Idiopathic Pulmonary Fibrosis Research Articles

Combination of losartan with pirfenidone: a protective anti-fibrotic against pulmonary fibrosis induced by bleomycin in rats.

Pirfenidone (PFD), one acceptable medication for treating idiopathic pulmonary fibrosis (IPF), is not well tolerated by patients at full doses. Hence, employing of some approaches such as combination therapy may be applicable for increasing therapeutic efficacy of PFD. Losartan (LOS), an angiotensin II receptor antagonist, could be a suitable candidate for combination therapy because of its stabilizing effect on the pulmonary function of IPF patients. Therefore, this study aimed to investigate the effects of LOS in combination with PFD on bleomycin (BLM)-induced lung fibrosis in rats. BLM-exposed rats were treated with LOS alone or in combination with PFD. The edema, pathological changes, level of transforming growth factor-β (TGF-β1), collagen content, and oxidative stress parameters were assessed in the lung tissues. Following BLM exposure, the inflammatory response, collagen levels, and antioxidant markers in rat lung tissues were significantly improvedby PFD, and these effects were improved by combination with LOS. The findings of this in vivo study suggest that the combined administration of PFD and LOS may provide more potent protection against IPF than single therapy through boosting its anti-inflammatory, anti-fibrotic, and anti-oxidant effects. These results hold promise in developing a more effective therapeutic strategy for treating of lung fibrosis.

Aging of alveolar type 2 cells induced by Lonp1 deficiency exacerbates pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and chronic disease that significantly impacts patient quality of life, and its incidence is on the rise. The pathogenesis of IPF remains poorly understood. Alveolar type 2 (AT2) cells are crucial in the onset and progression of IPF, yet the specific mechanisms involved are not well defined. Lon protease 1 (LONP1), known for its critical roles in various diseases, has an unclear function in IPF. Our research investigated the impact of Lonp1 gene deletion on AT2 cell functionality and its subsequent effect on IPF development. We generated a bleomycin-induced pulmonary fibrosis mouse model with a targeted Lonp1 knockout in AT2 cells and assessed the consequences on AT2 cell function and fibrosis progression. Additionally, we constructed the MLE12 cells with stable Lonp1 knockdown and utilized transcriptome sequencing to identify pathways altered by the Lonp1 knockdown. Our results indicated that mice with AT2 cell-specific Lonp1 knockout exhibited more severe fibrosis compared to controls. These mice exhibited a reduction in AT2 and AT1 cell populations, along with an increase in p53- and p21-positive AT2 cells. Lonp1 knockdown in MLE12 cells led to the upregulation of aging-associated pathways, with fibroblast growth factor 2 (Fgf2) gene emerging as a central gene interconnecting these pathways. Therefore, loss of Lonp1 appears to promote AT2 cell aging and exacerbate bleomycin-induced pulmonary fibrosis. Fgf2 emerges as a pivotal downstream gene associated with cellular senescence. This study uncovers the role of the Lonp1 gene in pulmonary fibrosis, presenting a novel target for investigating the pathological mechanisms and potential therapeutic approaches for IPF.

Feasibility and acceptability of remotely monitoring spirometry and pulse oximetry as part of interstitial lung disease clinical care: a single arm observational study.

Remote monitoring of patient-recorded spirometry and pulse oximetry offers an alternative approach to traditional hospital-based monitoring of interstitial lung disease (ILD). Remote spirometry has been observed to reasonably reflect clinic spirometry in participants with ILD but remote monitoring has not been widely incorporated into clinical practice. We assessed the feasibility of remotely monitoring patients within a clinical ILD service. Prospective, single-arm, open-label observational multi-centre study (NCT04850521). Inclusion criteria included ILD diagnosis, age ≥ 18 years, FVC ≥ 50% predicted. 60 participants were asked to record a single spirometry and oximetry measurement at least once daily, monitored weekly by their local clinical team. Feasibility was defined as ≥ 68% of participants with ≥ 70% adherence to study measurements and recording measurements ≥ 3 times/week throughout. A total of 60 participants were included in the analysis. 42/60 (70%) were male; mean age 67.8 years (± 11.2); 34/60 (56.7%) had idiopathic pulmonary fibrosis (IPF), Median ILD-GAP score was 3 (IQR 1-4.75). Spirometry adherence was achieved for ≥ 70% of study days in 46/60 participants (77%) and pulse oximetry adherence in 50/60 participants (83%). Recording ≥ 3 times/week every week was provided for spirometry in 41/60 participants (68%) and pulse oximetry in 43/60 participants (72%). Mean difference between recent clinic and baseline home spirometry was 0.31L (± 0.72). 85.7% (IQR 63.9-92.6%) home spirometry attempts/patient were acceptable or usable according to ERS/ATS spirometry criteria. Positive correlation was observed between ILD-GAP score and adherence to spirometry and oximetry (rho 0.24 and 0.38 respectively). Adherence of weekly monitoring by clinical teams was 80.95% (IQR 64.19-95.79). All participants who responded to an experience questionnaire (n = 33) found remote measurements easy to perform and 75% wished to continue monitoring their spirometry at the conclusion of the study. Feasibility of remote monitoring within an ILD clinical service was demonstrated over 3 months for both daily home spirometry and pulse oximetry of patients. Remote monitoring may be more acceptable to participants who are older or have more advanced disease. clinicaltrials.gov NCT04850521 registered 20th April 2021.

A nonsense mutation PARN (c.382C>T) in a patient with idiopathic pulmonary fibrosis.

A nonsense mutation PARN (c.382C>T) in a patient with idiopathic pulmonary fibrosis.

A prognostic model of idiopathic pulmonary fibrosis constructed based on macrophage and mitochondria-related genes

BackgroundStudies have shown that mitochondrial function and macrophages may play a role in the development of idiopathic pulmonary fibrosis (IPF). However, the understanding of the interactions and specific mechanisms between mitochondrial function and macrophages in pulmonary fibrosis is still very limited.MethodsTo construct a prognostic model for IPF based on Macrophage- related genes (MaRGs) and Mitochondria-related genes (MitoRGs), differential analysis was performed to achieve differentially expressed genes (DEGs) between IPF and Control groups in the GSE28042 dataset. Then, MitoRGs, MaRGs and DEGs were overlapped to screen out the signature genes. The univariate Cox analysis and the least absolute shrinkage and selection operator (LASSO) algorithm were implemented to achieve key genes. Furthermore, the independent prognostic analysis was employed. The ingenuity pathway analysis (IPA) was employed to further understand the molecular mechanisms of key genes.Next, the immune infiltration analysis was implemented to identify differential immune cells between two risk subgroups.ResultsThere were 4791 DEGs between IPF and Control groups. Furthermore, 26 signature genes were achieved by the intersection processing. Three key genes including ALDH2, MCL1, and BCL2A1 were achieved, and the risk model based on the key genes was created. In addition, a nomogram for survival forecasting of IPF patients was created based on riskScore, Age, and Gender, and we found that key genes were associated with classical pathways including ‘Apoptosis Signaling’, ‘PI3K/AKT Signaling’, and so on. Next, two differential immune cells including Monocytes and CD8 T cells were identified between two risk subgroups. Moreover, we found that MIR29B2CHG and hsa-mir-1-3p could regulate the expression of ALDH2.ConclusionWe achieved 3 key genes including ALDH2, MCL1,, and BCL2A1 associated with IPF, providing a new theoretical basis for clinical treatment of IPF.

[64Cu]Cu-PEG-FUD peptide for noninvasive and sensitive detection of murine pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease resulting in irreversible scarring within the lungs. However, the lack of biomarkers that enable real-time assessment of disease activity remains a challenge in providing efficient clinical decision-making and optimal patient care in IPF. Fibronectin (FN) is highly expressed in fibroblastic foci of the IPF lung where active extracellular matrix (ECM) deposition occurs. Functional upstream domain (FUD) tightly binds the N-terminal 70-kilodalton domain of FN that is crucial for FN assembly. In this study, we first demonstrate the capacity of PEGylated FUD (PEG-FUD) to target FN deposition in human IPF tissue ex vivo. We subsequently radiolabeled PEG-FUD with 64Cu and monitored its spatiotemporal biodistribution via μPET/CT imaging in mice using the bleomycin-induced model of pulmonary injury and fibrosis. We demonstrated [64Cu]Cu-PEG-FUD uptake 3 and 11 days following bleomycin treatment, suggesting that radiolabeled PEG-FUD holds promise as an imaging probe in aiding the assessment of fibrotic lung disease activity.

Protective Effects of Tunisian Orange Co-Product Extract and Oleuropein-Hesperidin Combination on Bleomycin-Induced Pulmonary Fibrosis in Rats.

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia with acute lung damage leading to the deterioration of lung function and increased mortality risk. In this study, we aimed to investigate the effects of the orange coproduct extract (OCE) and the combination of pure hesperidin and oleuropein (HO) on an experimental model of pulmonary fibrosis induced by bleomycin (BLM). Wistar rats were divided into 6 groups: the control group (G1), the BLM group (G2), 3 groups (G3, G4, G5) receiving a single dose of BLM combined with OCE extract at 100, 200 and 300 mg/kg and group 6 (G6) receiving a single dose of BLM combined with HO: both pure major phenolic compounds of OCE (hesperidin at 50 mg/kg) and olive leaves (oleuropein at 2.5 mg/kg). Oxidative stress in lung tissues was investigated using catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPX) assays and the measurement of malondialdehyde (MDA) and lactate dehydrogenase (LDH) levels. Treatment with OCE and HO were able to normalize the disturbance in oxidative markers' levels and showed a significant reduction in fibrosis score with no renal or hepatic toxic effects. In conclusion, OCE and HO exhibit antifibrotic effects on rat model of pulmonary fibrosis.

Involvement of necroptotic cell death in macrophages in progression of bleomycin and LPS-induced acute exacerbation of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is the severe form of interstitial pneumonias. Acute exacerbation (AE) of IPF is characterized by progressive lung fibrosis with the irreversible lung function decline and inflammation, and is often fatal with poor prognosis. However, the physiological and molecular mechanisms in AE of IPF are still not fully understood. In this study, we investigated the mechanism underlying AE of IPF, using bleomycin (BLM) and lipopolysaccharide (LPS) (BLM+LPS)-treated mice. The mice were treated with a single dose of 1.5 mg/kg BLM (on day 0) and/or 0.5 mg/kg LPS (on day 14), and maintained for another 7 days (total 21 days). Administration of BLM+LPS more severely aggravated the respiratory function, fibrosis, and inflammation in the lungs, together with the elevated interleukin-6 level in bronchoalveolar lavage fluid, than the control or BLM alone-treated mice. Moreover, the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay demonstrated that subsequent treatment with LPS elevated cell death in the lungs of BLM-administered mice. Furthermore, the expression levels of mixed lineage kinase domain-like protein (MLKL), a marker of necroptotic cell death, and CD68-positive macrophages were increased, and most of them were co-stained in the lungs of BLM+LPS-treated mice. These results, taken together, indicate that BLM+LPS treatment showed more exacerbated the respiratory function with extensive fibrosis and inflammation than treatment with BLM alone in mice. Fibrosis and inflammation in AE of IPF seen in BLM+LPS-administered mice included an increase in macrophages and their necroptotic cell death.

O-GlcNAc transferase regulates collagen deposition and fibrosis resolution in idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disease that is characterized by an excessive accumulation of extracellular matrix (ECM) proteins (e.g. collagens) in the parenchyma, which ultimately leads to respiratory failure and death. While current therapies exist to slow the progression, no therapies are available to resolve fibrosis.MethodsWe characterized the O-linked N-Acetylglucosamine (O-GlcNAc) transferase (OGT)/O-GlcNAc axis in IPF using single-cell RNA-sequencing (scRNA-seq) data and human lung sections and isolated fibroblasts from IPF and non-IPF donors. The underlying mechanism(s) of IPF were further investigated using multiple experimental models to modulate collagen expression and accumulation by genetically and pharmacologically targeting OGT. Furthermore, we hone in on the transforming growth factor-beta (TGF-β) effector molecule, Smad3, by co-expressing it with OGT to determine if it is modified and its subsequent effect on Smad3 activation.ResultsWe found that OGT and O-GlcNAc levels are upregulated in patients with IPF compared to non-IPF. We report that the OGT regulates collagen deposition and fibrosis resolution, which is an evolutionarily conserved process demonstrated across multiple species. Co-expression of OGT and Smad3 showed that Smad3 is O-GlcNAc modified. Blocking OGT activity resulted in decreased phosphorylation at Ser-423/425 of Smad3 attenuating the effects of TGF-β1 induced collagen expression/deposition.ConclusionOGT inhibition or knockdown successfully blocked and reversed collagen expression and accumulation, respectively. Smad3 is discovered to be a substrate of OGT and its O-GlcNAc modification(s) directly affects its phosphorylation state. These data identify OGT as a potential target in pulmonary fibrosis resolution, as well as other diseases that might have aberrant ECM/collagen accumulation.

Co-Delivery of Astaxanthin and siTGF-β1 via Ionizable Liposome Nanoparticles for Improved Idiopathic Pulmonary Fibrosis Therapy.

Alleviating the injury of type II alveolar epithelial cells (AEC 2s) and inhibiting the activation and differentiation of fibroblasts are significant for improving the therapeutic effect of idiopathic pulmonary fibrosis (IPF). To this aim, ionizable liposome nanoparticles (ASNPs) coloaded with antioxidant drug astaxanthin (AST) and small interfering RNA targeting transforming growth factor β1 (siTGF-β1) were developed for enhanced IPF therapy. ASNPs showed high loading and intracellular delivery efficiency for AST and siTGF-β1. After the injection of ASNPs in an IPF mice model, the loaded AST largely scavenged reactive oxygen species (ROS) in the diseased lung to reduce AEC2 apoptosis, thereby ensuring the integrity of the alveolar epithelium. Meanwhile, siTGF-β1, delivered by ASNPs, significantly silenced the expression of TGF-β1 in fibroblasts, inhibiting the differentiation of fibroblasts into myofibroblasts as well as reducing the excessive deposition of extracellular matrix (ECM). The combined use of the two drugs exhibited an excellent synergistic antifibrotic effect and was conducive to minimizing alveolar epithelial damage. This work provides a codelivery strategy of AST and siTGF-β1, which shows great promise for the treatment of IPF by simultaneously reducing alveolar epithelial damage and inhibiting fibroblast activation.

The Analysis of Proteomics by Machine Learning in Separating Idiopathic Pulmonary Fibrosis from Connective Tissue Disease-Interstitial Lung Disease.

The Analysis of Proteomics by Machine Learning in Separating Idiopathic Pulmonary Fibrosis from Connective Tissue Disease-Interstitial Lung Disease.

Revolutionizing the Treatment of Idiopathic Pulmonary Fibrosis: From Conventional Therapies to Advanced Drug Delivery Systems.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease that has been well-reported in the medical literature. Its incidence has risen, particularly in light of the recent COVID-19 pandemic. Conventionally, IPF is treated with antifibrotic drugs-pirfenidone and nintedanib-along with other drugs for symptomatic treatments, including corticosteroids, immunosuppressants, and bronchodilators based on individual requirements. Several drugs and biologicals such as fluorofenidone, thymoquinone, amikacin, paclitaxel nifuroxazide, STAT3, and siRNA have recently been evaluated for IPF treatment that reduces collagen formation and cell proliferation in the lung. There has been a great deal of research into various treatment options for pulmonary fibrosis using advanced delivery systems such as liposomal-based nanocarriers, chitosan nanoparticles, PLGA nanoparticles, solid lipid nanocarriers, and other nanoformulations such as metal nanoparticles, nanocrystals, cubosomes, magnetic nanospheres, and polymeric micelles. Several clinical trials are also ongoing for advanced IPF treatments. This article elaborates on the pathophysiology of IPF, its risk factors, and different advanced drug delivery systems for treating IPF. Although extensive preclinical data is available for these delivery systems, the clinical performance and scale-up studies would decide their commercial translation.

Platelet Activating Factor Receptor and Intercellular Adhesion Molecule-1 Expression Increases in the Small Airway Epithelium and Parenchyma of Patients with Idiopathic Pulmonary Fibrosis: Implications for Microbial Pathogenesis.

Background: Idiopathic pulmonary fibrosis (IPF) is an irreversible lung fibrotic disorder of unknown cause. It has been reported that bacterial and viral co-infections exacerbate disease pathogenesis. These pathogens use adhesion molecules such as platelet activating factor receptor (PAFR) and intercellular adhesion molecule-1 (ICAM-1) to gain cellular entry, causing infections. Methods: Immunohistochemical staining was carried out for lung resections from IPF patients (n = 11) and normal controls (n = 12). The quantification of PAFR and ICAM-1 expression is presented as a percentage in the small airway epithelium. Also, type 2 pneumocytes and alveolar macrophages were counted as cells per mm2 of the parenchymal area and presented as a percentage. All image analysis was done using Image Pro Plus 7.0 software. Results: PAFR expression significantly increased in the small airway epithelium (p < 0.0001), type 2 pneumocytes (p < 0.0001) and alveolar macrophages (p < 0.0001) compared to normal controls. Similar trend was observed for ICAM-1 expression in the small airway epithelium (p < 0.0001), type 2 pneumocytes (p < 0.0001) and alveolar macrophages (p < 0.0001) compared to normal controls. Furthermore, the proportion of positively expressed type 2 pneumocytes and alveolar macrophages was higher in IPF than in normal control. Conclusions: This is the first study to show PAFR and ICAM-1 expression in small airway epithelium, type 2 pneumocytes and alveolar macrophages in IPF. These findings could help intervene microbial impact and facilitate management of disease pathogenesis.

Tacrolimus alleviates pulmonary fibrosis progression through inhibiting the activation and interaction of ILC2 and monocytes

Idiopathic pulmonary fibrosis (IPF) is a heterogeneous group of lung diseases with different etiologies and characterized by progressive fibrosis. This disease usually causes pulmonary structural remodeling and decreased pulmonary function. The median survival of IPF patients is 2–5 years. Predominantly accumulation of type II innate immune cells accelerates fibrosis progression by secreting multiple pro-fibrotic cytokines. Group 2 innate lymphoid cells (ILC2) and monocytes/macrophages play key roles in innate immunity and aggravate the formation of pro-fibrotic environment. As a potent immunosuppressant, tacrolimus has shown efficacy in alleviating the progression of pulmonary fibrosis. In this study, we found that tacrolimus is capable of suppressing ILC2 activation, monocyte differentiation and the interaction of these two cells. This effect further reduced activation of monocyte-derived macrophages (Mo-M), thus resulting in a decline of myofibroblast activation and collagen deposition. The combination of tacrolimus and nintedanib was more effective than either drug alone. This study will reveal the specific process of tacrolimus alleviating pulmonary fibrosis by regulating type II immunity, and explore the potential feasibility of tacrolimus combined with nintedanib in the treatment of pulmonary fibrosis. This project will provide new ideas for clinical optimization of anti-pulmonary fibrosis drug strategies.

Administration of Gas6 attenuates lung fibrosis via inhibition of the epithelial-mesenchymal transition and fibroblast activation

The epithelial-mesenchymal transition (EMT) and fibroblast activation are major events in idiopathic pulmonary fibrosis pathogenesis. Here, we investigated whether growth arrest-specific protein 6 (Gas6) plays a protective role in lung fibrosis via suppression of the EMT and fibroblast activation. rGas6 administration inhibited the EMT in isolated mouse ATII cells 14 days post-BLM treatment based on morphologic cellular alterations, changes in mRNA and protein expression profiles of EMT markers, and induction of EMT-activating transcription factors. BLM-induced increases in gene expression of fibroblast activation-related markers and the invasive capacity of primary lung fibroblasts in primary lung fibroblasts were reversed by rGas6 administration. Furthermore, the hydroxyproline content and collagen accumulation in interstitial areas with damaged alveolar structures in lung tissue were reduced by rGas6 administration. Targeting Gas6/Axl signaling events with specific inhibitors of Axl (BGB324), COX-2 (NS-398), EP1/EP2 receptor (AH-6809), or PGD2 DP2 receptor (BAY-u3405) reversed the inhibitory effects of rGas6 on EMT and fibroblast activation. Finally, we confirmed the antifibrotic effects of Gas6 using Gas6−/− mice. Therefore, Gas6/Axl signaling events play a potential role in inhibition of EMT process and fibroblast activation via COX-2-derived PGE2 and PGD2 production, ultimately preventing the development of pulmonary fibrosis.

Circulating biomarkers and progression of idiopathic pulmonary fibrosis: data from the INMARK trial

BackgroundWe used data from the INMARK trial to investigate associations between circulating biomarkers of extracellular matrix (ECM) turnover, inflammation, and epithelial dysfunction and disease progression in subjects with idiopathic pulmonary fibrosis (IPF).MethodsSubjects with IPF and FVC ≥80% predicted were randomised 1:2 to receive nintedanib 150 mg bid or placebo for 12 weeks followed by open-label nintedanib for 40 weeks. Associations between baseline biomarker levels and the proportion of subjects with disease progression (decline in FVC ≥10% predicted or death) over 52 weeks were assessed in subjects randomised to placebo using logistic regression. Associations between baseline demographic/clinical characteristics and biomarker levels and disease progression over 52 weeks were analysed using multivariate models.ResultsOf 230 subjects who received placebo for 12 weeks then open-label nintedanib for 40 weeks, 70 (30.4%) had disease progression over 52 weeks. Baseline levels of CRPM, C3M, CRP, KL-6 and SP-D were not significantly associated with disease progression over 52 weeks in analyses corrected for multiple comparisons. In models including only baseline demographic/clinical characteristics, 61.2% to 64.2% of subjects were correctly classified as having or not having disease progression over 52 weeks. When both demographic/clinical characteristics and biomarker levels were included in the models, 50.0% to 64.5% of the test set were correctly classified.ConclusionsAmong subjects with IPF and preserved FVC, multivariate models based on demographic/clinical characteristics and biomarker levels at baseline did not provide an accurate prediction of which patients would progress.

A comparison of respiratory oscillometry and spirometry in idiopathic pulmonary fibrosis: performance time, symptom burden and test-retest reliability

Study questionIn large multinational patient surveys, spirometry (which requires repeated, reproducible maximal efforts) can be associated with cough, breathlessness and tiredness, particularly in those with idiopathic pulmonary fibrosis (IPF). Oscillometry is an effort-independent test of airways resistance and reactance. We hypothesised that oscillometry would take less time to perform and would be associated with reduced symptom burden than spirometry.Patients and methodsSpirometry and oscillometry were performed in sixty-six participants with IPF and repeated two weeks later. We compared time taken to perform tests, symptom burden and test-retest reliability with Bland-Altman plots and intraclass correlation coefficients (ICCs).ResultsOscillometry took significantly less time to perform than spirometry (mean (99% CI) −4.5 (−6.0 to −3.0) minutes) and was associated with lower symptom burden scores for cough (−1.3 (−1.7 to −0.8)), breathlessness (−1.0 (−1.4 to −0.5)), and tiredness (−0.5 (−0.9 to −0.2)). On Bland-Altman analysis, all measures showed good agreement, with narrow limits of agreement and the mean bias lying close to 0 in all cases. The ICC for Forced expiratory volume in one second (FEV1) and Forced Vital Capacity (FVC) were 0.94 and 0.89, and ranged between 0.70 and 0.90 for oscillometry measures.ConclusionOscillometry is quicker to perform and provokes less symptoms than spirometry in patients with IPF.

Genetics and Genomics of Pulmonary Fibrosis: Charting the Molecular Landscape and Shaping Precision Medicine.

Recent genetic and genomic advancements have elucidated the complex etiology of idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases (ILDs), emphasizing the contribution of heritable factors. This state-of-the-art review synthesizes evidence on significant genetic contributors to pulmonary fibrosis (PF), including rare genetic variants and common single nucleotide polymorphisms (SNPs). The MUC5B promoter variant is unusual, a common SNP that markedly elevates the risk of early and established PF. We address the utility of genetic variation in enhancing understanding of disease pathogenesis, clinical phenotypes, improving disease definitions, and informing prognosis and treatment response. Critical research gaps are highlighted, particularly the underrepresentation of non-European ancestries in PF genetic studies and the exploration of PF phenotypes beyond usual interstitial pneumonia (UIP)/IPF. We discuss the role of telomere length, often critically short in PF, and its link to progression and mortality, underscoring the genetic complexity involving telomere biology genes (TERT, TERC) and others like SFTPC and MUC5B. Additionally, we address the potential of gene-by-environment interactions to modulate disease manifestation, advocating for precision medicine in PF. Insights from gene expression profiling studies and multi-omic analyses highlight the promise for understanding disease pathogenesis and offer new approaches to clinical care, therapeutic drug development, and biomarker discovery. Finally, we discuss the ethical, legal, and social implications of genomic research and therapies in PF, stressing the need for sound practices and informed clinical genetic discussions. Looking forward, we advocate for comprehensive genetic testing panels and polygenic risk scores to improve the management of PF and related ILDs across diverse populations.

Genetic association between smoking and DLCO in idiopathic pulmonary fibrosis patients

BackgroundObservational studies have shown that smoking is related to the diffusing capacity of the lungs for carbon monoxide (DLCO) in individuals with idiopathic pulmonary fibrosis (IPF). Nevertheless, further investigation is needed to determine the causal effect between these two variables. Therefore, we conducted a study to investigate the causal relationship between smoking and DLCO in IPF patients using two-sample Mendelian randomization (MR) analysis.MethodsLarge-scale genome-wide association study (GWAS) datasets from individuals of European descent were analysed. These datasets included published lifetime smoking index (LSI) data for 462,690 participants and DLCO data for 975 IPF patients. The inverse-variance weighting (IVW) method was the main method used in our analysis. Sensitivity analyses were performed by MR‒Egger regression, Cochran’s Q test, the leave-one-out test and the MR-PRESSO global test.ResultsA genetically predicted increase in LSI was associated with a decrease in DLCO in IPF patients [ORIVW = 0.54; 95% CI 0.32–0.93; P = 0.02].ConclusionsOur study suggested that smoking is associated with a decrease in DLCO. Patients diagnosed with IPF should adopt an active and healthy lifestyle, especially by quitting smoking, which may be effective at slowing the progression of IPF.

NR2F2 alleviates pulmonary fibrosis by inhibition of epithelial cell senescence

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fatal, and aging-associated interstitial lung disease with a poor prognosis and limited treatment options, while the pathogenesis remains elusive. In this study, we found that the expression of nuclear receptor subfamily 2 group F member 2 (NR2F2), a member of the steroid thyroid hormone superfamily of nuclear receptors, was reduced in both IPF and bleomycin-induced fibrotic lungs, markedly in bleomycin-induced senescent epithelial cells. Inhibition of NR2F2 expression increased the expression of senescence markers such as p21 and p16 in lung epithelial cells, and activated fibroblasts through epithelial-mesenchymal crosstalk, inversely overexpression of NR2F2 alleviated bleomycin-induced epithelial cell senescence and inhibited fibroblast activation. Subsequent mechanistic studies revealed that overexpression of NR2F2 alleviated DNA damage in lung epithelial cells and inhibited cell senescence. Adenovirus-mediated Nr2f2 overexpression attenuated bleomycin-induced lung fibrosis and cell senescence in mice. In summary, these data demonstrate that NR2F2 is involved in lung epithelial cell senescence, and targeting NR2F2 may be a promising therapeutic approach against lung cell senescence and fibrosis.