Idiopathic Pulmonary Fibrosis Disease Research Articles

Timing impact on the initiation of pirfenidone therapy on idiopathic pulmonary fibrosis disease progression

In this editorial, we comment on the article by Lei et al, with a specific focus on the timing of the initiation of the antifibrotic agent pirfenidone (PFD) in the management of idiopathic pulmonary fibrosis (IPF) and its impact on lung function of IPF patients. PFD is an antifibrotic agent that is widely used in the management of IPF in both early and advanced stages. It inhibits various pathways and has antifibrotic, anti-inflammatory, and antioxidant properties. Despite dosage lowering, PFD slowed IPF progression and maintained functional capacity. The 6-min walk distance test indicated that patients tolerated adverse events well, and PFD significantly reduced the incidence of progression episodes and death. Even when a single disease-progression event occurred, continuing PFD treatment had benefits.

Co-Mn Complex Oxide Nanoparticles as Potential Reactive Oxygen Species Scavenging Agents for Pulmonary Fibrosis Treatment.

Idiopathic pulmonary fibrosis (IPF) is a chronic and age-related lung disease that has few treatment options. Reactive oxygen species (ROS) play an important role in the introduction and development of IPF. In the present study, we developed multifunctional Cobalt (Co)-Manganese (Mn) complex oxide nanoparticles (Co-MnNPs), which can scavenge multiple types of ROS. Benefiting from ROS scavenging activities and good biosafety, Co-MnNPs can suppress canonical and non-canonical TGF-β pathways and, thus, inhibit the activation of fibroblasts and the productions of extracellular matrix. Furthermore, the scavenging of ROS by Co-MnNPs reduce the LPS-induced expressions of pro-inflammatory factors in macrophages, by suppressing NF-κB signaling pathway. Therefore, Co-MnNPs can reduce the excessive extracellular matrix deposition and inflammatory responses in lungs and, thus, alleviate pulmonary fibrosis induced by bleomycin (BLM) in mice. Taken together, this work offers an anti-fibrotic agent for treatment of IPF and other ROS-related diseases.

Gene expression profile analysis of severe influenza-based modulation of idiopathic pulmonary fibrosis

BackgroundIt is known severe influenza infections and idiopathic pulmonary fibrosis (IPF) disease might stimulate each other. Till now, no associated mechanism has been reported.MethodWe collected the genetic pattern of expression of severe influenza (GSE111368) and IPF (GSE70866) from the Gene Expression Omnibus (GEO) database. Common differentially expressed genes (C-DEGs) were identified from the two datasets, and using this data, we conducted three forms of analyses, functional annotation, protein–protein interaction (PPI) network and module construction, and hub gene identification and co-expression analysis.ResultsIn all, 174 C-DEGs were selected for additional analyses. Based on our functional analysis, these C-DEGs mediated inflammatory response and cell differentiation. Furthermore, using cytoHubba, we identified 15 genes, namely, MELK, HJURP, BIRC5, TPX2, TK1, CDT1, UBE2C, UHRF1, CCNA2, TYMS, CDCA5, CDCA8, RAD54L, CCNB2, and ITGAM, which served as hub genes to possibly contribute to severe influenza patients with IPF disease as comorbidity. The hub gene expressions were further confirmed using two stand-alone datasets (GSE101702 for severe influenza and GSE10667 for IPF).ConclusionHerein, we demonstrated the significance of common pathways and critical genes in severe influenza and IPF etiologies. The identified pathways and genes may be employed as possible therapeutic targets for future therapy against severe influenza patients with IPF.

The Impact of Autoantibodies on Outcomes in Patients with Idiopathic Pulmonary Fibrosis: Post-Hoc Analyses of the Phase III ASCEND Trial.

Clinical practice guidelines recommend autoimmune serological testing in patients newly diagnosed with interstitial lung disease of apparently unknown cause who may have idiopathic pulmonary fibrosis (IPF), in order to exclude connective tissue disease (CTD). Autoantibody positivity has been associated with unique patient profiles and prognosis in patients with IPF who otherwise lack a CTD diagnosis. This post-hoc analysis of patients with IPF from the Phase III ASCEND trial (NCT01366209) evaluated the association of antinuclear antibodies (ANA), rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) status with baseline disease characteristics, disease progression [percent predicted forced vital capacity (%FVC), forced vital capacity (FVC) volume and progression-free survival (PFS)], and treatment outcomes with pirfenidone and placebo (%FVC, FVC and PFS). Of 555 participants, 244/514 (47.5%) were ANA positive (ANA+), 83/514 (16.1%) had high ANA+ (ANA titre≥1:160 or positive nucleolar- or centromere-staining patterns), 60/555 (10.8%) were RF positive (RF+) and/or anti-CCP positive (anti-CCP+) and 270/514 (52.5%) were autoantibody negative (AAb-). Baseline demographics and characteristics were generally comparable between autoantibody subgroups. Although not statistically significant, more placebo-treated participants with ANA+ or high ANA+ had a decline from baseline to Week 52 of≥10% in %FVC or death (48.7% and 55.9%, respectively) or in FVC volume or death (48.7% and 47.1%, respectively) compared with the AAb- group (%FVC or death: 42.0%; FVC volume or death: 42.0%). The RF+ and/or anti-CCP+ group was similar to AAb-. No differences were observed in PFS. A treatment benefit for pirfenidone versus placebo was observed regardless of autoantibody status [PFS: ANA+ HR (95% CI): 0.56 (0.37 to 0.86), P=0.007; AAb- HR (95% CI): 0.50 (0.32 to 0.78), P=0.002]. IPF disease course did not differ by autoantibody status in ASCEND. Pirfenidone had a treatment benefit regardless of the presence of ANA. ClinicalTrials.gov identifier, NCT01366209.

Toll-like Receptor 9 Inhibition Mitigates Fibroproliferative Responses in Translational Models of Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-Like Receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA (mtDNA). We aimed to show that TLR9 activation induces fibroproliferative responses that are abrogated by its antagonism by using two commercially-available indirect inhibitors and a proprietary, selective direct small molecule inhibitor. We employed two independent cohorts of patients with IPF, multiple in vitro fibroblast cell culture platforms, an in vivo mouse model, and an ex vivo human precision cut lung slices system to investigate the clinical and biologic significance of TLR9 in this disease. In two independent IPF cohorts, plasma mtDNA activates TLR9 in a manner associated with the expression of MCP-1, IL-6, TNFα, and IP-10 and worsened transplant-free survival. Our cell culture platform showed that TLR9 mediates fibroblast activation via TGFβ1 and stiff substrates, and that its antagonism, particularly direct inhibition, ameliorates this process, including production of these TLR9 associated pharmacodynamic endpoints. We further demonstrated that direct TLR9 inhibition mitigates these fibroproliferative responses in our in vivo and ex vivo models of pulmonary fibrosis. In this novel study, we found that direct TLR9 inhibition mitigates fibroproliferative responses in preclinical models of pulmonary fibrosis. Our work demonstrates the therapeutic potential of direct TLR9 antagonism in IPF and related fibrotic lung diseases.

ELIPF: Explicit Learning Framework for Pre-Emptive Forecasting, Early Detection and Curtailment of Idiopathic Pulmonary Fibrosis Disease

ELIPF: Explicit Learning Framework for Pre-Emptive Forecasting, Early Detection and Curtailment of Idiopathic Pulmonary Fibrosis Disease

Body mass index is associated with clinical outcomes in idiopathic pulmonary fibrosis

Association between body mass index (BMI) and prognosis in patients with idiopathic pulmonary fibrosis (IPF) remains uncertain. We investigated the association between BMI and clinical outcomes in patients with IPF using national health claims data. The study included 11,826 patients with IPF and rare incurable disease exemption codes (mean age: 68.9 years, male: 73.8%) and available BMI data who visited medical institutions between January 2002 and December 2018. Multivariable Cox proportional hazard models were used to evaluate the association of BMI with all-cause mortality and hospitalization. Based on BMI, 3.1%, 32.8%, 27.8%, and 36.4% were classified as underweight, normal, overweight, and obese, respectively. Multivariable analysis showed independent associations of overweight (hazard ratio [HR] 0.856, 95% confidence interval [CI] 0.801–0.916) and underweight (HR 1.538, 95% CI 1.347–1.757) with mortality in patients with IPF. Similarly, overweight (HR 0.887, 95% CI 0.834–0.943) and underweight (HR 1.265, 95% CI 1.104–1.449) were also associated with hospitalization in patients with IPF in the multivariable analysis. Spline HR curve analysis adjusted for all covariates revealed a non-linear relationship between BMI and mortality in patients with IPF. Our data suggest that BMI is associated with clinical outcomes in patients with IPF.

Supramolecular Nanofibers Ameliorate Bleomycin-Induced Pulmonary Fibrosis by Restoring Autophagy.

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease, with limited therapeutic options available. Impaired autophagy resulting from aberrant TRB3/p62 protein-protein interactions (PPIs) contributes to the progression of IPF. Restoration of autophagy by modulating the TRB3/p62 PPIs has rarely been reported for the treatment of IPF. Herein, peptide nanofibers are developed that specifically bind to TRB3 protein and explored their potential as a therapeutic approach for IPF. By conjugating with the self-assembling fragment (Ac-GFFY), a TRB3-binding peptide motif A2 allows for the formation of nanofibers with a stable α-helix secondary structure. The resulting peptide (Ac-GFFY-A2) nanofibers exhibit specific high-affinity binding to TRB3 protein in saline buffer and better capacity of cellular uptake to A2 peptide. Furthermore, the TRB3-targeting peptide nanofibers efficiently interfere with the aberrant TRB3/p62 PPIs in activated fibroblasts and fibrotic lung tissue of mice, thereby restoring autophagy dysfunction. The TRB3-targeting peptide nanofibers inhibit myofibroblast differentiation, collagen production, and fibroblast migration in vitro is demonstrated, as well as bleomycin-induced pulmonary fibrosis in vivo. This study provides a supramolecular method to modulate PPIs and highlights a promising strategy for treating IPF diseases by restoring autophagy.

Lysophosphatidic acid receptor 1 inhibition: a potential treatment target for pulmonary fibrosis.

Lysophosphatidic acid (LPA)-mediated activation of LPA receptor 1 (LPAR1) contributes to the pathophysiology of fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). These diseases are associated with high morbidity and mortality despite current treatment options. The LPA-producing enzyme autotaxin (ATX) and LPAR1 activation contribute to inflammation and mechanisms underlying fibrosis in preclinical fibrotic models. Additionally, elevated levels of LPA have been detected in bronchoalveolar lavage fluid from patients with IPF and in serum from patients with SSc. Thus, ATX and LPAR1 have gained considerable interest as pharmaceutical targets to combat fibrotic disease and inhibitors of these targets have been investigated in clinical trials for IPF and SSc. The goals of this review are to summarise the current literature on ATX and LPAR1 signalling in pulmonary fibrosis and to help differentiate the novel inhibitors in development. The mechanisms of action of ATX and LPAR1 inhibitors are described and preclinical studies and clinical trials of these agents are outlined. Because of their contribution to numerous physiologic events underlying fibrotic disease, ATX and LPAR1 inhibition presents a promising therapeutic strategy for IPF, SSc and other fibrotic diseases that may fulfil unmet needs of the current standard of care.

Smoking status and clinical outcome in idiopathic pulmonary fibrosis: a nationwide study

BackgroundSmoking status has been linked to the development of idiopathic pulmonary fibrosis (IPF). However, the effect of smoking on the prognosis of patients with IPF is unclear. We aimed to investigate the association between smoking status and all-cause mortality or hospitalisation by using national health claims data.MethodsIPF cases were defined as people who visited medical institutions between January 2002 and December 2018 with IPF and rare incurable disease exempted calculation codes from the National Health Insurance Database. Total 10,182 patients with available data on smoking status were included in this study. Ever-smoking status was assigned to individuals with a history of smoking ≥ 6 pack-years. The multivariable Cox proportional hazard model was used to evaluate the association between smoking status and prognosis.ResultsIn the entire cohort, the mean age was 69.4 years, 73.9% were males, and 45.2% were ever smokers (current smokers: 14.2%; former smokers: 31.0%). Current smokers (hazard ratio [HR]: 0.709; 95% confidence interval [CI]: 0.643–0.782) and former smokers (HR: 0.926; 95% CI: 0.862–0.996) were independently associated with all-cause mortality compared with non-smokers. Current smokers (HR: 0.884; 95% CI: 0.827–0.945) and former smokers (HR: 0.909; 95% CI: 0.862–0.959) were also associated with a reduced risk of all-cause hospitalisation compared with non-smokers. A non-linear association between smoking amount and prognosis was found in a spline HR curve and showed increasing risk below 6 pack-years.ConclusionEver-smoking status may be associated with favourable clinical outcomes in patients with IPF.

Acute exacerbation of idiopathic pulmonary fibrosis disease: a diagnosis model in China

ObjectiveTo develop and validate a diagnosis model to inform risk stratified decisions for idiopathic pulmonary fibrosis patients experiencing acute exacerbations (AE-IPF).MethodsIn this retrospective cohort study performed from 1 January 2016 to 31 December 2022, we used data from the West China Hospital of Sichuan University for model development and validation. Blood test results and the underlying diseases of patients were collected through the HIS system and LIS system. An algorithm for filtering candidate variables based on least absolute shrinkage and selection operator (LASSO) regression. Logistic regression was performed to develop the risk model. Multiple imputation handled missing predictor data. Model performance was assessed through calibration and diagnostic odds ratio.Results311 and 133 participants were included in the development and validation cohorts, respectively. 3 candidate predictors (29 parameters) were included. A logistic regression analysis revealed that dyspnea, percentage of CD4+ T-lymphocytes, and percentage of monocytes are independent risk factors for AE-IPF. Nomographic model was constructed using these independent risk factors, and the C-index was 0.69. For internal validation, the C-index was 0.69, and that indicated good accuracy. Diagnostic odds ratio was 5.40. Meanwhile, in mild, moderate, and severe subgroups, AE positivity rates were 0.37, 0.47, and 0.81, respectively. The diagnostic model can classify patients with AE-IPF into different risk classes based on dyspnea, percentage of CD4+ T-lymphocytes, and percentage of monocytes.ConclusionA diagnosis model was developed and validated that used information collected from HIS system and LIS system and may be used to risk stratify idiopathic pulmonary fibrosis patients experiencing acute exacerbations.

Machine learning identified MDK score has prognostic value for idiopathic pulmonary fibrosis based on integrated bulk and single cell expression data

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease that poses a significant challenge to medical professionals due to its increasing incidence and prevalence coupled with the limited understanding of its underlying molecular mechanisms. In this study, we employed a novel approach by integrating five expression datasets from bulk tissue with single-cell datasets; they underwent pseudotime trajectory analysis, switch gene selection, and cell communication analysis. Utilizing the prognostic information derived from the GSE47460 dataset, we identified 22 differentially expressed switch genes that were correlated with clinical indicators as important genes. Among these genes, we found that the midkine (MDK) gene has the potential to serve as a marker of Idiopathic pulmonary fibrosis because its cellular communicating genes are differentially expressed in the epithelial cells. We then utilized midkine and its cellular communication-related genes to calculate the midkine score. Machine learning models were further constructed through midkine and related genes to predict Idiopathic pulmonary fibrosis disease through the bulk gene expression datasets. The midkine score demonstrated a correlation with clinical indexes, and the machine learning model achieved an AUC of 0.94 and 0.86 in the Idiopathic pulmonary fibrosis classification task based on lung tissue samples and peripheral blood mononuclear cell samples, respectively. Our findings offer valuable insights into the pathogenesis of Idiopathic pulmonary fibrosis, providing new therapeutic directions and target genes for further investigation.

Nε-Carboxymethyl-Lysine Modification of Extracellular Matrix Proteins Augments Fibroblast Activation.

The extracellular matrix (ECM) is a dynamic complex protein network that provides structural integrity and plays an active role in shaping fibroblast behavior both in health and disease. Despite its essential functions, the impact of age-associated post-translational modifications on ECM-driven fibroblast activities such as proliferation, survival, fibroblast-to-myofibroblast transformation (FMT), and extracellular matrix production remains largely unknown. Nε-carboxymethyl-lysine (CML) is one of the well-characterized advanced glycation end-products (AGEs) that can occur on lysine residues within ECM proteins through non-enzymatic glycation. In this study, we determined the accumulation and the effects of the CML-modified ECM (CML-ECM) on fibroblast activation. Immunostainings and immunoblot analysis demonstrated significant increases in CML-AGE content in idiopathic pulmonary fibrosis (IPF) compared to age-matched healthy lungs. Gene expression analysis and fibroblast activation assays collectively implicate the ECM as a negative regulator of fibroblast activation. Notably, the CML modification of the ECM resulted in a significant decrease in its anti-fibrotic effects including proliferation, FMT, apoptosis, and ECM production. Together, the results of this study revealed an unexplored pathological role played by the CML-ECM on fibroblast activation, which has wide implications in IPF and other fibrotic diseases.

Investigating the role of platelets and platelet-derived transforming growth factor-β in idiopathic pulmonary fibrosis.

Transforming growth factor-β1 (TGFβ1) is the key profibrotic cytokine in idiopathic pulmonary fibrosis (IPF), but the primary source of this cytokine in this disease is unknown. Platelets have abundant stores of TGFβ1, although the role of these cells in IPF is ill-defined. In this study, we investigated whether platelets, and specifically platelet-derived TGFβ1, mediate IPF disease progression. Patients with IPF and non-IPF patients were recruited to determine platelet reactivity, and separate cohorts of patients with IPF were followed for mortality. To study whether platelet-derived TGFβ1 modulates pulmonary fibrosis (PF), mice with a targeted deletion of TGFβ1 in megakaryocytes and platelets (TGFβ1fl/fl.PF4-Cre) were used in the well-characterized bleomycin-induced pulmonary fibrosis (PF) animal model. In a discovery cohort, we found significantly higher mortality in patients with IPF who had elevated platelet counts within the normal range. However, our validation cohort did not confirm this observation, despite significantly increased platelets, neutrophils, active TGFβ1, and CCL5, a chemokine produced by inflammatory cells, in the blood, lung, and bronchoalveolar lavage (BAL) of patients with IPF. In vivo, we showed that despite platelets being readily detected within the lungs of bleomycin-treated mice, neither the degree of pulmonary inflammation nor fibrosis was significantly different between TGFβ1fl/fl.PF4-Cre and control mice. Our results demonstrate for the first time that platelet-derived TGFβ1 does not significantly mediate inflammation or fibrosis in a PF animal model. Furthermore, our human studies revealed blood platelet counts do not consistently predict mortality in IPF but other platelet-derived mediators, such as C-C chemokine ligand 5 (CCL5), may promote neutrophil recruitment and human IPF.NEW & NOTEWORTHY Platelets are a rich source of profibrotic TGFβ; however, the role of platelets in idiopathic pulmonary fibrosis (IPF) is unclear. We identified that patients with IPF have significantly more platelets, neutrophils, and active TGFβ in their airways than control patients. Using an animal model of IPF, we demonstrated that platelet-derived TGFβ does not significantly drive lung fibrosis or inflammation. Our findings offer a better understanding of platelets in both human and animal studies of IPF.

Analysis of tissue lipidomics and computed tomography pulmonary fat attenuation volume (CTPFAV ) in idiopathic pulmonary fibrosis.

There is increasing interest in the role of lipids in processes that modulate lung fibrosis with evidence of lipid deposition in idiopathic pulmonary fibrosis (IPF) histological specimens. The aim of this study was to identify measurable markers of pulmonary lipid that may have utility as IPF biomarkers. IPF and control lung biopsy specimens were analysed using a unbiased lipidomic approach. Pulmonary fat attenuation volume (PFAV) was assessed on chest CT images (CTPFAV ) with 3D semi-automated lung density software. Aerated lung was semi-automatically segmented and CTPFAV calculated using a Hounsfield-unit (-40 to -200HU) threshold range expressed as a percentage of total lung volume. CTPFAV was compared to pulmonary function, serum lipids and qualitative CT fibrosis scores. There was a significant increase in total lipid content on histological analysis of IPF lung tissue (23.16 nmol/mg) compared to controls (18.66 mol/mg, p = 0.0317). The median CTPFAV in IPF was higher than controls (1.34% vs. 0.72%, p < 0.001) and CTPFAV correlated significantly with DLCO% predicted (R2 = 0.356, p < 0.0001) and FVC% predicted (R2 = 0.407, p < 0.0001) in patients with IPF. CTPFAV correlated with CT features of fibrosis; higher CTPFAV was associated with >10% reticulation (1.6% vs. 0.94%, p = 0.0017) and >10% honeycombing (1.87% vs. 1.12%, p = 0.0003). CTPFAV showed no correlation with serum lipids. CTPFAV is an easily quantifiable non-invasive measure of pulmonary lipids. In this pilot study, CTPFAV correlates with pulmonary function and radiological features of IPF and could function as a potential biomarker for IPF disease severity assessment.

Abnormal bolus reflux on impedance-pH testing independently predicts 3-year pulmonary outcome and mortality in pulmonary fibrosis.

Gastroesophageal reflux has been associated with idiopathic pulmonary fibrosis (IPF), although the directionality of the relationship has been debated. Data on the value of objective reflux measures in predicting IPF disease progression and mortality remain limited. We aimed to evaluate the association between multichannel intraluminal impedance and pH testing (MII-pH) and 3-year pulmonary outcomes in IPF patients. This was a retrospective cohort study of adults with IPF who underwent pre-lung transplant MII-pH off acid suppression at a tertiary center. Patients were followed for 3years after MII-pH for poor pulmonary outcomes (hospitalization for respiratory exacerbation or death). A secondary analysis was performed using mortality as outcome of interest. Time-to-event analyses using Kaplan-Meier and Cox regression were performed to evaluate associations between MII-pH and poor outcomes. One hundred twenty-four subjects (mean age=61.7±8years, 62% male) were included. Increased bolus exposure time (BET) on MII-pH was associated with decreased time to poor pulmonary outcomes and death (log-ranked P-value=0.017 and 0.031, respectively). On multivariable Cox regression analyses controlling for potential confounders including age, sex, smoking history, body mass index, proton pump inhibitor use, baseline pulmonary function, and anti-fibrotic therapy, increased BET was an independent predictor for poor pulmonary outcomes [hazard ratio 3.18 (95% confidence interval: 1.25-8.09), P=0.015] and mortality [hazard ratio 11.3 (95% confidence interval: 1.37-63.9), P=0.025] over 3years. Increased BET on MII-pH is an independent predictor of poor pulmonary outcomes and mortality over 3years in IPF patients. These findings also support a role for gastroesophageal reflux in IPF disease progression and the potential impact of routine reflux testing and treatment.

Identification and immunological characterization of cuproptosis-related molecular clusters in idiopathic pulmonary fibrosis disease.

Idiopathic pulmonary fibrosis (IPF) has attracted considerable attention worldwide and is challenging to diagnose. Cuproptosis is a new form of cell death that seems to be associated with various diseases. However, whether cuproptosis-related genes (CRGs) play a role in regulating IPF disease is unknown. This study aims to analyze the effect of CRGs on the progression of IPF and identify possible biomarkers. Based on the GSE38958 dataset, we systematically evaluated the differentially expressed CRGs and immune characteristics of IPF disease. We then explored the cuproptosis-related molecular clusters, the related immune cell infiltration, and the biological characteristics analysis. Subsequently, a weighted gene co-expression network analysis (WGCNA) was performed to identify cluster-specific differentially expressed genes. Lastly, the eXtreme Gradient Boosting (XGB) machine-learning model was chosen for the analysis of prediction and external datasets validated the predictive efficiency. Nine differentially expressed CRGs were identified between healthy and IPF patients. IPF patients showed higher monocytes and monophages M0 infiltration and lower naive B cells and memory resting T CD4 cells infiltration than healthy individuals. A positive relationship was found between activated dendritic cells and CRGs of LIPT1, LIAS, GLS, and DBT. We also identified cuproptosis subtypes in IPF patients. Go and KEGG pathways analysis demonstrated that cluster-specific differentially expressed genes in Cluster 2 were closely related to monocyte aggregation, ubiquitin ligase complex, and ubiquitin-mediated proteolysis, among others. We also constructed an XGB machine model to diagnose IPF, presenting the best performance with a relatively lower residual and higher area under the curve (AUC= 0.700) and validated by external validation datasets (GSE33566, AUC = 0.700). The analysis of the nomogram model demonstrated that XKR6, MLLT3, CD40LG, and HK3 might be used to diagnose IPF disease. Further analysis revealed that CD40LG was significantly associated with IPF. Our study systematically illustrated the complicated relationship between cuproptosis and IPF disease, and constructed an effective model for the diagnosis of IPF disease patients.

Bioactive lipid lysophosphatidic acid species are associated with disease progression in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with significant mortality. Prognostic biomarkers to identify rapid progressors are urgently needed to improve patient management. Since the lysophosphatidic acid (LPA) pathway has been implicated in lung fibrosis in preclinical models and identified as a potential therapeutic target, we aimed to investigate if bioactive lipid LPA species could be prognostic biomarkers that predict IPF disease progression. LPAs and lipidomics were measured in baseline placebo plasma of a randomized IPF-controlled trial. The association of lipids with disease progression indices were assessed using statistical models. Compared to healthy, IPF patients had significantly higher levels of five LPAs (LPA16:0, 16:1, 18:1, 18:2, 20:4) and reduced levels of two triglycerides species (TAG48:4-FA12:0, -FA18:2) (false discovery rate < 0.05, fold change > 2). Patients with higher levels of LPAs had greater declines in diffusion capacity of carbon monoxide over 52 weeks (P < 0.01); additionally, LPA20:4-high (≥median) patients had earlier time to exacerbation compared to LPA20:4-low (<median) patients (hazard ratio (95% CI)): 5.71 (1.17–27.72) (P = 0.031). Higher baseline LPAs were associated with greater increases in fibrosis in lower lungs as quantified by high-resolution computed tomography at week 72 (P < 0.05). Some of these LPAs were positively associated with biomarkers of profibrotic macrophages (CCL17, CCL18, OPN, and YKL40) and lung epithelial damage (SPD and sRAGE) (P < 0.05). In summary, our study established the association of LPAs with IPF disease progression, further supporting the role of the LPA pathway in IPF pathobiology.

Bioinformatics-based investigation on the genetic influence between SARS-CoV-2 infections and idiopathic pulmonary fibrosis (IPF) diseases, and drug repurposing

Some recent studies showed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and idiopathic pulmonary fibrosis (IPF) disease might stimulate each other through the shared genes. Therefore, in this study, an attempt was made to explore common genomic biomarkers for SARS-CoV-2 infections and IPF disease highlighting their functions, pathways, regulators and associated drug molecules. At first, we identified 32 statistically significant common differentially expressed genes (cDEGs) between disease (SARS-CoV-2 and IPF) and control samples of RNA-Seq profiles by using a statistical r-package (edgeR). Then we detected 10 cDEGs (CXCR4, TNFAIP3, VCAM1, NLRP3, TNFAIP6, SELE, MX2, IRF4, UBD and CH25H) out of 32 as the common hub genes (cHubGs) by the protein–protein interaction (PPI) network analysis. The cHubGs regulatory network analysis detected few key TFs-proteins and miRNAs as the transcriptional and post-transcriptional regulators of cHubGs. The cDEGs-set enrichment analysis identified some crucial SARS-CoV-2 and IPF causing common molecular mechanisms including biological processes, molecular functions, cellular components and signaling pathways. Then, we suggested the cHubGs-guided top-ranked 10 candidate drug molecules (Tegobuvir, Nilotinib, Digoxin, Proscillaridin, Simeprevir, Sorafenib, Torin 2, Rapamycin, Vancomycin and Hesperidin) for the treatment against SARS-CoV-2 infections with IFP diseases as comorbidity. Finally, we investigated the resistance performance of our proposed drug molecules compare to the already published molecules, against the state-of-the-art alternatives publicly available top-ranked independent receptors by molecular docking analysis. Molecular docking results suggested that our proposed drug molecules would be more effective compare to the already published drug molecules. Thus, the findings of this study might be played a vital role for diagnosis and therapies of SARS-CoV-2 infections with IPF disease as comorbidity risk.

Pulmonary vessel volume in idiopathic pulmonary fibrosis compared with healthy controls aged > 50 years

Idiopathic pulmonary fibrosis (IPF) is characterised by progressive fibrosing interstitial pneumonia with an associated irreversible decline in lung function and quality of life. IPF prevalence increases with age, appearing most frequently in patients aged > 50 years. Pulmonary vessel-like volume (PVV) has been found to be an independent predictor of mortality in IPF and other interstitial lung diseases, however its estimation can be impacted by artefacts associated with image segmentation methods and can be confounded by adjacent fibrosis. This study compares PVV in IPF patients (N = 21) with PVV from a healthy cohort aged > 50 years (N = 59). The analysis includes a connected graph-based approach that aims to minimise artefacts contributing to calculation of PVV. We show that despite a relatively low extent of fibrosis in the IPF cohort (20% of the lung volume), PVV is 2–3 times higher than in controls. This suggests that a standardised method to calculate PVV that accounts for tree connectivity could provide a promising tool to provide early diagnostic or prognostic information in IPF patients and other interstitial lung disease.