Progression Of IPF Research Articles

Senescent lung-resident mesenchymal stem cells drive pulmonary fibrogenesis through FGF-4/FOXM1 axis

BackgroundIdiopathic pulmonary fibrosis (IPF) is an age-related disease featured with abnormal fibrotic response and compromised lung function. Cellular senescence is now considered as an essential driving mechanism for IPF. Given the poor knowledge of the mechanisms underpinning IPF progression, understanding the cellular processes and molecular pathways is critical for developing effective therapies of IPF.MethodsLung fibrosis was induced using bleomycin in C57BL/6 mice. Cellular senescence was measured by immunofluorescence. The effects of FGF-4 on fibroblast activation markers and signaling molecules were assessed with western blot and qPCR.ResultsWe demonstrated elevated abundance of senescent mesenchymal stem cells (MSCs) in IPF lung tissues, which was tightly correlated with the severity of pulmonary fibrosis in vivo. In addition, senescent MSCs could effectively induce the phenotype of pulmonary fibrosis both in vitro and in vivo. To further confirm how senescent MSCs regulate IPF progression, we demonstrate that FGF-4 is significantly elevated in senescent MSCs, which can induce the activation of pulmonary fibroblasts. In vitro, FGF-4 can activate Wnt signaling in a FOXM1-dependent manner. Inhibition of FOXM1 via thiostrepton effectively impairs FGF-4-induced activation of pulmonary fibroblast and dramatically suppresses the development of pulmonary fibrosis.ConclusionThese findings reveal that FGF-4 plays a crucial role in senescent MSCs-mediated pulmonary fibrogenesis, and suggests that strategies aimed at deletion of senescent MSCs or blocking the FGF-4/FOXM1 axis could be effective in the therapy of IPF.

Causal relationship between circulating glutamine levels and idiopathic pulmonary fibrosis: a two-sample mendelian randomization study

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive and debilitating respiratory disease with a median survival of less than 5 years. In recent years, glutamine has been reported to be involved in the regulation of collagen deposition and cell proliferation in fibroblasts, thereby influencing the progression of IPF. However, the relationships between glutamine and the incidence, progression, and treatment response of IPF remain unclear. Our study aimed to investigate the relationship between circulating glutamine levels and IPF, as well as its potential as a therapeutic target.MethodsWe performed a comprehensive Mendelian Randomization (MR) analysis using the most recent genome-wide association study summary-level data. A total of 32 single nucleotide polymorphisms significantly correlated to glutamine levels were identified as instrumental variables. Eight MR analysis methods, including inverse variance weighted, MR-Egger, weighted median, weighted mode, constrained maximum likelihood, contamination mixture, robust adjusted profile score, and debiased inverse-variance weighted method, were used to assess the relationship between glutamine levels with IPF.ResultsThe inverse variance weighted analysis revealed a significant inverse correlation between glutamine levels and IPF risk (Odds Ratio = 0.750; 95% Confidence Interval : 0.592–0.951; P = 0.017). Sensitivity analyses, including MR-Egger regression and MR-PRESSO global test, confirmed the robustness of our findings, with no evidence of horizontal pleiotropy or heterogeneity.ConclusionOur study provides novel evidence for a causal relationship between lower circulating glutamine levels and increased risk of IPF. This finding may contribute to the early identification of high-risk individuals for IPF, disease monitoring, and development of targeted therapeutic strategies.

Identification of key mitochondria-related genes and their potential crosstalk role with immune pattern in Idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) stands out as a life-threatening and one of the most severe interstitial lung diseases. The pathogenesis of IPF is not fully understood, while recent studies have highlighted the association of mitochondrial dysfunction with IPF. This study is dedicated to pinpointing crucial genes related to mitochondria that potentially impact the advancement of IPF, thereby offering new perspectives on the pathogenesis of this condition. MethodsThe Gene Expression Omnibus (GEO) database was utilized to download three datasets (GSE32537, GSE92592, and GSE150910), following which a comprehensive analysis was conducted to identify differentially expressed mitochondria-related genes (DEMTRGs) in the IPF lung tissues. Subsequently, GO and KEGG enrichment analysis of the DEMTRGs was performed. Next, external datasets and in vivo experiments were performed to validate their expression. Additionally, a Logistic regression model based on key DEMTRGs was constructed, and the model’s ability to distinguish between IPF and controls was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC). Finally, gene set enrichment analysis (GSEA) and CIBERSORT algorithm were conducted. ResultsWe identified five key DEMTRGs (ALDH18A1, ALDH1B1, MCCC1, ACAT1, and PDHA1), ALDH18A1 and ALDH1B1 exhibited upregulated expression levels, whereas MCCC1, ACAT1, and PDHA1 showed downregulation in the lung tissue of individuals with IPF. The expression levels of these key DEMTRGs were validated by an independent external dataset (GSE53845) and the bleomycin-induced pulmonary fibrosis mice. In addition, the ROCs indicated that the diagnostic model constructed based on key DEMTRGs could effectively distinguish between IPF and controls (AUC>0.8). GSEA analysis and immune-related analysis shed light on the potential mechanisms through which these key DEMTRGs influence IPF. ConclusionOur research has pinpointed key genes associated with mitochondria that may ultimately contribute to the progression of IPF by exerting regulatory effects on mitochondrial function, thereby influencing multiple cellular processes.

Exosomal circRNAs in the plasma serve as novel biomarkers for IPF diagnosis and progression prediction

BackgroundIdiopathic Pulmonary Fibrosis (IPF) is a type of chronic interstitial pneumonia, often fatal, with elusive causes and a bleak prognosis. Its treatment options are limited and largely ineffective. Early detection and precise diagnosis are pivotal in managing the disease effectively and enhancing patient survival rates. Recently, the quest for trustworthy biomarkers for IPF has gained momentum. Notably, emerging studies indicate that circular RNAs (circRNAs) found in exosomes may hold significant potential as valuable diagnostic markers.MethodsIn this study, we initially explored the expression profile of circRNAs in exosomes sourced from the blood of IPF patients and healthy volunteers, employing a human circRNA microarray. We then utilized RT-qPCR to corroborate the dysregulated circRNAs identified by the microarray during the training phase. Next, the circRNAs that displayed a significant increase during the training phase were selected for further validation in a larger cohort encompassing 113 IPF patients and 76 healthy volunteers. Ultimately, the expression level and function of hsa_circ_0044226 were substantiated through a series of in vivo and in vitro experiments.ResultsUtilizing a human circRNA microarray, we identified 11 dysregulated circRNAs in the exosomes derived from the blood of IPF patients and control volunteers. Subsequent RT-qPCR analysis revealed significant increases in three circRNAs (hsa_circ_0044226, hsa_circ_0004099, hsa_circ_0008898) within the IPF patients. Notably, hsa_circ_0044226 was markedly elevated in patients experiencing acute exacerbation of IPF (AE-IPF) compared to those with stable IPF (S-IPF). Additionally, an upregulation of hsa_circ_0044226 was observed in the blood exosomes derived from a bleomycin-induced IPF mouse model.ConclusionThe expression levels of hsa_circ_0044226, hsa_circ_0004099, and hsa_circ_0008898 in plasma exosomes introduce a new paradigm of biomarkers for the diagnosis and progression of IPF.

Comprehensive analysis of an endoplasmic reticulum stress-related gene prediction model and immune infiltration in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease. This study aimed to investigate the involvement of endoplasmic reticulum stress (ERS) in IPF and explore its correlation with immune infiltration. ERS-related differentially expressed genes (ERSRDEGs) were identified by intersecting differentially expressed genes (DEGs) from three Gene Expression Omnibus datasets with ERS-related gene sets. Gene Set Variation Analysis and Gene Ontology were used to explore the potential biological mechanisms underlying ERS. A nomogram was developed using the risk signature derived from the ERSRDEGs to perform risk assessment. The diagnostic value of the risk signature was evaluated using receiver operating characteristics, calibration, and decision curve analyses. The ERS score of patients with IPF was measured using a single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm. Subsequently, a prognostic model based on the ERS scores was established. The proportion of immune cell infiltration was assessed using the ssGSEA and CIBERSORT algorithms. Finally, the expression of ERSRDEGs was validated in vivo and in vitro via RT-qPCR. This study developed an 8-ERSRDEGs signature. Based on the expression of these genes, we constructed a diagnostic nomogram model in which agouti-related neuropeptide had a significantly greater impact on the model. The area under the curve values for the predictive value of the ERSRDEGs signature were 0.975 and 1.000 for GSE70866 and GSE110147, respectively. We developed a prognostic model based on the ERS scores of patients with IPF. Furthermore, we classified patients with IPF into two subtypes based on their signatures. The RT-qPCR validation results supported the reliability of most of our conclusions. We developed and verified a risk model using eight ERSRDEGs. These eight genes can potentially affect the progression of IPF by regulating ERS and immune responses.

Pyroptosis-related signatures predict immune characteristics and prognosis in IPF

The purpose of this work was to use integrated bioinformatics analysis to screen for pyroptosis-related genes (PRGs) and possible immunological phenotypes linked to the development and course of IPF. Transcriptome sequencing datasets GSE70866, GSE47460 and GSE150910 were obtained from GEO database. From the GSE70866 database, 34 PRGs with differential expression were found in IPF as compared to healthy controls. In addition, a diagnostic model containing 4 genes PRGs (CAMP, MKI67, TCEA3 and USP24) was constructed based on LASSO logistic regression. The diagnostic model showed good predictive ability to differentiate between IPF and healthy, with ROC-AUC ranging from 0.910 to 0.997 in GSE70866 and GSE150910 datasets. Moreover, based on a combined cohort of the Freiburg and the Siena cohorts from GSE70866 dataset, we identified ten PRGs that might predict prognosis for IPF. We constructed a prognostic model that included eight PRGs (CLEC5A, TREM2, MMP1, IRF2, SEZ6L2, ADORA3, NOS2, USP24) by LASSO Cox regression and validated it in the Leuven cohort. The risk model divided IPF patients from the combined cohort into high-risk and low-risk subgroups. There were significant differences between the two subgroups in terms of IPF survival and GAP stage. There is a close correlation between leukocyte migration, plasma membrane junction, and poor prognosis in a high-risk subgroup. Furthermore, a high-risk score was associated with more plasma cells, activated NK cells, monocytes, and activated mast cells. Additionally, we identified HDAC inhibitors in the cMAP database that might be therapeutic for IPF. To summarize, pyroptosis and its underlying immunological features are to blame for the onset and progression of IPF. PRG-based predictive models and drugs may offer new treatment options for IPF.

LncRNA GAS5 suppresses TGF-β1-induced transformation of pulmonary pericytes into myofibroblasts by recruiting KDM5B and promoting H3K4me2/3 demethylation of the PDGFRα/β promoter

BackgroundIdiopathic pulmonary fibrosis (IPF) is a condition that may cause persistent pulmonary damage. The transformation of pericytes into myofibroblasts has been recognized as a key player during IPF progression. This study aimed to investigate the functions of lncRNA growth arrest-specific transcript 5 (GAS5) in myofibroblast transformation during IPF progression.MethodsWe created a mouse model of pulmonary fibrosis (PF) via intratracheal administration of bleomycin. Pericytes were challenged with exogenous transforming growth factor-β1 (TGF-β1). To determine the expression of target molecules, we employed quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemical and immunofluorescence staining. The pathological changes in the lungs were evaluated via H&E and Masson staining. Furthermore, the subcellular distribution of GAS5 was examined using FISH. Dual-luciferase reporter assay, ChIP, RNA pull-down, and RIP experiments were conducted to determine the molecular interaction.ResultsGAS5 expression decreased whereas PDGFRα/β expression increased in the lungs of IPF patients and mice with bleomycin-induced PF. The in vitro overexpression of GAS5 or silencing of PDGFRα/β inhibited the TGF-β1-induced differentiation of pericytes to myofibroblasts, as evidenced by the upregulation of pericyte markers NG2 and desmin as well as downregulation of myofibroblast markers α-SMA and collagen I. Further mechanistic analysis revealed that GAS5 recruited KDM5B to promote H3K4me2/3 demethylation, thereby suppressing PDGFRα/β expression. In addition, KDM5B overexpression inhibited pericyte–myofibroblast transformation and counteracted the promotional effect of GAS5 knockdown on pericyte–myofibroblast transformation. Lung fibrosis in mice was attenuated by GAS5 overexpression but promoted by GAS5 deficiency.ConclusionGAS5 represses pericyte–myofibroblast transformation by inhibiting PDGFRα/β expression via KDM5B-mediated H3K4me2/3 demethylation in IPF, identifying GAS5 as an intervention target for IPF.

Development and validation of the prognostic model based on autophagy-associated genes in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease. Many studies suggest that autophagy may be related to disease progression and prognosis in IPF. However, the mechanisms involved have not been fully elucidated. We incorporated 232 autophagy-associated genes (AAGs) and two datasets, GSE28042 and GSE27957, from the GEO database. Univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) regression were used to construct the autophagy-associated prognostic model. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to investigate the functions of these autophagy-associated genes. CIBERSORT algorithm was used to calculate the immune cell infiltration between patients in the high-risk score and low-risk score groups. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) was performed to explore the mRNA expression of five genes in the autophagy-associated risk model. We constructed a 5-autophagy-associated genes signature based on Univariate Cox analysis and LASSO regression. In our autophagy-associated risk model, IPF patients in the high-risk group demonstrated a poor overall survival rate compared to patients in the low-risk group. For 1-, 2-, and 3-year survival rates, the AUC predictive value of the AAG signature was 0.670, 0.787, and 0.864, respectively. These results were validated in the GSE27957 cohort, confirming the good prognostic effect of our model. GO and KEGG pathway analyses enriched immune-related pathways between the high-risk and low-risk groups. And there was also a significant difference in immune cell infiltration between two groups. And the results of qRT-PCR showed that the expression levels of FOXO1, IRGM, MYC, and PRKCQ were significantly decreased in the Peripheral Blood Mononuclear Cell (PBMC) of IPF patient samples. Our study constructed and validated an autophagy-associated risk model based on MYC, MAPK1, IRGM, PRKCQ, and FOXO1. And those five genes may influence the progression of IPF by regulating immune responses and immune cells.

A novel seven-gene risk profile in BALF to identify high-risk patients with idiopathic pulmonary fibrosis.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a fatal heterogeneous disease with a varied clinical course that is difficult to predict. Accurate predictive models are urgently needed to identify individuals with poor survival for the optimal timing of referral for transplantation and provide some clues for mechanistic research on disease progression.MethodsWe obtained the gene expression profiles of bronchoalveolar lavage fluid (BALF) from the Gene Expression Omnibus. Individuals from the GPL14550 platform were assigned to the derivation cohort (n=112) and individuals from the GPL17077 platform to the validation cohort (n=64). Univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses were applied to select candidate genes for overall survival. A nomogram model was constructed based on Cox hazard regression analysis. The model was assessed by C-statistic, calibration curve, and decision curve analysis (DCA) and was externally validated.ResultsA nomogram model comprising seven genes was constructed. Excellent discrimination and calibration were observed in the derivation (C-index 0.815) and validation (C-index 0.812) cohorts. The AUCs for predicting 1-, 2- and 3-year survival were 0.857, 0.918, 0.930 in the derivation cohort and 0.850, 0.880, 0.925 in the validation cohort, respectively. DCA confirmed the clinical applicability of the model. A risk score based on the model was an independent prognostic predictor and could divide patients into high- and low-risk groups. The Kaplan-Meier analysis displayed that high-risk patients exhibited significantly poorer survival compared with low-risk patients. Gene Set Enrichment Analysis (GSEA) showed that high-risk patients were primarily enriched in inflammatory hallmarks, and single sample GSEA (ssGSEA) indicated that the high-risk group is closely correlated with the immune process. These lead to increased insight into mechanisms associated with IPF progression that inflammation mediated by immune response might be involved in the disease progression.ConclusionsThe novel BALF seven-gene model performed well in risk stratification and individualized survival prediction for patients with IPF, facilitating personalized management of IPF patients. It deepened the understanding of the role of inflammation in IPF progression, which needs to be further studied.

Prognostic Role of NLR, PLR and MHR in Patients With Idiopathic Pulmonary Fibrosis.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with low survival time. Since the pathophysiological progression of IPF is closely associated with immunological and inflammatory responses, immune biomarkers, including neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and monocyte-high density lipoprotein ratio (MHR), have the potential to predict overall survival in IPF patients.MethodsA total of 278 patients with IPF were finally enrolled. The demographic and clinical characteristics of the patients at baseline were recorded. Multivariable Cox regression analysis was used to evaluate the association between the three biomarkers and overall survival in both the total cohort and acute exacerbation subgroup.ResultsThe median follow-up was 5.84 months. After adjusting for confounders, we found that only elevated NLR was associated with worse overall survival (OR = 1.019, 95% CI 1.001-1.037, P =0.041) by using multivariable Cox regression analysis. In 116 acute exacerbation IPF patients, the results of the Cox multiple regression model also indicated that the NLR was a significant prognostic factor (OR= 1.022, 95% CI 1.001-1.044, P =0.036). The NLR before death was also significantly higher than that at admission in nonsurvival acute exacerbation IPF patients (P=0.014). No significant differences were found in PLR (P=0.739) or MHR changes (P=0.478).ConclusionsOur results indicated that elevated NLR expression is associated with shorter overall survival in IPF patients, which is independent of other prognostic factors. The NLR may be regarded as a reliable prognostic biomarker for IPF patients.

Identification of Hub Genes in Idiopathic Pulmonary Fibrosis and NSCLC Progression:Evidence From Bioinformatics Analysis.

Background: Lung cancer is the most common comorbidity of idiopathic pulmonary fibrosis. Thus there is an urgent need for the research of IPF and carcinogenesis Objective: The objective of this study was to explore hub genes which are common in pulmonary fibrosis and lung cancer progression through bioinformatic analysis. Methods: All the analysis was performed in R software. Differentially expressed genes (DEGs) were explored by comparing gene expression profiles between IPF tissues and healthy lung tissues from GSE24206, GSE53845, GSE101286 and GSE110147 datasets. Venn Diagram analysis was used to identify the overlapping genes, while GO and KEGG pathway enrichment analysis were used to explore the biological functions of the DEGs using clusterprofiler package. Hub genes were identified by analyzing protein-protein interaction networks using Cytoscape software. Nomogram was constructed using the rms package. Tumor immune dysfunction and exclusion (TIDE) and Genomics of Drug Sensitivity in Cancer (GDSC) analysis was used to quantify the immunotherapy and chemotherapy sensitivity of non-small cell lung cancer (NSCLC) patients. Results: COL1A1, COL3A1, MMP1, POSTN1 and TIMP3 were identified as the top five hub genes. The five hub genes were used to construct a diagnostic nomogram that was validated in another IPF dataset. Since the hub genes were also associated with lung cancer progression, we found that the nomogram also had diagnostic value in NSCLC patients. These five genes achieved a statistically difference of overall survival in NSCLC patients (p < 0.05). The expression of the five hub genes was mostly enriched in fibroblasts. Fibroblasts and the hub genes also showed significant ability to predict the susceptibility of NSCLC patients to chemotherapy and immunotherapy. Conclusion: We identified five hub genes as potential biomarkers of IPF and NSCLC progression. This finding may give insight into the underlying molecular mechanisms of IPF and lung cancer progression and provides potential targets for developing new therapeutic agents for IPF patients.

Bacterial and viral coinfection in idiopathic pulmonary fibrosis patients: the prevalence and possible role in disease progression

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive interstitial pneumonia of unknown aetiology with a mean survival rate of less than 3 years. No previous studies have been performed on the role of co-infection (viral and bacterial infection) in the pathogenesis and progression of IPF. In this study, we investigated the role of viral/bacterial infection and coinfection and their possible association with pathogenesis and progression of IPF.MethodsWe investigated the prevalence and impact of bacterial and viral coinfection in IPF patients (n = 67) in the context of pulmonary function (FVC, FEV1 and DLCO), disease status and mortality risk. Using principal component analysis (PCA), we also investigated the relationship between distribution of bacterial and viral co-infection in the IPF cohort.ResultsOf the 67 samples, 17.9% samples were positive for viral infection, 10.4% samples were positive for bacterial infection and 59.7% samples were positive coinfection. We demonstrated that IPF patients who were co-infected had a significantly increased risk of mortality compared (p = 0.031) with IPF patients who were non-infected [Hazard ratio: 8.12; 95% CI 1.3–26.9].ConclusionIn this study, we report for the first time that IPF patients who were coinfected with bacterial and viral infection have significantly decreased FVC and DLCO (% predicted). Besides, the results demonstrated the increased AE-IPF, increased incidence of death and risk of mortality in infected/coinfected patients compared to non-infected IPF patients.

Clinical management and acute exacerbations in patients with idiopathic pulmonary fibrosis in Spain: results from the OASIS study

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive disease associated with decline in lung function and poor prognosis entailing significant impairment in quality of life and high socioeconomic burden. The aim of this study was to characterize clinical management and resources utilization of patients with IPF in Spain, according to predicted forced vital capacity (FVC) % at baseline.MethodsProspective, non-interventional, multicentric real-world data study in patients with IPF in Spain with 12-months follow-up. Clinical management and resources utilization during study period were recorded and compared between groups. FVC decline and acute exacerbations occurrence and associated healthcare resource use were also analysed. FVC decline after 12 months was estimated as relative change.Results204 consecutive patients with IPF were included and divided according to baseline FVC % predicted value. At baseline, patients with FVC < 50% received significantly more pharmacological and non-pharmacological treatments, and more help from caregiver. During the 12-months follow-up, patients with FVC < 50% required more specialized care visits, emergency visits, hospitalizations, pulmonary functions tests, non-health resource use (special transportation), and pharmacological treatments (p < 0.05 for all comparisons). Moreover, patients with FVC < 50% at baseline experienced more AE-IPF (p < 0.05), requiring more health-related resources use (primary care visits, p < 0.05). FVC decline was observed in all groups over the 12 months. FVC decreased on average by 2.50% (95% CI: − 5.98 to 0.98) along the year. More patients experienced an FVC decline > 10% in the more preserved lung function groups than in the FVC < 50% group, because of their already deteriorated condition.ConclusionsWe observed a significantly higher annual IPF-related resource use in patients with more impaired lung function at baseline. Since FVC decreases irrespective of FVC% predicted at baseline, slowing IPF progression to maintain patients at early disease stages is relevant to improve IPF management and to optimize resource use.Trial registration: EU PAS register number EUPAS19387 [June 01, 2017].

Extracellular Vesicles in Pulmonary Fibrosis Models and Biological Fluids of Interstitial Lung Disease Patients: A Scoping Review.

Introduction: Interstitial lung diseases (ILDs) are a heterogeneous group of diffuse parenchymal lung disorders characterized by the pathogenetic involvement of interstitium. Therefore, an elucidation of the etiology and pathogenesis as well as the identification of diagnostic and prognostic biomarkers of such diseases is more compelling than ever. It is of note that there is increasing evidence of the involvement of extracellular vesicles (EVs) in the pathogenesis of lung diseases including lung cancer, chronic obstructive pulmonary disease and pulmonary fibrosis. It has been speculated that EVs play a pivotal role as mediators of intercellular communication, as well as the highlighting of the role of EVs as co-operators in the development of lung diseases such as IPF. Methods: The present study aimed to carry out a systematic exploratory search of the literature (through the scoping review approach) to identify and systematize the main results of the pathogenetic role of EVs in pulmonary fibrosis models and biological fluids from ILD patients, including plasma, bronchoalveolar lavage (BAL) and sputum. Conclusion: Fibroblast-to-mesenchymal differentiation, collagen and extracellular matrix deposition are key mechanisms in the development and progression of IPF. EV-coupled miRNA are important modulators of biological processes in terms of intercellular communication as shown in pulmonary fibrosis models as well as biofluids. The helpfulness of EVs as diagnostic and theranostic markers is worth further investigation. The evolving potential of EVs to translate effective EV-based therapies into clinical practice is of growing interest, due to the urgent need for novel therapeutic strategies for IPF patients.

Dysfunctional lactate metabolism in human alveolar type II cells from idiopathic pulmonary fibrosis lung explant tissue

BackgroundIdiopathic Pulmonary Fibrosis (IPF) is the most common and progressive form of the interstitial lung diseases, leading most patients to require lung transplants to survive. Despite the relatively well-defined role of the fibroblast in the progression of IPF, it is the alveolar type II epithelial cell (AEC2) that is now considered the initiation site of damage, driver of disease, and the most efficacious therapeutic target for long-term resolution. Based on our previous studies, we hypothesize that altered lactate metabolism in AEC2 plays a pivotal role in IPF development and progression, affecting key cellular and molecular interactions within the pulmonary microenvironment.MethodsAEC2s isolated from human patient specimens of non-fibrotic and IPF lungs were used for metabolic measurements, lactate dehydrogenase (LDH) analyses and siRNA-mediated knockdown experiments.ResultsAEC2s isolated from human IPF lung explant tissues had lower rates of oxidative metabolism and were more glycolytic lactate-producing cells than were AEC2 from control, non-fibrotic lung explant tissues. Consistent with this shift in metabolism, patient-derived IPF AEC2s exhibited LDH tetramers that have higher ratios of LDHA:LDHB (i.e., favoring pyruvate to lactate conversion) than control AEC2s. Experimental manipulation of LDHA subunit expression in IPF AEC2s restored the bioenergetic profile characteristic of AEC2 from non-fibrotic lungs.ConclusionsThese results are consistent with the concept that altered lactate metabolism may be an underlying feature of AEC2 dysfunction in IPF and may be a novel and important target for therapeutic treatment.

Turnover of type I and III collagen predicts progression of idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of fibrillar collagens in the alveolar space resulting in reduced pulmonary function and a high mortality rate. Biomarkers measuring the turnover of type I and III collagen could provide valuable information for prognosis and treatment decisions in IPF.MethodsSerological biomarkers reflecting the formation of type III collagen (PRO-C3) and degradation of type I (C1M) and III collagen (C3M) were evaluated in a real-world cohort of 178 newly diagnosed IPF patients. Blood samples and clinical data were collected at baseline, six, and 12 months. Baseline and longitudinal biomarker levels were related to disease progression of IPF (defined as ≥ 5% decline in forced vital capacity (FVC) and/or ≥ 10% decline in diffusing capacity for carbon monoxide (DLco) and/or all-cause mortality at 12 months). Furthermore, we analysed differences in percentage change of biomarker levels from baseline between patients receiving antifibrotic treatment or not.ResultsIncreased baseline levels of type I and III collagen turnover biomarkers were associated with a greater risk of disease progression within 12 months compared to patients with a low baseline type I and III collagen turnover. Patients with progressive disease had higher serum levels of C1M (P = 0.038) and PRO-C3 (P = 0.0022) compared to those with stable disease over one year. There were no differences in biomarker levels between patients receiving pirfenidone, nintedanib, or no antifibrotics.ConclusionBaseline levels of type I and III collagen turnover were associated with disease progression within 12 months in a real-world cohort of IPF patients. Longitudinal biomarker levels of type I and III collagen turnover were related to progressive disease. Moreover, antifibrotic therapy did not affect type I and III collagen turnover biomarkers in these patients. PRO-C3 and C1M may be potential biomarkers for a progressive disease behavior in IPF.

Potential for inhibition of checkpoint kinases 1/2 in pulmonary fibrosis and secondary pulmonary hypertension

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterised by exuberant tissue remodelling and associated with high unmet medical needs. Outcomes are even worse when IPF results in secondary...

Prognostic role of Krebs von den Lungen-6 (KL-6) measurement in idiopathic pulmonary fibrosis: a systematic review and meta-analysis.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial disease with limited therapeutic options. The measurement of Krebs von den Lungen-6 (KL-6) glycoprotein has been proposed for evaluating the risk of IPF progression and predicting patient prognosis, but the robustness of available evidence is unclear. We searched Medline and Embase databases for peer-reviewed literature from inception to April 2020. Original articles investigating KL-6 as prognostic marker for IPF were retrieved. Considered outcomes were the risk of developing acute exacerbation (AE) and patient survival. Meta-analysis of selected studies was conducted, and quantitative data were uniformed as odds ratio (OR) or hazard ratio (HR) estimates, with corresponding 95% confidence intervals (CI). Twenty-six studies were included in the systematic review and 14 were finally meta-analysed. For AE development, the pooled OR (seven studies) for KL-6 was 2.72 (CI 1.22-6.06; p=0.015). However, a high degree of heterogeneity (I2=85.6%) was found among selected studies. Using data from three studies reporting binary data, a pooled sensitivity of 72% (CI 60-82%) and a specificity of 60% (CI 52-68%) were found for KL-6 measurement in detecting insurgence of AE in IPF patients. Pooled HR (seven studies) for mortality prediction was 1.009 (CI0.983-1.036; p=0.505). Although our meta-analysis suggested that IPF patients with increased KL-6 concentrations had a significant increased risk of developing AE, the detection power of the evaluated biomarker is limited. Furthermore, no relationship between biomarker concentrations and mortality was found. Caution is also needed when extending obtained results to non-Asian populations.

A study design for statistical learning technique to predict radiological progression with an application of idiopathic pulmonary fibrosis using chest CT images

BackgroundIdiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by an unpredictable decline in lung function. Predicting IPF progression from the early changes in lung function tests have known to be a challenge due to acute exacerbation. Although it is unpredictable, the neighboring regions of fibrotic reticulation increase during IPF's progression. With this clinical information, quantitative characteristics of high-resolution computed tomography (HRCT) and a statistical learning paradigm, the aim is to build a model to predict IPF progression. DesignA paired set of anonymized 193 HRCT images from IPF subjects with 6–12 month intervals were collected retrospectively. The study was conducted in two parts: (1) Part A collects the ground truth in small regions of interest (ROIs) with labels of “expected to progress” or “expected to be stable” at baseline HRCT and develop a statistical learning model to classify voxels in the ROIs. (2) Part B uses the voxel-level classifier from Part A to produce whole-lung level scores of a single-scan total probability's (STP) baseline. MethodsUsing annotated ROIs from 71 subjects' HRCT scans in Part A, we applied Quantum Particle Swarm Optimization–Random Forest (QPSO-RF) to build the classifier. Then, 122 subjects' HRCT scans were used to test the prediction. Using Spearman rank correlations and survival analyses, we ascertained STP associations with 6–12 month changes in quantitative lung fibrosis and forced vital capacity. ConclusionThis study can serve as a reference for collecting ground truth, and developing statistical learning techniques to predict progression in medical imaging.

Statins: cause of fibrosis or the opposite? Effect of cardiovascular drugs in idiopathic pulmonary fibrosis

Background and objectiveIdiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial lung disease with poor prognosis despite the recent availability of two antifibrotic drugs. Patients are more susceptible to cardiovascular comorbidities. In this study, we aimed to determine the impact of concomitant cardiovascular drugs on disease progression and survival in a modern IPF cohort. MethodsThe database of a tertiary referral centre for interstitial lung diseases in Belgium was reviewed for statin, antiaggregant, anticoagulant and metformin therapy. For a study period of four years, we noted both FVC% and DLCO% trajectories along with survival as outcome measurements. Results323 patients were included of which 45% had at least one cardiovascular comorbidity. 274 (86%) patients received antifibrotic therapy. Statin users (n = 171) displayed significantly slower annual FVC% (difference 2.9%, CI 1.6–4.4, p < 0.001) and DLCO% decline (difference 1.3%, CI 0.24–2.3, p = 0.013). Results for antiaggregant therapy (n = 152) were inconclusive: we found a trend for slower FVC decline (p = 0.098) and a numerically decrease in survival rates (HR 1.63, p = 0.074) in a multivariate Cox analysis. Anticoagulant use (n = 49) showed a trend towards worse DLCO decline (difference −1.3%, CI -2.6 - 0.02, p = 0.055).r Metformin (n = 28) therapy did not affect IPF progression in terms of pulmonary function test evolution or survival. ConclusionThis retrospective study demonstrated a benefit of statin therapy on IPF progression. Our observations emphasize the need for large clinical trials analysing the effect of statins, as well as other cardiovascular drugs, in the management of IPF patients.