cryobiopsy, but CTD–ILD with a UIP pattern, FHP with a UIP pattern and IPF generally cannot be distinguished. [ABSTRACT FROM AUTHOR]

Background: IPF is a chronic disease with impaired diaphragmatic function. In the vast majority of patients, lung function gradually deteriorates until intractable respiratory failure occurs. Aim of work: To assess diaphragmatic ultrasound in IPF patients and its relation to functional parameters. Subjects and methods: This study used a case–control design and involved IPF patients who were either attending an outpatient clinic or admitted to a ward at Ain Shams University Hospitals and Abbassia Chest Hospital. Forty-five participants were included and split up into 3 groups: group A: 15 IPF cases suffering from hypoxia. Group B: 15 IPF patients without hypoxia or respiratory failure. Group C: 15 healthy participants as controls. Result: Groups A and B had considerably decreased diaphragm excursion (QB), thickness of diaphragm at the end of inspiration, diaphragm thickness fraction, and diaphragm thickness fraction % when compared to the control group. Patients' diaphragm excursion during deep breathing was significantly smaller in group A than it was in the controls. The diaphragm excursion (QB and DB), the thickness of the diaphragm at the end of inspiration, the thickness fraction, and the fraction % were positively associated with FVC, FEF 25–75, FEV1, 6MWT, the O2 sat before, the O2 sat after, and the O2 at RA, while they were negatively correlated with FEV1/FVC. There was no difference between groups in diaphragm thickness at the end of expiration. Conclusion: Diaphragmatic ultrasound parameters demonstrated strong correlations with pulmonary function parameters, 6-min walk test, and oxygen saturation levels. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is an irreversible lung condition that progresses over time, which ultimately results in respiratory failure and mortality. In this study, we found that PLAC8 was downregulated in the lungs of IPF patients based on GEO data, in bleomycin (BLM)-induced lungs of mice, and in primary murine alveolar epithelial type II (pmATII) cells and human lung epithelial cell A549 cells. Overexpression of PLAC8 facilitated autophagy and inhibited apoptosis of pmATII cells and A549 cells in vitro. Moreover, inhibition of autophagy or overexpression of p53 partially abolished the effects of PLAC8 on cell apoptosis. ATII cell-specific overexpression of PLAC8 alleviated BLM-induced pulmonary fibrosis in mice. Mechanistically, PLAC8 interacts with VCP-UFD1-NPLOC4 complex to promote p53 degradation and facilitate autophagy, resulting in inhibiting apoptosis of alveolar epithelial cells and attenuating pulmonary fibrosis. In summary, these findings indicate that PLAC8 may be a key target for therapeutic interventions in pulmonary fibrosis. PLAC8 attenuates pulmonary fibrosis and inhibits apoptosis of alveolar epithelial type II cells via facilitating autophagy and VCP-mediated p53 degradation. [ABSTRACT FROM AUTHOR]

Automated tools for quantification of idiopathic pulmonary fibrosis (IPF) can aid in ensuring reproducibility, however their complexity and costs can differ substantially. In this retrospective study, two automated tools were compared in 45 patients with biopsy proven (12/45) and imaging-based (33/45) IPF diagnosis (mean age 74 ± 9 years, 37 male) for quantification of pulmonary fibrosis in CT. First, a tool that identifies multiple characteristic lung texture features was applied to measure multi-texture fibrotic lung (MTFL) by combining the amount of ground glass, reticulation, and honeycombing. Opacity-based fibrotic lung (OFL) was measured by a second tool that performs a simpler binary classification of tissue into either normal or opacified lung and was originally developed for quantifying pneumonia. Differences in quantification of MTFL and OFL were assessed by Mann-Whitney U-test and Pearson correlation (r). Also, correlation with spirometry parameters (percent predicted total lung capacity (TLC), percent predicted vital capacity (VC), percent predicted forced expiratory volume in 1 s (FEV1), diffusing capacity of the lungs for carbon monoxide (DLCO), partial pressure of oxygen (PO2) and carbon dioxide (PCO2)) were assessed by r. The prognostic values for 3-year patient survival of OFL, LSS and MTFL were investigated by multivariable Cox-proportional-hazards (CPH) models including sex, age and TLC and including sex, age and VC. Also, Kaplan-Meier analysis with log rank test between subgroups separated by median OFL and MTFL were conducted. No significant difference between OFL and MTFL was observed (median and interquartile range: OFL = 29% [20-38%], MTFL = 31% [19-45%]; P = 0.44). For OFL significant correlation was observed to MTFL (r = 0.93, P < 0.01) and VC (r=-0.50, P = 0.03). For MTFL no significant correlation to spirometry parameters was found. The total time for one analysis was lower for the automated MTFL (MTFL: 313 ± 25s vs. OFL: 612 ± 61s, P < 0.001). Both analyses were significant predictors in the multivariable CPH analysis including TLC (hazard-ratios: MTFL 1.03 [1.01–1.06], P = 0.02; OFL 1.03 [1.00-1.06], P = 0.03). No parameter was a significant predictor in the CPH models including VC (hazard-ratios: MTFL 1.01 [0.98–1.04], P = 1; OFL 1.01 [0.97–1.05], P = 1). OFL showed significance in Kaplan-Meier analysis (MTFL: P = 0.17; OFL: P = 0.03). Using a simple opacity-based quantification of pulmonary fibrosis in IPF patients displayed similar results and prognostic value compared to a more complex multi-texture based analysis. [ABSTRACT FROM AUTHOR]

Background: This study aims to compare Lung Ultrasound (LUS) findings with High-Resolution Computerized Tomography (HRCT) and Pulmonary Function Tests (PFTs) to detect the severity of lung involvement in patients with Usual Interstitial Pneumonia (UIP) and Non-Specific Interstitial Pneumonia (NSIP). Methods: A cross-sectional study was conducted on 35 UIP and 30 NSIP patients at a referral hospital. All patients underwent LUS, HRCT, and PFT. LUS findings such as B-lines, pleural fragmentation, and pleural thickening were compared with HRCT-based lung involvement and PFT parameters. Results: In UIP patients, B-lines > 18 and pleural fragmentation significantly differentiated between < 50% and > 50% HRCT involvement. A logistic regression model showed that B-lines > 18 (OR = 39, p = 0.04) and pleural fragmentation (OR = 22, p = 0.037) independently predicted > 50% HRCT involvement. ROC analysis of the model revealed 84.2% sensitivity and 84.5% specificity. Furthermore, the crude number of B-lines (OR = 1.2, p = 0.038) and > 50% HRCT involvement (OR = 9.5, p = 0.045) independently predicted severe DLCO impairment, with a sensitivity of 94.7% and specificity of 84.5%. Linear regression showed that each additional B-line was associated with a 0.4% decrease in DLCO (Beta = -0.377, p = 0.043), independent of patient diagnosis. In NSIP patients, no significant correlation was observed between LUS findings and > 50% HRCT involvement (p > 0.05), though B-line numbers and pleural thickening increased in cases with severe DLCO impairment (p < 0.05). Conclusions: LUS shows promise as a sensitive, radiation-free alternative to HRCT in monitoring the severity of UIP. It is particularly valuable in predicting the extent of lung involvement and severe DLCO impairment in UIP patients but has limited application in NSIP. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis, nomogram model for its prognosis and acute exacerbation was constructed. Methods: Two hundred and sixty eight patients with IPF were grouped with different severity according to fibrosis area, serum Club cell secretory protein 16(CC16) was compared between these groups. All patients were randomly divided into training and testing sets. COX regression and LASSO algorithm were used to screen featured characteristics. Then nomogram models were constructed, ROC curve, calibration curve and decision curve analysis(DCA) were conducted to evaluate the performance of model. Expression of CC16 were detected in fibrotic human lung tissues, bronchoalveolar lavage fluid (BALF) and Bleomycin(BLM)-treated mouse lung tissues and serums. Results: Serum CC16 gradually increased with the severity of fibrosis, and was especially high in AE-IPF group. CC16 and diffusion capacity for carbon monoxide (DLCO) were screened as characteristic variables to construct nomogram model for IPF prognosis. The survival was significantly lower in high-risk group scored by the model. The area under ROC curves(AUCs) for 1-year and 2-year mortality prediction were 0.866 and 0.916, respectively. This model performed better than gender-age-physiology (GAP) index for predicting 2-year and 3-year mortality. Another nomogram model for acute exacerbation of IPF based on CC16, Krebs von den Lungen-6(KL-6) and DLCO was developed, the AUC was 0.815. Expression of CC16 obviously up-regulated in fibrotic lung tissues, BALF and BLM-treated mice lung tissues and serums. Conclusions: The nomogram model based on CC16 performed good predictive ability for prognosis and acute exacerbation of IPF. [ABSTRACT FROM AUTHOR]

AbstractIdiopathic Pulmonary Fibrosis (IPF) is a chronic respiratory disorder for which pirfenidone is the recommended first-line anti-fibrotic treatment. While pirfenidone has demonstrated efficacy in slowing the progression of IPF, its use is associated with several challenges and unresolved issues that impact patient outcomes. Pirfenidone administration can result in gastrointestinal side effects, photosensitivity reactions, and significant drug interactions, particularly in patients with hepatic impairment. For those who experience intolerable side effects, dose reductions or temporary discontinuations are frequently employed. However, there is limited data on the efficacy of reduced doses, creating uncertainty about the balance between tolerability and therapeutic benefit.The aim of this study is to evaluate the currently proposed dosage adjustments and to develop new dosage regimens tailored to the needs of patients. Simulations were conducted to explore pirfenidone pharmacokinetics under various challenging conditions, including dose titration, withdrawal, retitration, moderate and severe hepatic impairment, co-administration of moderate (e.g. omeprazole) and strong (e.g. smoking) inducers of the CYP1A2 enzyme, gastrointestinal adverse events, and photosensitivity reactions.Simulations led to specific recommendations for physicians regarding dosage regimens in each condition. The recommended dosage adjustments are designed to maintain concentrations within acceptable levels, ensuring both safe and effective treatment.Idiopathic Pulmonary Fibrosis (IPF) is a chronic respiratory disorder for which pirfenidone is the recommended first-line anti-fibrotic treatment. While pirfenidone has demonstrated efficacy in slowing the progression of IPF, its use is associated with several challenges and unresolved issues that impact patient outcomes. Pirfenidone administration can result in gastrointestinal side effects, photosensitivity reactions, and significant drug interactions, particularly in patients with hepatic impairment. For those who experience intolerable side effects, dose reductions or temporary discontinuations are frequently employed. However, there is limited data on the efficacy of reduced doses, creating uncertainty about the balance between tolerability and therapeutic benefit.The aim of this study is to evaluate the currently proposed dosage adjustments and to develop new dosage regimens tailored to the needs of patients. Simulations were conducted to explore pirfenidone pharmacokinetics under various challenging conditions, including dose titration, withdrawal, retitration, moderate and severe hepatic impairment, co-administration of moderate (e.g. omeprazole) and strong (e.g. smoking) inducers of the CYP1A2 enzyme, gastrointestinal adverse events, and photosensitivity reactions.Simulations led to specific recommendations for physicians regarding dosage regimens in each condition. The recommended dosage adjustments are designed to maintain concentrations within acceptable levels, ensuring both safe and effective treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Acute exacerbation (AEx) of interstitial pneumonia is the most common lethal adverse event related to the pharmacological treatment of patients with lung cancer complicated with interstitial pneumonia. Although small cell lung cancer (SCLC) is linked to poor prognosis, it exhibits good response to chemotherapy. Few previous research studies have investigated the safety and efficacy of treatment for advanced SCLC complicated with idiopathic interstitial pneumonia (IIP). We conducted a single-arm phase II study to evaluate the safety and efficacy of carboplatin plus etoposide for the treatment of patients with SCLC complicated with IIP. Methods: Chemotherapy-naïve patients with advanced SCLC complicated with IIP were enrolled. Patients received carboplatin every 21–28 days at a dose of area under the curve 4–6 on day 1 and etoposide at a dose of 80–100 mg/m2 on days 1–3. Results: Thirty-one patients were enrolled between December 2009 and December 2022. A median of four cycles of carboplatin plus etoposide were administered. Acute exacerbation of idiopathic interstitial pneumonia was not observed; the rate of AEx was 0% (95% confidence interval [CI]: 0–9.6%, p = 0.038). The objective response rate was 83.9% (95% CI: 82.5–85.2). The median progression-free survival and overall survival were 5.9 (95% CI: 4.7–6.8) months and 14.0 (95% CI: 7.6–27.6) months, respectively. The 1-year survival rate was 61% (95% CI 41–76). Conclusions: The carboplatin plus etoposide treatment was tolerable and effective in SCLC patients complicated with IIP. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which repetitive epithelial injury and incomplete alveolar repair result in accumulation of profibrotic intermediate/transitional "aberrant" epithelial cell states. The mechanisms leading to the emergence and persistence of aberrant epithelial populations in the distal lung remain incompletely understood. By interrogating single-cell RNA sequencing (scRNA-seq) data from patients with IPF and a mouse model of repeated lung epithelial injury, we identified persistent activation of hypoxia-inducible factor (HIF) signaling in these aberrant epithelial cells. Using mouse genetic lineage-tracing strategies together with scRNA-seq, we found that these disease-emergent aberrant epithelial cells predominantly arose from airway-derived (Scgb1a1-CreER–traced) progenitors and exhibited transcriptional programs of Hif2a activation. In mice treated with repetitive intratracheal bleomycin, deletion of Epas1 (Hif2a) but not Hif1a, from airway-derived progenitors, or administration of the small-molecule HIF2 inhibitor PT-2385, using both prevention and rescue approaches, attenuated experimental lung fibrosis, reduced the appearance of aberrant epithelial cells, and promoted alveolar repair. In mouse alveolar organoids, genetic or pharmacologic inhibition of Hif2 promoted alveolar differentiation of airway-derived epithelial progenitors. In addition, treatment of human distal lung organoids with PT-2385 increased colony-forming efficiency, enhanced protein and transcriptional markers of alveolar type 2 epithelial cell maturation, and prevented the emergence of aberrant epithelial cells. Together, these studies showed that HIF2 activation drives the emergence of aberrant epithelial populations after repetitive injury and that targeted HIF2 inhibition may represent an effective therapeutic strategy to promote functional alveolar repair in IPF and other interstitial lung diseases. Editor's summary: Idiopathic pulmonary fibrosis (IPF) may develop from repetitive lung epithelial injury and aberrant repair. Here, McCall and colleagues reanalyzed single-cell RNA sequencing data from IPF lungs to better understand the role of "aberrant basaloid" cells that arise from epithelial cells in the context of the disease. They identified hypoxia-inducible factor (HIF) signaling as a driver of these cells and used repetitive bleomycin injury in mice with conditional deletion of HIF genes as well as lineage labeling to show that secretory cell–specific deletion of Epas1, the gene that encodes Hif2α, could protect mice from fibrosis and enhance alveolar repair. Preventative or therapeutic application of a small-molecule inhibitor of HIF2 ameliorated bleomycin-induced fibrosis in mice, suggesting inhibition of HIF2 as a potential therapy for patients with IPF. —Melissa L. Norton [ABSTRACT FROM AUTHOR]

BAL cellular analysis is often recommended during the initial diagnostic evaluation of fibrotic interstitial lung disease (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 remain sparse. In patients with fibrotic ILD, are BAL findings associated with radiologic features, patterns, and clinical diagnoses? Patients with fibrotic ILD who underwent BAL for diagnostic evaluation and who were 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 using thresholds of lymphocytosis > 20% and neutrophils > 4.5%. High-resolution CT (HRCT) scans were scored (anonymized to clinical data) for specific features and percentage lung involvement. Radiologists classified HRCT scans according to guideline-defined patterns for idiopathic pulmonary fibrosis and fibrotic hypersensitivity pneumonitis; then, MDD diagnoses were assigned, considering all available data. Bronchoscopy with cellular analysis was performed in 209 of 1,593 patients (13%). Lymphocyte % was weakly negatively correlated with total fibrosis % (r = –0.16, P =.023) but not statistically significantly correlated with ground glass opacity % (r = 0.01, P =.94). A mixed BAL pattern was the most frequent in all radiologic patterns (range, 45%-69%), with a minority classifiable according to BAL guidelines. BAL lymphocytosis appeared with similar frequency across HRCT patterns of fibrotic hypersensitivity pneumonitis (21%) and usual interstitial pneumonia (18%). Only 5% of patients with MDD-based fibrotic hypersensitivity pneumonitis had a guideline-defined isolated lymphocytosis > 15%. 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. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with a median survival of 3–5 years. Antifibrotic therapies like pirfenidone and nintedanib slow progression, but the outcomes vary. Gender may influence disease presentation, progression, and response to treatment. This study evaluates the impact of gender on the 5-year survival, pharmacological management, and clinical outcomes of patients with IPF. Methods: A retrospective cohort study of 254 IPF patients was conducted, with 164 (131 males:33 females) having complete data. Patients underwent spirometry, DLCO, and 6 min walk tests. Data on comorbidities, smoking, antifibrotic therapy type, dosage adjustments, and adverse events were collected. We used Kaplan–Meier survival curves and logistic regression to assess gender-related differences in outcomes. Results: Men had worse lung function at diagnosis (FVC 74.9 ± 18.5 vs. 87.2 ± 20.1% of pred.; p < 0.001) and a higher smoking prevalence (74% vs. 30%; p < 0.001). Women had better survival (51.2 vs. 40.8 ± 19.2 months; p = 0.005) despite more frequent biopsy use (36% vs. 17%; p = 0.013). Women tolerated longer therapy better (p = 0.001). No differences were found between patients receiving reduced antifibrotic dosing and those receiving full dosing. Conclusions: Gender has a significant impact on IPF outcomes, with women demonstrating better survival and tolerance to long-term therapy. In contrast, reducing antifibrotic treatment does not appear to significantly affect survival outcomes. These findings underscore the need for future research on gender-specific management approaches. [ABSTRACT FROM AUTHOR]

Objective Although clinical and genetic risk factors have been identified for rheumatoid arthritis-associated interstitial lung disease (RA-ILD), there are no current tools allowing for risk stratification. We sought to develop and validate an ILD risk model in a large, multicentre, prospective RA cohort. Methods Participants in the Veterans Affairs RA (VARA) registry were genotyped for 12 single nucleotide polymorphisms (SNPs) associated with idiopathic pulmonary fibrosis. ILD was validated through systematic record review. A genetic risk score (GRS) was computed from minor alleles weighted by effect size with ILD, using backward selection. The GRS was combined with clinical risk factors within a logistic regression model. Internal validation was completed using bootstrapping, and model performance was assessed by the area under the receiver operating curve (AUC). Results Of 2386 participants (89% male, mean age 69.5 years), 9.4% had ILD. Following backward selection, five SNPs contributed to the GRS. The GRS and clinical factors outperformed clinical factors alone in discriminating ILD (AUC 0.675 vs 0.635, P  < 0.001). The shrinkage-corrected performance for combined and clinical-only models was 0.667 (95% CI 0.628, 0.712) and 0.623 (95% CI 0.584, 0.651), respectively. Twenty percent of the cohort had a combined risk score below a cut-point with >90% sensitivity. Conclusion A clinical and genetic risk model discriminated ILD in a large, multicentre RA cohort better than a clinical-only model, excluding 20% of the cohort from low-yield testing. These results demonstrate the potential utility of a GRS in RA-ILD and support further investigation into individualized risk stratification and screening. [ABSTRACT FROM AUTHOR]

We aimed to study transcriptional and phenotypic changes in circulating immune cells associated with increased risk of mortality in COVID-19, resolution of pulmonary fibrosis in post-COVID-19-interstitial lung disease (ILD), and persistence of idiopathic pulmonary fibrosis (IPF). Whole blood and peripheral blood mononuclear cells (PBMCs) were obtained from 227 subjects with COVID-19, post-COVID-19 interstitial lung disease (ILD), IPF, and controls. We measured a 50-gene signature (nCounter, Nanostring) previously found to be predictive of IPF and COVID-19 mortality along with plasma levels of several biomarkers by Luminex. In addition, we performed single-cell RNA sequencing (scRNA-seq) in PBMCs (10x Genomics) to determine the cellular source of the 50-gene signature. We identified the presence of three genomic risk profiles in COVID-19 based on the 50-gene signature associated with low-, intermediate-, or high-risk of mortality and with significant differences in proinflammatory and profibrotic cytokines. Patients with COVID-19 in the high-risk group had increased expression of seven genes in CD14+HLA-DRlowCD163+ monocytic-myeloid-derived suppressive cells (7Gene-M-MDSCs) and decreased expression of 43 genes in CD4 and CD8 T cell subsets. The loss of 7Gene-M-MDSCs and increased expression of these 43 genes in T cells was seen in survivors with post-COVID-19-ILD. On the contrary, patients with IPF had low expression of the 43 genes in CD4 and CD8 T cells. Collectively, we showed that a 50-gene, high-risk profile, predictive of IPF and COVID-19 mortality is characterized by a genomic imbalance in monocyte and T-cell subsets. This imbalance reverses in survivors with post-COVID-19-ILD highlighting genomic differences between post-COVID-19-ILD and IPF. NEW & NOTEWORTHY: Changes in the 50-gene signature, reflective of increase in CD14+HLA-DRlowCD163+ monocytes and decrease in CD4 and CD8 T cells, are associated with increased mortality in COVID-19. A reversal of this pattern can be seen in post-COVID-19-ILD, whereas its persistence can be seen in IPF. Modulating the imbalance between HLA-DRlow monocytes and T cell subsets should be investigated as a potential strategy to treat pulmonary fibrosis associated with severe COVID-19 and progressive IPF. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and devastating lung disorder. In response to transforming growth factor-β (TGF-β), normal lung cells proliferate and differentiate into myofibroblasts, which are instrumental in promoting disease progression. Small interfering RNA (siRNA) targeting heat shock protein 47 (HSP47) has been demonstrated to alleviate IPF by blocking collagen synthesis and secretion. Exosomes (EXOs) have been investigated for drug delivery due to their superior carrier properties. However, their loading efficiency has been a limiting factor in widely application as drug carriers. In this study, an ultrasonic microfluidic method was employed to enhance the loading efficiency of siHSP47 into EXOs, achieving 31.1% efficiency rate. EXOs were isolated from human embryonic kidney cells (293F) and loaded with siHSP47 (EXO-siHSP47). The findings indicated that EXO-siHSP47 penetrated the collagen barrier and effectively silenced HSP47 expression in activated fibroblasts in vitro. Western blotting and immunofluorescence analyses confirmed that EXO-siHSP47 significantly reduced the secretion and deposition of extracellular matrix (ECM) proteins. Wound healing and Transwell migration assays demonstrated that EXO-siHSP47 inhibited fibroblast differentiation and migration. In conclusion, 293F-derived EXOs loaded with siHSP47 present a promising therapeutic strategy for IPF. [ABSTRACT FROM AUTHOR]

Gastroesophageal reflux disease occurs when the barrier at the esophagogastric junction is weakened, allowing for transient relaxations of the lower esophageal sphincter or disruption of the esophagogastric junction. This leads to the refluxate traveling up the esophagus, and potentially into the pharynx, where it can be aspirated into the airway. The refluxate can cause a range of symptoms, including sore throat, coughing, wheezing, and shortness of breath, which may occur with or without visible airway inflammation. Both experimental and clinical studies have shown that aspirated refluxate can directly damage the airway lining and trigger immune responses that contribute to airway injury and inflammation. While traditional diagnostic tests for gastroesophageal reflux disease can identify abnormal reflux patterns, there is a need for more specific methods to predict airway inflammation or therapeutic outcomes related to reflux aspiration. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Chronic cough is a distressing and prevalent symptom in interstitial lung disease (ILD), significantly impairing quality of life (QoL) and contributing to disease progression, particularly in idiopathic pulmonary fibrosis (IPF). It is associated with physical discomfort, psychological distress, and social isolation and is often refractory to conventional therapies. The pathophysiology of cough in ILD is complex and multifactorial, involving neural hypersensitivity, structural lung changes, inflammatory processes, and comorbid conditions such as gastroesophageal reflux disease (GERD). Evaluating cough in ILD relies on subjective and objective tools to measure its severity, frequency, and impact on daily life, although standardization of these measures remains challenging. Management strategies span pharmacological interventions, including neuromodulators such as opiates, antifibrotic agents, pharmacologic and surgical GERD treatments, and non-pharmacological approaches like behavioral therapies, cough suppression techniques, and pulmonary rehabilitation and physiotherapy. Emerging treatments, such as P2X3 receptor antagonists and airway hydration therapies, offer promising avenues but require further investigation through robust clinical trials. This review aims to demonstrate the importance of addressing cough in ILD as a significant symptom and present objective and subjective methods of quantifying coughs, while providing insights into effective and emerging therapeutic options. By highlighting these potential therapies, we hope to guide healthcare practitioners in considering them through a thorough evaluation of benefits and risks on a case-by-case basis, with relevance both in the U.S. and internationally. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Diffuse interstitial lung diseases (ILD) include conditions with identifiable causes such as chronic eosinophilic pneumonia (CEP), sarcoidosis (SAR), chronic hypersensitivity pneumonitis (CHP), and connective tissue disease-associated interstitial pneumonia (CTD), as well as idiopathic interstitial pneumonia (IIP) of unknown origin. In non-IIP diffuse lung diseases, bronchoalveolar lavage (BAL) fluid appearance is diagnostic. This study examines lymphocyte subsets in BAL fluid and peripheral blood of 56 patients with diffuse ILD, excluding idiopathic pulmonary fibrosis (IPF), who underwent BAL for diagnostic purposes. Patients were classified into CEP, SAR, CHP, CTD, and IIP groups, and clinical data, BAL cell analysis, and peripheral blood mononuclear cell analysis were compared. Eosinophils and type 3 innate lymphocytes (ILC3s) were significantly increased in the BAL fluid of the CEP group. Receiver operating characteristic curve analysis identified eosinophils ≥ 8% in BAL cells and ILC3s ≥ 0.0176% in the BAL lymphocyte fraction as thresholds distinguishing CEP. SAR patients exhibited significantly elevated CD4/CD8 ratios in the BAL fluid, with a ratio of 3.95 or higher and type 1 innate lymphoid cell frequency ≥ 0.254% as differentiation markers. High Th1 cell frequency (≥17.4%) in BAL lymphocytes in IIP, elevated serum KL-6 (≥2081 U/mL) and SP-D (≥261 ng/mL) in CHP, and increased BAL neutrophils (≥2.0%) or a low CD4/CD8 ratio (≤1.2) in CTD serve as distinguishing markers for each ILD. Excluding CEP and SAR, CD4+ T cell frequencies, including Th1, Th17, and Treg cells in peripheral blood, may differentiate IIP, CHP, and CTD. [ABSTRACT FROM AUTHOR]

Impaired alveolar epithelial regeneration in patients with idiopathic pulmonary fibrosis (PF) or chronic obstructive pulmonary disease is attributed to telomere dysfunction in type II alveolar epithelial cells (A2Cs). Genetic susceptibility, aging, and toxicant exposures, including tobacco smoke (TS), contribute to telomere dysfunction in A2Cs. Here we investigated whether improvement of telomere function plays a role in CSP7 (Cav1 scaffolding domain peptide)–mediated protection of A2Cs against ongoing senescence and apoptosis during bleomycin-induced PF as well as alveolar injury caused by chronic TS exposure. We found a significant telomere shortening in A2Cs isolated from idiopathic PF and chronic obstructive pulmonary disease lungs in line with other studies. These cells showed increased p53 in addition to its posttranslational modification with induction of activated caspase-3 and β-galactosidase, suggesting a p53-mediated loss of A2C renewal. Further, we found increased expression of SIAH-1, a p53-inducible E3 ubiquitin ligase known to downregulate TRF2 (telomere repeats binding factor 2). Consistent with the loss of TRF2 and upregulation of TRF1, TERT (telomerase reverse transcriptase) was downregulated in A2Cs. A2Cs from fibrotic lungs of mice repeatedly instilled with bleomycin or isolated from a chronic TS exposure–induced lung injury model showed reduced telomere length; induction of p53, PAI-1, SIAH1, and TRF1; as well as loss of TRF2 and TERT, which were reversed in wild-type mice after treatment with CSP7. Interestingly, PAI-1−/− mice, or those lacking microRNA-34a expression in A2Cs, resisted telomere dysfunction, whereas uPA−/− mice failed to respond to CSP7 treatment, suggesting p53-microRNA-34a feed-forward induction and that the p53-uPA pathway contributes to telomere dysfunction. [ABSTRACT FROM AUTHOR]

The study published in the Annals of the American Thoracic Society investigates the factors related to the persistence of antifibrotic therapy in patients with idiopathic pulmonary fibrosis (IPF) in the United States. The analysis found that patients who persisted with antifibrotic therapy were less likely to have anxiety or depression, had higher diffusing capacity for carbon monoxide, and had lower all-cause mortality compared to nonpersisters. The study highlights the importance of understanding patient characteristics to enhance adherence to long-term treatment plans for IPF. [Extracted from the article]

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. Plain language summary: Potential of phosphodiesterase 4B inhibition in the treatment of progressive pulmonary fibrosis Progressive (worsening) lung fibrosis leads to loss of lung function and premature death. The drugs currently used to treat progressive lung fibrosis slow down loss of lung function, but lung function continues to worsen. In addition, these drugs have side-effects such as diarrhoea, which mean that some patients are unable to keep taking them. Phosphodiesterase-4B (PDE4B) is an enzyme that is involved in pathways that lead to inflammation and fibrosis (scarring) of the lungs. Reducing the activity of PDE4B is being investigated as a way to slow down the progression of lung fibrosis. Nerandomilast is a drug that reduces the activity of PDE4B. Clinical trials are comparing changes in lung function over a year in patients with progressive lung fibrosis who are given nerandomilast or a placebo (dummy). The results of these trials will be announced in the first half of 2025. [ABSTRACT FROM AUTHOR]

Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-like receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA. Objectives: We aimed to show that TLR9 activation induces fibroproliferative responses that are abrogated by its antagonism by using two commercially available indirect inhibitors and a proprietary, selective direct small-molecule inhibitor. Methods: We employed two independent cohorts of patients with IPF, multiple in vitro fibroblast cell culture platforms, an in vivo mouse model, and an ex vivo human precision-cut lung slices system to investigate the clinical and biologic significance of TLR9 in this disease. Measurements and Main Results: In two independent IPF cohorts, plasma mitochondrial DNA activates TLR9 in a manner associated with the expression of monocyte chemoattractant protein 1, IL-6, tumor necrosis factor-α, and IFN-γ–inducible protein 10 and worsened transplant-free survival. Our cell culture platform showed that TLR9 mediates fibroblast activation via transforming growth factor-β1 and stiff substrates and that its antagonism, particularly direct inhibition, ameliorates this process, including production of these TLR9-associated pharmacodynamic endpoints. We further demonstrated that direct TLR9 inhibition mitigates these fibroproliferative responses in our in vivo and ex vivo models of pulmonary fibrosis. Conclusions: In this novel study, we found that direct TLR9 inhibition mitigates fibroproliferative responses in preclinical models of pulmonary fibrosis. Our work demonstrates the therapeutic potential of direct TLR9 antagonism in IPF and related fibrotic lung diseases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Chronic lung diseases such as Chronic Obstructive Pulmonary Disease, Interstitial Lung Disease (ILD), and Pulmonary Hypertension (PH) are characterized by progressive symptoms such as dyspnea, fatigue, and muscle weakness, often leading to physical inactivity, and reduced quality of life. Many patients also experience significantly impaired exercise tolerance. While pulmonary, cardiovascular, respiratory, and peripheral muscle dysfunction contribute to exercise limitations, recent evidence suggests that hypoxia and impairments in cerebral oxygenation may also play a role in exercise intolerance. This narrative review (i) summarizes studies investigating cerebral oxygenation responses during exercise in patients with different types of chronic lung diseases and (ii) discusses possible mechanisms behind the blunted cerebral oxygenation during exercise reported in many of these conditions; however, the extent of cerebral desaturation and the intensity at which it occurs can vary. These differences depend on the specific pathophysiology of the lung disease and the presence of comorbidities. Notably, reduced cerebral oxygenation during exercise in fibrotic-ILD has been linked with the development of dyspnea and early exercise termination. Understanding the effects of chronic lung disease on cerebral oxygenation during exercise may improve our understanding of exercise intolerance mechanisms and help identify therapeutic strategies to enhance brain health and exercise capacity in these patients. [ABSTRACT FROM AUTHOR]

Yan Tan,1,&ast; Baojiang Qian,1,&ast; Qiurui Ma,2 Kun Xiang,1 Shenglan Wang1 1Department of Respiratory and Critical Care Medicine, the First People’s Hospital of Yunnan Province, Kunming, People’s Republic of China; 2Medical School of Kunming University of Science and Technolog, Kunming, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shenglan Wang, Email lhcwsl919127@163.comBackground: Studies suggest that immune and inflammation processes may be involved in the development of idiopathic pulmonary fibrosis (IPF); however, their roles remain unclear. This study aims to identify key genes associated with immune response and inflammation in IPF using bioinformatics.Methods: We identified differentially expressed genes (DEGs) in the GSE93606 dataset and GSE28042 dataset, then obtained differentially expressed immune- and inflammation-related genes (DE-IFRGs) by overlapping DEGs. Two machine learning algorithms were used to further screen key genes. Genes with an area under curve (AUC) of > 0.7 in receiver operating characteristic (ROC) curves, significant expression and consistent trends across datasets were considered key genes. Based on these key genes, we carried out nomogram construction, enrichment and immune analyses, regulatory network mapping, drug prediction, and expression verification.Results: 27 DE-IFRGs were identified by intersecting 256 DEGs, 1793 immune-related genes, and 1019 inflammation-related genes. Three genes (RNASE3, S100A12, S100A8) were obtained by crossing two machine algorithms (Boruta and LASSO),which had good diagnostic performance with AUC values. These key genes were all enriched in the same pathways, such as GOCC_azurophil_granule, IL-12 signalling and production in macrophages is the pathway with the strongest role for key genes. Six distinct immune cells, including naive CD4 T cells, T cells CD4 memory resting, T cells regulatory (Tregs), Monocytes, Macrophages M2, Neutrophils were identified. Real-time quantitative polymerase chain reaction (RT-qPCR) results were consistent with the training and validation sets, and the expression of these key genes was significantly upregulated in the IPF samples.Conclusion: This study identified three key genes (RNASE3, S100A12 and S100A8) associated with immune response and inflammation in IPF, providing valuable insights into the diagnosis and treatment of IPF.Summary: This study focuses on cutting-edge research in IPF, with special attention to the development dynamics and application potential of IPF. By systematically reviewing the research results in recent years, this paper aims to provide a comprehensive perspective on the latest field. It is submitted to the journal not only because of its high international recognition, but also because of its emphasis on a progress in this field. The research scope covers a wide range of content from basic theory to practical cases, which has a guiding effect on clinical research.This manuscript is closely related to the core purpose and readership of Journal of Inflammation Research, a journal known for its in-depth and comprehensive coverage of the immune system and encouragement of original research. The content of this study is highly aligned with the journal’s advocacy of pushing the boundaries of knowledge in the immune system and is expected to bring new insights to journal readers and positively influence the future direction of research in the field.Keywords: bioinformatics, idiopathic pulmonary fibrosis, immunity, inflammation, machine learning

Xiangfei Huang, Wen Yu, Aiping Wei, Xifeng Wang, Shibiao Chen Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of ChinaCorrespondence: Shibiao Chen, Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China, Email Chenlaoshi1111@163.comAbstract: While TRIM proteins are extensively studied in the context of lung tumors, their roles in non-tumor chronic lung diseases remain underexplored. This review delves into the emerging significance of TRIM family proteins in the pathogenesis of idiopathic pulmonary fibrosis (IPF), asthma, chronic obstructive pulmonary disease (COPD), and pulmonary hypertension (PH). TRIM proteins modulate key pathological processes, including inflammation, fibrosis, and cellular remodeling, contributing to disease progression. We highlight their potential as biomarkers and therapeutic targets, offering promising avenues for drug development in these debilitating respiratory disorders. However, the translation of these findings into clinical applications faces significant challenges. These include the dual functional nature of TRIM proteins, their context-dependent roles, the complexity of their downstream signaling networks, and the limitations of current therapeutic strategies in achieving tissue-specific targeting with minimal off-target effects. Addressing these challenges will require innovative approaches and interdisciplinary efforts to unlock the therapeutic potential of TRIM proteins in non-tumor chronic lung diseases.Keywords: TRIM proteins, chronic lung diseases, idiopathic pulmonary fibrosis, COPD, asthma, pulmonary hypertension

Abstract Background Idiopathic pulmonary fibrosis (IPF) is the most common Interstitial Lung Disease (ILD). It is characterized by dyspnoea and a progressive decline in lung function, which negatively affects life. This study aimed to evaluate Health-Related Quality of Life (HRQoL) in IPF patients in Latin American countries. Methods Six countries (Argentina, Bolivia, Colombia, Chile, Mexico, and the Dominican Republic) enrolled patients with IPF. They answered the Saint George’s Respiratory Questionnaire for Idiopathic Pulmonary Fibrosis (SGRQ-I) and the Hospital Anxiety and Depression Scale (HADS). Demographic characteristics, the Torvan index, and a lung function test were also assessed. IPF was diagnosed according to the ATS/ERS/JRS/ALAT 2018 criteria. Results We enlisted 75 patients diagnosed with IPF; 81% were male, with an average age of 74 ± 7. The total SGRQ-I score was 49 ± 23, with a higher score in the activity domain of 70 ± 23. Torvan index average was 17 ± 6. We found that 28% presented anxiety and 35% depression. Besides, we observed that patients requiring oxygen had a worse quality of life (total SGRQ-I 62 ± 22 vs. 45 ± 22, p = 0.003) without finding differences in antifibrotic therapy. We did not find differences in HRQoL when dividing groups according to their altitude above sea level, except for a higher frequency of anxiety in patients living at sea level. Conclusions We found similar data compared to those reported in real-life European populations. We also found that anxiety and depression are prevalent. However, they are often underdiagnosed and, therefore, left untreated.

Abstract The traditional Chinese medicine compound preparation known as Jinbei Oral Liquid (JBOL) consists of 12 herbs, including Astragalus membranaceus (Fisch.) Bge, Codonopsis pilosula (Franch.) Nannf, et al. Having been used for over 30 years in the treatment of pulmonary diseases, JBOL was evaluated in this study in order to assess its effect on idiopathic pulmonary fibrosis as well as its safety (ChiCTR2000035351, Chictr.org.cn.09/08/2020). A double-blind, multicenter, randomized, proof-of-concept trial was conducted to assess the efficacy of oral JBOL 40 ml and Corbrin Capsules 1 g compared to a placebo and Corbrin Capsules in patients with idiopathic pulmonary fibrosis (IPF). Over a 26-week period, patients received the active treatment or placebo three times daily, in a 1:1 ratio. This clinical study uses a randomized method, with a cycle of every 4 patients. TCM doctors at or above the deputy director level of the research center conduct TCM dialectics on IPF patients. To assess efficacy, over the duration of the trial, we measured serial changes in a composite indicator encompassing time to first acute exacerbation of IPF (first hospitalization or death due to respiratory cause), total lung capacity (TLC) (mL), predicted forced vital capacity (FVC%), forced vital capacity (FVC) (mL), predicted diffusing capacity of the lungs for carbon monoxide (predicted DLco%), 6-minute walk distance (6MWD), St. George’s Respiratory Questionnaire (SGRQ) total score, and arterial oxygen partial pressure (PaO2) from baseline to week 26 versus placebo. A total of 103 patients were screened, and 72 received the study medication. Of these, 68 patients were included in the analysis set, with 34 receiving JBOL and 34 receiving a placebo. After 26 weeks, a statistically significant reduction in total lung capacity (TLC) was observed for the JBOL group, with a change of 136 mL compared to -523 mL for the placebo group (difference 659 mL, 95% CI -1215 to -104 mL, p = 0.02). The study found that the change in FVC% predicted was − 1.48% and − 3.58% for the JBOL and placebo groups, respectively (difference of 2.10%, 95% CI -7.13 to 2.93, p = 0.41). Additionally the differences between the two groups in changes in FVC (mL), DLCO % predicted, PaO2 (mmHg) measures were − 67 mL (95% CI -238 to 104), -7.74% (95% CI -17.26 to 1.79), and − 3.57 mmHg (95% CI -10.02 to 2.87), respectively. Treatment with JBOL compared to placebo resulted in sequential changes in acute exacerbation, with no significant difference in SGRQ scores. It was not found that there was a statistically significant difference between the JBOL and placebo groups in TEAE reporting and serious TEAE reporting. Compared to the placebo group, there was a statistically significant reduction (p

Abstract Background A growing body of evidence suggests that prolonged use of inhaled corticosteroids (ICS) and proton pump inhibitors (PPIs) is associated with increased risks of pneumonia. A substantial proportion of people with idiopathic pulmonary fibrosis (IPF) are prescribed PPIs or ICS to treat common comorbidities, giving rise to concerns that use of these medications may be associated with potential harms in this patient population. Methods We used UK Clinical Practice Research Datalink (CPRD) Aurum primary care data linked to national mortality and hospital admissions data to create a cohort of people diagnosed with IPF on or after 1 January 2010. Patients were assigned to one of three exposure categories according to their prescribing history in the 12 months prior to IPF diagnosis as follows: “regular” users (≥ 4 prescriptions), “irregular” users (1–3 prescriptions) and “non-users” (no prescriptions). We explored the association between PPI/ICS prescription and pneumonia hospitalisation and all-cause mortality using multinomial Cox regression models. Results A total of 17,105 people met our study inclusion criteria; 62.6% were male and 15.9% were current smokers. Median age at IPF diagnosis was 76.7 years (IQR: 69.6–82.7). 19.9% were regularly prescribed PPIs, and 16.0% ICS, prior to IPF diagnosis. Regular prescribing of PPIs and ICS was positively associated with hospitalisation for pneumonia; the adjusted HR for pneumonia hospitalisation comparing regular PPI users with non-users was 1.14 (95%CI: 1.04–1.24); for regular ICS users the corresponding HR was 1.40 (95%CI: 1.25–1.55). We also observed a small increased risk for all-cause mortality in the “regular ICS user” group compared with the “non-user” control group (HRadj = 1.19, 1.06–1.33). We found no evidence of an association between PPI prescribing and all-cause mortality. Conclusion Prolonged prescription of medications used to treat common comorbidities in IPF may be associated with increased risks for severe respiratory infections. These findings point to a need to adopt an adequate risk–benefit balance approach to the prescribing of ICS-containing inhalers and PPIs in people with IPF without evidence of comorbidities, especially older patients and/or those with more advanced disease in whom respiratory infections are more likely to result in poorer outcomes.

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.

Yan Wang,1,2 Baichuan Xu,1,2 Jiajia Wang,1,3,4 Suyun Li,1,3,4 Yang Xie1,3,4 1National Regional Traditional Chinese Medicine (Lung Disease) Diagnosis and Treatment Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, 450046, People’s Republic of China; 2The First Clinical College of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, 450000, People’s Republic of China; 3Henan University of Traditional Chinese Medicine Respiratory Disease Diagnosis and Treatment and New Drug Research and Development Provincial and Ministry Co-Built Collaborative Innovation Center, Zhengzhou, Henan, 450046, People’s Republic of China; 4Henan Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Respiratory Diseases, Zhengzhou, Henan, 450046, People’s Republic of ChinaCorrespondence: Yang Xie; Suyun Li, Email xieyanghn@163.com; lisuyun2000@126.comObjective: To evaluate the effectiveness and safety of traditional Chinese medicine (TCM) ion introduction therapy in the treatment of patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF).Methods: This study adopts a prospective cohort study design, with 60 AE-IPF patients as the research subjects. Divided into an exposed group and a non exposed group, with 30 cases in each group, based on the frequency of TCM ion introduction treatment as the exposure factor. Follow-up for 1 year to observe the acute exacerbation of the patient. The main indicator is the annual incidence of acute exacerbation, and the secondary indicators are hospitalization time, readmission rate, time to first acute exacerbation, mortality rate, all-cause mortality rate, inflammatory indicators, quality of life, etc.Results: 51 patients completed a one-year clinical observation, including 27 in the exposed group and 24 in the non exposed group. Compared to the non exposed group, significant differences were observed in the annual incidence of acute exacerbation [incidence rate ratios (IRR) = 0.556, 95% CI: 0.315, 0.980; P = 0.035] and hospitalization time (P = 0.040), readmission rate (IRR = 0.533, 95% CI: 0.288, 0.988; P = 0.037), time to first acute exacerbation (P = 0.045), and quality of life (P < 0.05). However, there was no statistically significant difference in mortality rate and all-cause mortality rate between the two groups (P > 0.05).Conclusion: Compared to the non exposed group, TCM ion introduction can reduce the annual incidence of acute exacerbation of IPF patients. Hospitalization time, readmission rate, time to first acute exacerbation, quality of life improved, but mortality rate and all-cause mortality rate did not improve.Keywords: TCM, ion introduction, idiopathic pulmonary fibrosis, acute exacerbation, incidence

Abstract Background Acute exacerbation (AEx) of interstitial pneumonia is the most common lethal adverse event related to the pharmacological treatment of patients with lung cancer complicated with interstitial pneumonia. Although small cell lung cancer (SCLC) is linked to poor prognosis, it exhibits good response to chemotherapy. Few previous research studies have investigated the safety and efficacy of treatment for advanced SCLC complicated with idiopathic interstitial pneumonia (IIP). We conducted a single-arm phase II study to evaluate the safety and efficacy of carboplatin plus etoposide for the treatment of patients with SCLC complicated with IIP. Methods Chemotherapy-naïve patients with advanced SCLC complicated with IIP were enrolled. Patients received carboplatin every 21–28 days at a dose of area under the curve 4–6 on day 1 and etoposide at a dose of 80–100 mg/m2 on days 1–3. Results Thirty-one patients were enrolled between December 2009 and December 2022. A median of four cycles of carboplatin plus etoposide were administered. Acute exacerbation of idiopathic interstitial pneumonia was not observed; the rate of AEx was 0% (95% confidence interval [CI]: 0–9.6%, p = 0.038). The objective response rate was 83.9% (95% CI: 82.5–85.2). The median progression-free survival and overall survival were 5.9 (95% CI: 4.7–6.8) months and 14.0 (95% CI: 7.6–27.6) months, respectively. The 1-year survival rate was 61% (95% CI 41–76). Conclusions The carboplatin plus etoposide treatment was tolerable and effective in SCLC patients complicated with IIP.

The appearance of senescent cells in age-related diseases has spurred the search for compounds that can target senescent cells in tissues, termed senolytics. However, a major caveat with current senolytic screens is the use of cell lines as targets where senescence is induced in vitro, which does not necessarily reflect the identity and function of pathogenic senescent cells in vivo. Here, we developed a new pipeline leveraging a fluorescent murine reporter that allows for isolation and quantification of p16Ink4a+ cells in diseased tissues. By high-throughput screening in vitro, precision-cut lung slice (PCLS) screening ex vivo, and phenotypic screening in vivo, we identified a HSP90 inhibitor, XL888, as a potent senolytic in tissue fibrosis. XL888 treatment eliminated pathogenic p16Ink4a+ fibroblasts in a murine model of lung fibrosis and reduced fibrotic burden. Finally, XL888 preferentially targeted p16INK4a-hi human lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis (IPF), and reduced p16INK4a+ fibroblasts from IPF PCLS ex vivo. This study provides proof of concept for a platform where p16INK4a+ cells are directly isolated from diseased tissues to identify compounds with in vivo and ex vivo efficacy in mice and humans, respectively, and provides a senolytic screening platform for other age-related diseases.

Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8-9, 2022. This workshop was held virtually and was organized into three topic areas: 1) novel models and research tools to better study pulmonary fibrosis and uncover new therapies, 2) early disease risk factors and methods to improve diagnosis, and 3) innovative approaches toward clinical trial design for pulmonary fibrosis. In this workshop report, we summarize the content of the presentations and discussions, enumerating research opportunities for advancing our understanding of the pathogenesis, treatment, and outcomes of pulmonary fibrosis.

Reciprocal interactions between alveolar fibroblasts and epithelial cells are crucial for lung homeostasis, injury repair, and fibrogenesis, but underlying mechanisms remain unclear. To investigate, we administered the fibroblast-selective TGF-β1 signaling inhibitor epigallocatechin gallate (EGCG) to interstitial lung disease (ILD) patients undergoing diagnostic lung biopsy and conducted single-cell RNA-Seq on spare tissue. Biopsies from untreated patients showed higher fibroblast TGF-β1 signaling compared with nondisease donor or end-stage ILD tissues. In vivo, EGCG downregulated TGF-β1 signaling and several proinflammatory and stress pathways in biopsy samples. Notably, EGCG reduced fibroblast secreted frizzled-related protein 2 (sFRP2), an unrecognized TGF-β1 fibroblast target gene induced near type II alveolar epithelial cells (AEC2s) in situ. Using AEC2-fibroblast coculture organoids and precision-cut lung slices (PCLSs) from nondiseased donors, we found TGF-β1 signaling promotes a spread AEC2 KRT17+ basaloid state, whereupon sFRP2 then activates a mature cytokeratin 5+ (Krt5+) basal cell program. Wnt-receptor Frizzled 5 (Fzd5) expression and downstream calcineurin signaling were required for sFRP2-induced nuclear NFATc3 accumulation and KRT5 expression. These findings highlight stage-specific TGF-β1 signaling in ILD and the therapeutic potential of EGCG in reducing idiopathic pulmonary fibrosis-related (IPF-related) transcriptional changes and identify TGF-β1/noncanonical Wnt pathway crosstalk via sFRP2 as a mechanism for dysfunctional epithelial signaling in IPF/ILD.

Aging and cellular senescence are increasingly recognized as key contributors to pulmonary fibrosis. However, our understanding in the context of scleroderma-associated interstitial lung disease (SSc-ILD) is limited. To investigate, we leveraged previously established lung aging- and cell-specific senescence signatures to determine their presence and potential relevance to SSc-ILD. We performed a gene expression meta-analysis of lung tissues from 38 SSc-ILD and 18 healthy controls and found that markers (GDF15, COMP, and CDKN2A) and pathways (p53) of senescence were significantly increased in SSc-ILD. When probing the established aging and cellular senescence signatures, we found that epithelial and fibroblast senescence signatures had a 3.6- and 3.7-fold enrichment, respectively, in the lung tissue of SSc-ILD and that lung aging genes (CDKN2A, FRZB, PDE1A, and NAPI12) were increased in SSc-ILD. These signatures were also enriched in SSc skin and associated with degree of skin involvement (limited vs. diffuse cutaneous). To further support these findings, we examined telomere length (TL), a surrogate for aging, in the lung tissue and found that, independent of age, SSc-ILD had significantly shorter telomeres than controls in type II alveolar cells in the lung. TL in SSc-ILD was comparable to idiopathic pulmonary fibrosis, a disease of known aberrant aging. Taken together, this study provides novel insight into the possible mechanistic effects of accelerated aging and aberrant cellular senescence in SSc-ILD pathogenesis.