Search Results (702)

Background: Transbronchial lung cryobiopsy (TBLC) has a high incidence of adverse events. This study aimed to investigate the relationship between the occurrence of these events and the condition of the pathology samples or pathological diagnosis in TBLC. Methods: We studied 102 patients who underwent TBLC for the diagnosis of interstitial lung disease. We analyzed the association between the condition or diagnosis of pathology samples and the occurrence of TBLC-related adverse events, including hemorrhage, pneumothorax, and acute exacerbation of interstitial lung disease. Results: The adverse events occurred in 19 patients (18.6%), of which hemorrhage was the most common (14 patients, 13.7%). The patients who experienced adverse events, especially hemorrhage, were less likely to have successful sampling with TBLC and showed lower diagnostic confidence in the pathology results. The diagnostic confidence was level A in 50 cases (49.0%) and level C in 23 cases (22.6%). TBLC-related adverse events, including hemorrhage, were significantly more common in patients with lower pathological confidence levels. Conclusions: TBLC-related adverse events, particularly hemorrhage, can lead to fewer successful samples and lower levels of diagnostic confidence. Full article

Background: Over the last few years, a few imaging studies have performed conventional transthoracic echocardiography (TTE) implemented with speckle tracking echocardiography (STE) for the assessment of biventricular mechanics in patients with non-advanced idiopathic pulmonary fibrosis (IPF). This systematic review and meta-analysis aimed at evaluating the overall effect of mild-to-moderate IPF on the main indices of biventricular systolic function assessed by TTE and STE. Methods: All imaging studies assessing right ventricular (RV)-global longitudinal strain (GLS), left ventricular (LV)-GLS, tricuspid annular plane systolic excursion (TAPSE), and left ventricular ejection fraction (LVEF) in IPF patients vs. healthy controls, selected from PubMed, Scopus, and EMBASE databases, were included. Continuous data (RV-GLS, LV-GLS, TAPSE, and LVEF) were pooled as standardized mean differences (SMDs) comparing the IPF group with healthy controls. The SMD of RV-GLS was calculated using the random-effect model, whereas the SMDs of LV-GLS, TAPSE, and LVEF were calculated using the fixed-effect model. Results: The full texts of 6 studies with 255 IPF patients and 195 healthy controls were analyzed. Despite preserved TAPSE and LVEF, both RV-GLS and LV-GLS were significantly, although modestly, reduced in the IPF patients vs. the controls. The SMD was large (−1.01, 95% CI −1.47, −0.54, p < 0.001) for RV-GLS, medium (−0.62, 95% CI −0.82, −0.42, p < 0.001) for LV-GLS, small (−0.42, 95% CI −0.61, −0.23, p < 0.001) for TAPSE, and small and not statistically significant (−0.20, 95% CI −0.42, 0.03, p = 0.09) for LVEF assessment. Between-study heterogeneity was high for the studies assessing RV-GLS (I² = 80.5%), low-to-moderate for those evaluating LV-GLS (I² = 41.7%), and low for those measuring TAPSE (I² = 16.4%) and LVEF (I² = 7.63%). The Egger’s test yielded a p-value of 0.60, 0.11, 0.31, and 0.68 for the RV-GLS, LV-GLS, TAPSE, and LVEF assessment, respectively, indicating no publication bias. On meta-regression analysis, none of the moderators was significantly associated with effect modification for RV-GLS (all p > 0.05). The sensitivity analysis supported the robustness of the results. Conclusions: RV-GLS impairment is an early marker of subclinical myocardial dysfunction in mild-to-moderate IPF. STE should be considered for implementation in clinical practice for early detection of RV dysfunction in IPF patients without advanced lung disease. Full article

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. Full article

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. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by repetitive alveolar injuries with excessive deposition of extracellular matrix (ECM) proteins. A crucial need in understanding IPF pathogenesis is identifying cell types associated with histopathological regions, particularly local fibrosis centers known as fibroblast foci. To address this, we integrated published spatial transcriptomics and single-cell RNA sequencing (scRNA-seq) transcriptomics and adopted the Query method and the Overlap method to determine cell type enrichments in histopathological regions. Distinct fibroblast cell types are highly associated with fibroblast foci, and transitional alveolar type 2 and aberrant KRT5-/KRT17+ (KRT: keratin) epithelial cells are associated with morphologically normal alveoli in human IPF lungs. Furthermore, we employed laser capture microdissection-directed mass spectrometry to profile proteins. By comparing with another published similar dataset, common differentially expressed proteins and enriched pathways related to ECM structure organization and collagen processing were identified in fibroblast foci. Importantly, cell type enrichment results from innovative spatial proteomics and scRNA-seq data integration accord with those from spatial transcriptomics and scRNA-seq data integration, supporting the capability and versatility of the entire approach. In summary, we integrated spatial multi-omics with scRNA-seq data to identify disease-associated cell types and potential targets for novel therapies in IPF intervention. The approach can be further applied to other disease areas characterized by spatial heterogeneity. Full article

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. Full article

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. Full article

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. Full article

Background: The degree of exercise-induced oxygen desaturation and outcomes following antifibrotic drug therapy in asymptomatic patients with fibrosing interstitial lung disease (FILD) remain unclear. Methods: We compared clinical data, incidence of annual FILD progression, overall survival, and tolerability after initiating nintedanib between 58 patients with dyspnea and 18 patients without. Annual FILD progression was defined as >10% decrease in forced vital capacity (FVC), >15% decrease in diffusing capacity of the lungs for carbon monoxide (D_LCO), developing acute exacerbations, or FILD-related death within 1 year of starting nintedanib. Outcomes between the two groups were adjusted for covariates, including age, gender, FVC, D_LCO, and diagnosis of idiopathic pulmonary fibrosis, all known prognostic factors for FILD. Results: In 6-min walk test, incidence of decrease to <90% of SpO₂ was significantly lower in non-dyspnea group than in dyspnea group (24% vs. 55%, p = 0.028), but incidence of >4% decreases showed no significant difference (71% vs. 89%, p = 0.11) The incidence of annual progression was significantly lower in non-dyspnea than in dyspnea group (17% vs. 53%, adjusted p = 0.026). The relative change in D_LCO was significantly slower in non-dyspnea group (adjusted p = 0.036), but FVC was not (adjusted p = 0.067). Overall survival was longer in non-dyspnea group (adjusted p = 0.0089). The discontinuation rate and therapeutic period of nintedanib were not significantly different between the groups. Conclusions: Asymptomatic patients with FILD have severe exercise-induced oxygen desaturation and better outcomes after nintedanib therapy than symptomatic patients. Antifibrotic drug therapy should not be avoided solely because of a lack of symptoms. Full article

Background/Objectives: A novel patient group with chronic pulmonary fibrosis is emerging post COVID-19. To identify patients at risk of developing post-COVID-19 lung fibrosis, we here aimed to identify systemic proteins that overlap with fibrotic markers identified in patients with idiopathic pulmonary fibrosis (IPF) and may predict COVID-19-induced lung fibrosis. Methods: Ninety-two proteins were measured in plasma samples from hospitalized patients with moderate and severe COVID-19 in Sweden, before the introduction of the vaccination program, as well as from healthy individuals. These measurements were conducted using proximity extension assay (PEA) technology with a panel including inflammatory and remodeling proteins. Histopathological alterations were evaluated in explanted lung tissue. Results: Connecting to IPF pathology, several proteins including decorin (DCN), tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) and chemokine (C-X-C motif) ligand 13 (CXCL13) were elevated in COVID-19 patients compared to healthy subjects. Moreover, we found incrementing expression of monocyte chemotactic protein-3 (MCP-3) and hepatocyte growth factor (HGF) when comparing moderate to severe COVID-19. Conclusions: Both extracellular matrix- and inflammation-associated proteins were identified as overlapping with pulmonary fibrosis, where we found DCN, TNFRSF12A, CXCL13, CXCL9, MCP-3 and HGF to be of particular interest to follow up on for the prediction of disease severity. Full article

Idiopathic pulmonary fibrosis (IPF) is associated with a significantly increased risk of thrombotic events and mortality. This review explores the complex bidirectional relationship between pulmonary fibrosis and thrombosis, discussing epidemiological evidence, pathogenetic mechanisms, and therapeutic implications, with a particular focus on the emerging role of extracellular vesicles (EVs) as crucial mediators linking fibrosis and coagulation. Coagulation factors directly promote fibrosis, while fibrosis itself activates thrombotic pathways. Retrospective studies suggest the benefits of anticoagulants in IPF, but prospective trials have faced challenges. Novel anticoagulants, profibrinolytic therapies, and agents targeting protease-activated receptors (PARs) show promise in preclinical studies and early clinical trials. EVs have emerged as key players in the pathogenesis of interstitial lung diseases (ILDs), serving as vehicles for intercellular communication and contributing to both fibrosis and coagulation. EV-based approaches, such as EV modulation, engineered EVs as drug delivery vehicles, and mesenchymal stem cell-derived EVs, represent promising therapeutic strategies. Ongoing research should focus on optimizing risk–benefit profiles, identifying predictive biomarkers, evaluating combination strategies targeting thrombotic, fibrotic, and inflammatory pathways, and advancing the understanding of EVs in ILDs to develop targeted interventions. Full article

Histone deacetylases (HDACs) are enzymes that play an essential role in the onset and progression of cancer. As a consequence, a variety of HDAC inhibitors (HDACis) have been developed as potent anticancer agents, several of which have been approved by the FDA for cancer treatment. However, recent accumulated research results have suggested that HDACs are also involved in several other pathophysiological conditions, such as fibrotic, inflammatory, neurodegenerative, and autoimmune diseases. Very recently, the HDAC inhibitor givinostat has been approved by the FDA for an indication beyond cancer: the treatment of Duchenne muscular dystrophy. In recent years, more and more HDACis have been developed as tools to understand the role that HDACs play in various disorders and as a novel therapeutic approach to fight various diseases other than cancer. In the present perspective article, we discuss the development and study of HDACis as anti-fibrotic and anti-inflammatory agents, covering the period from 2020–2024. We envision that the discovery of selective inhibitors targeting specific HDAC isozymes will allow the elucidation of the role of HDACs in various pathological processes and will lead to the development of promising treatments for such diseases. Full article

Idiopathic pulmonary fibrosis (IPF) is a chronic and lethal interstitial lung disease (ILD) of unknown origin, characterized by limited treatment efficacy and a fibroproliferative nature. It is marked by excessive extracellular matrix deposition in the pulmonary parenchyma, leading to progressive lung volume decline and impaired gas exchange. The chemokine system, a network of proteins involved in cellular communication with diverse biological functions, plays a crucial role in various respiratory diseases. Chemokine receptors trigger the activation, proliferation, and migration of lung-resident cells, including pneumocytes, endothelial cells, alveolar macrophages, and fibroblasts. Around 50 chemokines can potentially interact with 20 receptors, expressed by both leukocytes and non-leukocytes such as tissue parenchyma cells, contributing to processes such as leukocyte mobilization from the bone marrow, recirculation through lymphoid organs, and tissue influx during inflammation or immune response. This narrative review explores the complexity of the chemokine system in the context of IPF and the bleomycin-induced lung fibrosis mouse model. The goal is to identify specific chemokines and receptors as potential therapeutic targets. Recent progress in understanding the role of the chemokine system during IPF, using experimental models and molecular diagnosis, underscores the complex nature of this system in the context of the disease. Despite advances in experimental models and molecular diagnostics, discovering an effective therapy for IPF remains a significant challenge in both medicine and pharmacology. This work delves into microarray results from lung samples of IPF patients and murine samples at different stages of bleomycin-induced pulmonary fibrosis. By discussing common pathways identified in both IPF and the experimental model, we aim to shed light on potential targets for therapeutic intervention. Dysregulation caused by abnormal chemokine levels observed in IPF lungs may activate multiple targets, suggesting that chemokine signaling plays a central role in maintaining or perpetuating lung fibrogenesis. The highlighted chemokine axes (CCL8-CCR2, CCL19/CCL21-CCR7, CXCL9-CXCR3, CCL3/CCL4/CCL5-CCR5, and CCL20-CCR6) present promising opportunities for advancing IPF treatment research and uncovering new pharmacological targets within the chemokine system. Full article

Idiopathic pulmonary fibrosis (IPF) is the most common type of fibrosis in lungs, characterized as a chronic and progressive interstitial lung disease involving pathological findings of fibrosis with a median survival of 3 years. Despite the knowledge accumulated regarding IPF from basic and clinical research, an effective medical therapy for the condition remains to be established. Thus, it is necessary for further research, including stem cell therapy, which will provide new insights into and expectations for IPF treatment. Recently, it has been reported that one of the new therapeutic candidates for IPF is adipose-derived mesenchymal stem cells (ADSCs), which have several benefits, such as easy accessibility and minimal morbidity compared to bone marrow-derived mesenchymal stem cells. Therefore, we investigated the possibility of ADSCs as a therapeutic candidate for IPF. Using human lung fibroblasts (LFs) from IPF patients, we demonstrated that human IPF LFs cocultured with ADSCs led to reduced fibrosis-related genes. Further analysis revealed that ADSCs prevented the activation of the ERK signaling pathway in IPF LFs via the upregulation of protein tyrosine phosphatase receptor-type R (PTPRR), which negatively regulates the ERK signaling pathway. Moreover, we demonstrated that intravascular administration of ADSCs improved the pathogenesis of bleomycin-induced pulmonary fibrosis with reduced collagen deposition in histology and hydroxyproline quantification and collagen markers such as the gene expression of types I and III collagen and α-smooth muscle actin (α-SMA) in a murine model. ADSC transfer was also investigated in a humanized mouse model of lung fibrosis induced via the infusion of human IPF LFs, because the bleomycin installation model does not fully recapitulate the pathogenesis of IPF. Using the humanized mouse model, we found that intravascular administration of ADSCs also improved fibrotic changes in the lungs. These findings suggest that ADSCs are a promising therapeutic candidate for IPF. Full article

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, disabling disorder of unknown etiology, poor prognosis, and limited therapeutic options. Previously, 3′5-dimaleamylbenzoic acid (3′5-DMBA) was shown to exert resolving effects in IPF, offering a promising alternative for treating this disease; however, the molecular mechanisms associated with this effect have not been explored. Objetive: We evaluated the potential antifibrotic mechanisms of 3′5-DMBA by network pharmacology (NP) and molecular docking (MD). Methods: 3′5-DMBA-associated targets were identified by screening in SwissTargetPrediction. IPF-associated targets were identified using lung tissue meta-analysis and public databases. Common targets were identified, and a protein–protein interaction (PPI) network was constructed; we ranked the proteins in the PPI network by topological analysis. MD validated the binding of 3′5-DMBA to the main therapeutic targets. Results: A total of 57 common targets were identified between 3′5-DMBA and IPF; caspase 8, 9, 3, and 7; myeloid leukemia-induced cell differentiation protein Mcl-1; and poly [ADP-ribose] polymerase 1 are primary targets regulating PPI networks. Functional analysis revealed that the common targets are involved in the pathological features of tissue fibrosis and primarily in the apoptotic process. MD revealed favorable interaction energies among the three main targets regulating PPI networks. Conclusions: NP results suggest that the antifibrotic effect of 3′5-DMBA is due to its regulation of the pathological features of IPF, mainly by modulating signaling pathways leading to apoptosis, suggesting its therapeutic potential to treat this disease. Full article