Pathogenesis Of Idiopathic Pulmonary Fibrosis Research Articles

Epithelial stem cells from human small bronchi offer a potential for therapy of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia with restrictive ventilation. Recently, the structural and functional defects of small airways have received attention in the early pathogenesis of IPF. This study aimed to elucidate the characteristics of small airway epithelial dysfunction in patients with IPF and explore novel therapeutic interventions to impede IPF progression by targeting the dysfunctional small airways. Airway trees spanning the proximal-distal axis were harvested from control lungs and explanted lungs with end-stage IPF undergoing transplant. Qualified basal cells (BCs, p63/Krt5/ITGA6/NGFR) were expanded, and their cellular functions, feasibility, safety and efficacy for transplantation therapy in IPF were validated with experiments invitro and mouse model. Single-cell RNA-sequencing was employed to elucidate the underlying mechanisms governing the BCs based therapy. Based upon these evidences, three patients with advanced IPF and small airway dysfunction received autologous-BCs transplantation. Post-transplantation assessments included lung function, exercise capacity and high resolution computed tomography (HRCT) scans were analyzed to quantify the clinical benefits conferred by the BCs transplantation. An overall landscape of senescent phenotype in airway epithelial cells and airway stem/progenitor cells along the proximal-distal axis of the airway tree in IPF were outlined. In contrast to the cells situated in distal airways, BCs located in small bronchi in IPF displayed a non-senescent phenotype, with comparable proliferative, differentiative capabilities, and similar transcriptomic profiles to normal controls. In a mouse model of pulmonary fibrosis, BCs exhibited promising protective efficacy and safety for transplantation therapy. Autologous BCs transplantation in three advanced IPF patients with small airway dysfunction yielded significant clinical improvements in pulmonary function, particularly evidence in lung volume and small airway function. Epithelia of small bronchi in IPF contain functional and expandable basal stem cells, which exert therapeutic benefits via bronchoscopic implantation. Our findings offer a potential for IPF treatment by targeting small airways. National Natural Science Foundation of China (82430001, 81930001, and 81900059), Shanghai Shenkang Hospital Development Center (SHDC2020CR3063B), Department of Science and Technology of Shandong Province (2024HWYQ-058).

Histone methyltransferase KMT2A promotes pulmonary fibrogenesis via targeting pro-fibrotic factor PU.1 in fibroblasts.

Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease driven by both environmental and genetic factors. Epigenetics refers to changes in gene expression or cellular phenotype that do not involve alterations to DNA sequence. KMT2A is a member of the SET family which catalyses H3K4 methylation. Through microarray and single-cell sequencing data, we discovered KMT2A-positive fibroblasts were increased in IPF lung tissues. KMT2A level was increased in IPF and bleomycin-induced pulmonary fibrosis mice lung tissues collected in our centre. Mice with AAV6-induced KMT2A knockdown in fibroblast showed attenuatedpulmonary fibrosis after bleomycin treatment. Bioinformation also revealed that transcription factor PU.1 was a target of KMT2A. We demonstrated that PU.1 levels were increased in IPF tissues, bleomycin-induced mice lung tissues and primary fibrotic fibroblasts. KMT2A knockdown decreases PU.1 expression in vitro while KMT2A overexpression induces PU.1 activation. PU.1 fibroblast-specific knockout mice showed attenuated lung fibrosis induced by bleomycin. Furthermore, we demonstrated KMT2A up-regulated PU.1 in fibroblasts by catalysing H3K4me3 at the promoter of the PU.1 gene. The KMT2A transcription complex inhibitor mm102 treatment attenuated bleomycin-induced pulmonary fibrosis. The current study indicated that histone modification participates in the pathogenesis of IPF and KMT2A may have the potential to be a therapeutic target of IPF treatment. KMT2A plays a role in pulmonary fibrogenesis. KMT2A regulates PU.1 transcription in fibroblasts through H3K4me3 at promoter. KMT2A inhibitor attenuates pulmonary fibrosis in mice.

The Relationship Between Differential Expression of Non-coding RNAs (TP53TG1, LINC00342, MALAT1, DNM3OS, miR-126-3p, miR-200a-3p, miR-18a-5p) and Protein-Coding Genes (PTEN, FOXO3) and Risk of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a rapidly progressive interstitial lung disease of unknown pathogenesis with no effective treatment currently available. Given the regulatory roles of lncRNAs (TP53TG1, LINC00342, H19, MALAT1, DNM3OS, MEG3), miRNAs (miR-218-5p, miR-126-3p, miR-200a-3p, miR-18a-5p, miR-29a-3p), and their target protein-coding genes (PTEN, TGFB2, FOXO3, KEAP1) in the TGF-β/SMAD3, Wnt/β-catenin, focal adhesion, and PI3K/AKTsignaling pathways, we investigated the expression levels of selected genes in peripheral blood mononuclear cells (PBMCs) and lung tissue from patients with IPF. Lung tissue and blood samples were collected from 33 newly diagnosed, treatment-naive patients and 70 healthy controls. Gene expression levels were analyzed by RT-qPCR. TaqMan assays and TaqMan MicroRNA assay were employed to quantify the expression of target lncRNAs, mRNAs, and miRNAs. Our study identified significant differential expression in PBMCs from IPF patients compared to healthy controls, including lncRNAs MALAT1 (Fold Change = 3.809, P = 0.0001), TP53TG1 (Fold Change = 0.4261, P = 0.0021), and LINC00342 (Fold Change = 1.837, P = 0.0448); miRNAs miR-126-3p (Fold Change = 0.102, P = 0.0028), miR-200a-3p (Fold Change = 0.442, P = 0.0055), and miR-18a-5p (Fold Change = 0.154, P = 0.0034); and mRNAs FOXO3 (Fold Change = 4.604, P = 0.0032) and PTEN (Fold Change = 2.22, P = 0.0011). In lung tissue from IPF patients, significant expression changes were observed in TP53TG1 (Fold Change = 0.2091, P = 0.0305) and DNM3OS (Fold Change = 4.759, P = 0.05). Combined analysis of PBMCs expression levels for TP53TG1, MALAT1, miRNA miR-126-3p, and PTEN distinguished IPF patients from healthy controls with an AUC = 0.971, sensitivity = 0.80, and specificity = 0.955 (P = 6 × 10-8). These findings suggest a potential involvement of the identified ncRNAs and mRNAs in IPF pathogenesis. However, additional functional validation studies are needed to elucidate the precise molecular mechanisms by which these lncRNAs, miRNAs, and their targets contribute to PF.

Proteomic Approach to Study the Effect of Pneumocystis jirovecii Colonization in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and interstitial disease with an unclear cause, believed to involve genetic, environmental, and molecular factors. Recent research suggested that Pneumocystis jirovecii (PJ) could contribute to disease exacerbations and severity. This article explores how PJ colonization might influence the pathogenesis of IPF. We performed a proteomic analysis to study the profile of control and IPF patients, with/without PJ. We recruited nine participants from the Virgen del Rocio University Hospital (Seville, Spain). iTRAQ and bioinformatics analyses were performed to identify differentially expressed proteins (DEPs), including a functional analysis of DEPs and of the protein–protein interaction networks built using the STRING database. We identified a total of 92 DEPs highlighting the protein vimentin when comparing groups. Functional differences were observed, with the glycolysis pathway highlighted in PJ-colonized IPF patients; as well as the pentose phosphate pathway and miR-133A in non-colonized IPF patients. We found 11 protein complexes, notably the JAK-STAT signaling complex in non-colonized IPF patients. To our knowledge, this is the first study that analyzed PJ colonization’s effect on IPF patients. However, further research is needed, especially on the complex interactions with the AKT/GSK-3β/snail pathway that could explain some of our results.

Genetic variation reveals the therapeutic potential of BRSK2 in idiopathic pulmonary fibrosis

BackgroundCurrent 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.MethodsWe 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.ResultsMultiple 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.ConclusionsBRSK2 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.

Novel Integration of Spatial and Single-Cell Omics Data Sets Enables Deeper Insights into IPF Pathogenesis.

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.

Common biomarkers of idiopathic pulmonary fibrosis and systemic sclerosis based on WGCNA and machine learning

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.

Complement factor H drives idiopathic pulmonary fibrosis by autocrine C3 regulation, suppressing macrophage phagocytosis and enhancing fibrotic progression.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease with limited therapeutic options. In this study, we identified Complement Factor H (CFH) as a critical regulator in the pathogenesis of IPF, contributing to fibrotic progression through autocrine regulation of complement component C3 and suppression of macrophage phagocytosis. Transcriptomic analysis of IPF lung tissues revealed upregulation of CFH and enrichment of pro-fibrotic pathways, including M2 macrophage infiltration. Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning further validated CFH as a key gene associated with macrophage polarization and fibrotic remodeling. Functional studies demonstrated that CFH deficiency in mouse models attenuated bleomycin-induced pulmonary fibrosis, as evidenced by reduced collagen deposition, improved lung function, and decreased macrophage infiltration. Mechanistically, CFH deficiency enhanced macrophage efferocytosis and autophagy, reducing macrophage-mediated inflammation and fibrosis. Moreover, siRNA-loaded liposomes targeting CFH mitigated pulmonary fibrosis in vivo, further supporting the therapeutic potential of CFH modulation. These findings highlight CFH as a promising therapeutic target for IPF and underscore the importance of complement regulation in macrophage-driven fibrosis.

Idiopathic Pulmonary Fibrosis Is Associated With Type 1 Diabetes: A Two-Sample Mendelian Randomization Study.

The pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear; previous studies revealed the underlying connection between IPF and diabetes, but there is no consensual opinion. This study is aimed at examining the association between Type 1 diabetes (T1D) and IPF using Mendelian randomization (MR). In our two-sample MR study, we selected single nucleotide polymorphisms (SNPs) that are strongly associated with T1D in a genome-wide association study (GWAS) from IEU (dataset: ebi-a-GCST005536) and obtained their corresponding effect estimates on T1D risk in an IPF GWAS from IEU (dataset: finn-b-IPF). We conducted a multivariable Mendelian randomization (MVMR) analysis to eliminate the interference of aging. In the outcome of inverse-variance weighted (IVW) method, T1D showed a promoting effect on IPF (odds ratio (OR): 1.132, p = 0.005). The statistics passed the MR-PRESSO test, and no outliers were observed (global test p = 0.238). MVMR study was performed, and the aging-adjusted result remains almost the same (OR = 1.132, OR_95% CI: 1.034-1.239, p = 0.007). Our study shows a causal relation between T1D and IPF; further investigation should be conducted.

PPARG/SPP1/CD44 signaling pathway in alveolar macrophages: Mechanisms of lipid dysregulation and therapeutic targets in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease. It is characterized by inflammation and fibrosis in the lung parenchyma and interstitium. Given its poor prognosis and limited treatment options, understanding the underlying molecular mechanisms is crucial. Recent evidence suggests that lipid metabolism plays a pivotal role in IPF pathogenesis, however, the precise mechanisms remain poorly understood. To address this, we analyzed 12 bulk RNA-seq and 2 single-cell RNA-seq datasets from the GEO database using machine learning approaches. As a result, we identified four key lipid-related genes-PPARG, SPP1, CASP3, and PECAM1-that are expressed across various cell types. Specifically, in alveolar macrophages (AMs), we observed that PPARG was significantly downregulated, while SPP1 was highly expressed. Importantly, PPARG serves as a transcriptional regulator of SPP1, which in turn mediates intercellular signaling via CD44. Based on these findings, we propose a novel PPARG/SPP1/CD44 signaling pathway in AMs, which modulates lipid metabolism and likely contributes to the progression of fibrosis in IPF. Moreover, network pharmacology analysis identified several herbal compounds that target PPARG, offering potential therapeutic opportunities. In conclusion, these findings highlight the critical role of lipid metabolism in IPF and present novel molecular targets for the development of future therapeutic strategies.

A novel mouse model of pulmonary fibrosis: twice-repeated oropharyngeal bleomycin administration mimicking human pathology.

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible lung disease with high mortality and limited treatment options. While single-dose bleomycin-induced models are commonly used to investigate the pathogenesis of IPF, they fail to adequately replicate the complex pathological features in human patients, thereby hindering comprehensive investigations. Previous studies utilizing repetitive bleomycin injections have demonstrated a closer resemblance to human IPF pathology; however, the time- and resource-intensive nature of this approach presents significant drawbacks. Here, we propose a novel methodology involving twice-repeated oropharyngeal administration of bleomycin in mice, which closely mirrors the pathological manifestations observed in IPF patients. This model exhibited the honeycomb-like cyst formation, fibroblastic foci, bronchiolization of alveolar epithelium, emergence of metaplastic alveolar KRT5+ basal cells, and sustainability of these fibrotic phenotypes, thereby providing a robust model for IPF. Our findings establish a more efficient and translatable preclinical platform for investigating IPF pathogenesis and exploring potential therapeutic strategies.

Computational deconvolution of cell type-specific gene expression in COPD and IPF lungs reveals disease severity associations

BackgroundChronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are debilitating diseases associated with divergent histopathological changes in the lungs. At present, due to cost and technical limitations, profiling cell types is not practical in large epidemiology cohorts (n > 1000). Here, we used computational deconvolution to identify cell types in COPD and IPF lungs whose abundances and cell type-specific gene expression are associated with disease diagnosis and severity.ResultsWe analyzed lung tissue RNA-seq data from 1026 subjects (COPD, n = 465; IPF, n = 213; control, n = 348) from the Lung Tissue Research Consortium. We performed RNA-seq deconvolution, querying thirty-eight discrete cell-type varieties in the lungs. We tested whether deconvoluted cell-type abundance and cell type-specific gene expression were associated with disease severity. The abundance score of twenty cell types significantly differed between IPF and control lungs. In IPF subjects, eleven and nine cell types were significantly associated with forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), respectively. Aberrant basaloid cells, a rare cells found in fibrotic lungs, were associated with worse FVC and DLCO in IPF subjects, indicating that this aberrant epithelial population increased with disease severity. Alveolar type 1 and vascular endothelial (VE) capillary A were decreased in COPD lungs compared to controls. An increase in macrophages and classical monocytes was associated with lower DLCO in IPF and COPD subjects. In both diseases, lower non-classical monocytes and VE capillary A cells were associated with increased disease severity. Alveolar type 2 cells and alveolar macrophages had the highest number of genes with cell type-specific differential expression by disease severity in COPD and IPF. In IPF, genes implicated in the pathogenesis of IPF, such as matrix metallopeptidase 7, growth differentiation factor 15, and eph receptor B2, were associated with disease severity in a cell type-specific manner.ConclusionsUtilization of RNA-seq deconvolution enabled us to pinpoint cell types present in the lungs that are associated with the severity of COPD and IPF. This knowledge offers valuable insight into the alterations within tissues in more advanced illness, ultimately providing a better understanding of the underlying pathological processes that drive disease progression.

Adipose-Derived Mesenchymal Stem Cells (ADSCs) Have Anti-Fibrotic Effects on Lung Fibroblasts from Idiopathic Pulmonary Fibrosis (IPF) Patients.

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.

Triangle correlations of lung microbiome, host physiology and gut microbiome in a rat model of idiopathic pulmonary fibrosis

Changes in lung and gut microbial communities have been associated with idiopathic pulmonary fibrosis (IPF). This study aimed to investigate correlations between microbial changes in the lung and gut and host physiological indices in an IPF model, exploring potential mechanisms of the lung-gut axis in IPF pathogenesis. IPF model rats were established via trans-tracheal injection of bleomycin, with assessments of hematological indices, serum cytokines, lung histopathology, and microbiome alterations. Significant differences in microbial structure and composition were observed in the IPF model compared to controls, with 14 lung and 7 gut microbial genera showing significant abundance changes. Further analysis revealed 20 significant correlations between pulmonary and gut genera. Notably, 11 pairs of correlated genera were linked to the same IPF-related physiological indices, such as hydroxyproline, mean corpuscular volume (MCV), and red cell distribution width-standard deviation (RDW-SD). We identified 24 instances where a lung and a gut genus were each associated with the same physiological index, forming "lung genus—index—gut genus" relationships. Mediation analysis showed that indices like hydroxyproline, MCV, and RDW-SD mediated correlations between 10 lung genera (e.g., Cetobacterium, Clostridium XVIII ) and the gut genus Allobaculum. This study first describes gut-lung microbial interactions in pulmonary fibrosis. Mediation analysis suggests pathways underlying "lung genus—host index—gut genus" and "gut genus—host index—lung genus" correlations, thus providing clues to further elucidate the mechanisms of the “gut-lung axis” in IPF pathogenesis.

Computed tomography morphological assessments of central airways in interstitial lung abnormalities and idiopathic pulmonary fibrosis

BackgroundLittle is known about whether central airway morphological changes beyond traction bronchiectasis develop and affect clinical outcomes in patients with idiopathic pulmonary fibrosis (IPF). This study aimed to compare central airway structure comprehensively between patients with IPF, subjects with interstitial lung abnormality (ILA), and those without ILA (control) using computed tomography (CT). We further examined the prognostic impact of IPF-specific CT airway parameters in patients with IPF.MethodsThis retrospective study included male patients with IPF, and male health checkup subjects divided into those with ILA and control based on lung cancer screening CT. Using an artificial intelligence-based segmentation technique, the extent of fibrotic regions in the lung was quantified. After airway tree segmentation, CT parameters for central airway morphology, including the lumen area of the extrapulmonary airways (LAextra), wall and lumen area of the segmental/subsegmental intrapulmonary airways (WAintra and LAintra), tracheal distortion (tortuosity and curvature) and bifurcation angle of the main carina, were calculated.ResultsThere were 106 patients with IPF, 53 subjects with ILA, and 1295 controls. Multivariable models adjusted for age, height and smoking history revealed that LAintra and WAintra were larger in both ILA and IPF, and that tracheal tortuosity and curvature were higher in IPF, but not in ILA, than in the control, whereas the bifurcation angle did not differ between the 3 groups. According to multivariable Cox proportional hazards models including only patients with IPF, increased WAintra was significantly associated with greater mortality (standardized hazard ratio [95% confidence interval] = 1.58 [1.17, 2.14]), independent of the volume of fibrotic regions, normal-appearing regions, or the whole airway tree in the lung.ConclusionIncreased lumen area and wall thickening of the central airways may be involved in the pathogenesis of ILA and IPF, and wall thickening may affect the prognosis of patients with IPF.

Bexotegrast Shows Dose-dependent Integrin αvβ6 Receptor Occupancy in Lungs of Participants with Idiopathic Pulmonary Fibrosis: A Phase 2, Open-Label Clinical Trial.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by dyspnea and loss of lung function. Transforming growth factor-beta (TGF-β) activation mediated by αv integrins is central to the pathogenesis of IPF. Bexotegrast (PLN 74809) is an oral, once-daily, dual-selective inhibitor of αvβ6 and αvβ1 integrins under investigation for the treatment of IPF. Positron emission tomography (PET) using an αvβ6-specific PET tracer could confirm target engagement of bexotegrast in the lungs of participants with IPF. Objectives: This Phase 2 study (NCT04072315) evaluated αvβ6 receptor occupancy in the lung, as assessed by changes from baseline in αvβ6 PET tracer uptake, following single dose administration of bexotegrast to participants with IPF. Methods: In this open-label, single-center, single-arm study, adults with IPF received up to 2 single doses of bexotegrast, ranging from 60 to 320 mg with or without background IPF therapy (pirfenidone or nintedanib). At baseline and approximately 4 hours after each orally administered bexotegrast dose, a 60-minute dynamic PET/CT scan was conducted following administration of an αvβ6-specific PET probe ([18F]FP-R01-MG-F2). αvβ6 receptor occupancy by bexotegrast was estimated from the changes in PET tracer uptake following bexotegrast. Pharmacokinetics, safety, and tolerability of bexotegrast were also assessed. Results: Eight participants completed the study. Total and unbound plasma bexotegrast concentrations increased in a dose-dependent manner, and regional PET volume of distribution (VT) values decreased in a dose- and concentration-dependent manner. The VT data fit a simple saturation model, producing an unbound bexotegrast EC50 estimate of 3.32 ng/mL. Estimated maximum receptor occupancy was 35%, 53%, 71%, 88%, and 92% following single 60, 80, 120, 240, and 320-mg doses of bexotegrast, respectively. No treatment-emergent adverse events related to bexotegrast were reported. Conclusions: Dose- and concentration-dependent αvβ6 receptor occupancy by bexotegrast was observed by PET imaging, supporting once-daily 160 to 320 mg dosing to evaluate efficacy in clinical trials of IPF. Trial registration number: NCT04072315 Primary source of funding: Pliant Therapeutics, Inc. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Extracellular Vesicles in Idiopathic Pulmonary Fibrosis: Pathogenesis, Biomarkers and Innovative Therapeutic Strategies.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible interstitial lung disease caused by aberrant deposition of extracellular matrix in the lungs with significant morbidity and mortality. The therapeutic choices for IPF remain limited. Extracellular vesicles (EVs), as messengers for intercellular communication, are cell-secreted lipid bilayer nanoscale particles found in body fluids, and regulate the epithelial phenotype and profibrotic signaling pathways by transporting bioactive cargo to recipients in the pathogenesis of IPF. Furthermore, an increasing number of studies suggests that EVs derived from stem cells can be employed as a cell-free therapeutic approach for IPF, given their intrinsic tissue-homing capabilities and regeneration characteristics. This review highlights new sights of EVs in the pathogenesis of IPF, their potential as diagnostic and prognostic biomarkers, and prospects as novel drug delivery systems and next-generation therapeutics against IPF. Notably, bringing engineering strategies to EVs holds great promise for enhancing the therapeutic effect of anti-pulmonary fibrosis and promoting clinical transformation.

YAP Alleviates Pulmonary Fibrosis Through Promoting Alveolar Regeneration via Modulating the Stemness of Alveolar Type 2 Cells.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with no cure except transplantation. Abnormal alveolar epithelial regeneration is a key driver of IPF development. The function of Yes1 Associated Transcriptional Regulator (YAP) in alveolar regeneration and IPF pathogenesis remains elusive. Here, we first revealed the activation of YAP in alveolar epithelium 2 cells (AEC2s) from human IPF lungs and fibrotic mouse lungs. Notably, conditional deletion of YAP in mouse AEC2s exacerbated bleomycin-induced pulmonary fibrosis. Intriguingly, we showed in both conditional knockout mice and alveolar organoids that YAP deficiency impaired AEC2 proliferation and differentiation into alveolar epithelium 1 cells (AEC1s). Mechanistically, YAP regulated expression levels of genes associated with cell cycle progression and AEC1 differentiation. Furthermore, overexpression of YAP in vitro promoted cell proliferation. These results indicate the critical role of YAP in alveolar regeneration and IPF pathogenesis. Our findings provide new insights into the regulation of alveolar regeneration and IPF pathogenesis, paving the road for developing novel treatment strategies.

Single-Cell RNA Sequencing Reveals Monocyte-Derived Interstitial Macrophages with a Pro-Fibrotic Phenotype in Bleomycin-Induced Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with limited effective therapies. Interstitial macrophages (IMs), especially those derived from monocytes, play an unknown role in IPF pathogenesis. By using single-cell RNA sequencing (scRNA-seq), bleomycin (BLM)-induced pulmonary fibrosis mouse lungs were analyzed to characterize the cellular landscape and heterogeneity of macrophages in this model. scRNA-seq was used to identify distinct interstitial macrophage subpopulations in fibrotic lungs, with monocyte-derived macrophages exhibiting a pro-fibrotic gene expression profile enriched in wound healing, extracellular matrix (ECM) remodeling, and pro-fibrotic cytokine production functions. A pseudotime analysis revealed that IMs originated from monocytes and differentiated along a specific trajectory. A cell-cell communication analysis demonstrated strong interactions between monocyte-derived interstitial macrophages (Mo-IMs) and fibroblasts through the transforming growth factor beta (TGFβ), secreted phosphoprotein 1 (SPP1), and platelet-derived growth factor (PDGF) signaling pathways. Flow cytometry validated the presence and expansion of Mo-IMs subpopulations in BLM-treated mice. This study reveals the cellular heterogeneity and developmental trajectory of lung macrophages in early BLM-induced pulmonary fibrosis, highlighting the crucial role of Mo-IMs with a pro-fibrotic phenotype in IPF pathogenesis via interactions with fibroblasts. Targeting these specific macrophage subpopulations and associated signaling pathways may provide novel therapeutic strategies for IPF.

What Is on the Horizon for Treatments in Idiopathic Pulmonary Fibrosis?

Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal lung disease most commonly encountered in older individuals. Several decades of research have contributed to a better understanding of its pathogenesis, though only two drugs thus far have shown treatment efficacy, i.e., by slowing the decline of lung function. The pathogenesis of IPF remains incompletely understood and involves multiple complex interactions and mechanisms working in tandem or separately to result in unchecked deposition of extracellular matrix components and collagen characteristic of the disease. These mechanisms include aberrant response to injury in the alveolar epithelium, inappropriate communication between epithelial cells and mesenchymal cells, imbalances between oxidative injury and tissue repair, recruitment of inflammatory pathways that induce fibrosis, and cell senescence leading to sustained activation and proliferation of fibroblasts and myofibroblasts. Targeted approaches to each of these mechanistic pathways have led to recent clinical studies evaluating the safety and efficacy of several agents. This review highlights selected concepts in the pathogenesis of IPF as a rationale for understanding current or future therapeutic approaches, followed by a review of several selected agents and their recent or active clinical studies. Current novel therapies include approaches to attenuating or modifying specific cellular or signaling processes in the fibrotic pathway, modifying inflammatory and metabolic derangements, and minimizing inappropriate cell senescence.