Lung Disease Of Unknown Etiology Research Articles

Novel therapeutic strategies and drugs for idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease of unknown etiology. Currently, drugs used to treat IPF in clinical practice exhibit severe side effects and limitations. To address these issues, this paper discusses the therapeutic effects of preclinical targeted drugs (such as STAT3 and TGF-β/Smad pathway inhibitors, chitinase inhibitors, PI3K and phosphodiesterase inhibitors, etc.) and natural products on IPF. Through a summary of current research progress, it is found that natural products possess multitarget effects, stable therapeutic efficacy, low side effects, and nondrug dependence. Furthermore, we discuss the significant prospects of natural product molecules in combating fibrosis by influencing the immune system, expecting that current analytical data will aid in the development of new drugs or the investigation of active ingredients in natural products for potential IPF treatments in the future.

Occupational and environmental risk factors for idiopathic pulmonary fibrosis: A case-control study

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease of unknown etiology. The aim of this study was to evaluate the environmental and occupational risk factors of IPF. MethodsThis hospital-based, case-control study included 206 patients with IPF selected from the Seoul National University Bundang Hospital Interstitial Lung Disease registry and 167 controls without lung disease. Data on occupation, lifestyle, transportation, and types of environmental and occupational dust exposure were obtained using a questionnaire. IPF diagnosis was confirmed based on the recent guidelines, and the possibility of hypersensitivity pneumonitis was excluded. Multiple logistic regression was performed to determine the risk factors for IPF. ResultsAfter adjusting for age and sex, ever-smokers (odds ratio [OR], 2.35; 95 % confidence interval [CI]: 1.51–3.68) and individuals who smoked more than 30 pack-years (OR, 2.79; 95%CI: 1.70–4.68) showed an increased risk for IPF. Any occupational dust exposure (adjusted OR, 2.08; 95%CI: 1.19–3.72), especially exposure to chemicals (adjusted OR, 3.52; 99%CI: 1.56–9.05), was associated with IPF after adjusting for age, sex, and smoking. ConclusionsSmoking and occupational dust exposure are associated with an increased risk for IPF. Both factors have dose and duration-dependent relationships with the risk for IPF.

Idiopathic Pulmonary Fibrosis: From Common Microscopy to Single-Cell Biology and Precision Medicine.

Idiopathic pulmonary fibrosis is a chronic, progressive, and usually fatal lung disease of unknown etiology and is included in the large, complex, and heterogeneous group of interstitial lung diseases (ILD). IPF is characterized by an aberrant activation of epithelial cells and fibroblasts and excessive accumulation of extracellular matrix, resulting in the progressive destruction of the lung architecture. Here we approach the fascinating historical evolution of our knowledge about this disorder from the past century, when most efforts were focused on ILD classification and terminology, until the current century, when the explosive progress in molecular genetics, epigenetics, and multiomics, as well as the development of complex computational tools, resulted in a huge advance in unveiling the pathogenic mechanisms of the disease. Recent advances in artificial intelligence, machine and deep learning, and artificial neural networks show promising results in identifying lung fibrotic patterns in high-resolution computed tomography or helping to create a tissue genomic classifier for specific diagnosis. Finally, incipient approaches to precision medicine are ongoing in the area of pharmacogenetics.

Potential role of SIRT-1 and SIRT-3 as biomarkers for the diagnosis and prognosis of idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a debilitating and progressive lung disease of unknown aetiology, characterized by the relentless deposition of fibrotic tissue. Biomarkers may play a pivotal role as indicators of disease presence, progression, and treatment response. Sirtuins, a family of enzymes with ADP ribosyltransferase or deacetylase activity, have been implicated in several diseases, including pulmonary fibrosis.MethodsA cross-sectional, prospective, observational single-center study was conducted to investigate the potential role of serum SIRTs levels as biomarkers in patients with IPF. Demographic, clinical, and functional data and serological samples were collected from 34 patients with IPF followed at the Interstital Lung and Rare Diseases Outpatient Clinic of the Vanvitelli Pneumology Clinic, Monaldi Hospital, Naples, Italy and from 19 age-matched controls.ResultsSerum SIRT-1 levels were significantly reduced in IPF patients compared to controls (median IPF 667 [435–858] pg/mL versus controls 925 [794–1173] pg/mL; p < 0.001 ). In contrast, serum SIRT-3 levels were significantly increased in IPF patients compared to controls (median IPF 338 [230–500] pg/mL versus controls 154 [99.8–246] pg/mL; p < 0.001). There were no statistically significant differences in serum SIRT-6 and SIRT-7 levels between IPF and controls. In addition, we found a significant positive correlation between SIRT-1 and lung function parameters such as FEV1% (ϱ=0.417;p = 0.016), FVC% (ϱ=0.449;p = 0.009) and DLCO% (ϱ=0.393;p = 0.024), while a significant negative correlation was demonstrated between SIR-1 and GAP score, demonstrating a significant reduction in SIRT-1 in advanced Gender-Age-Physiology (GAP) stages 2–3 compared to GAP stage 1 (p = 0.008).ConclusionsThis prospective, cross-sectional study showed that SIRT-1 was associated with lung function and IPF severity and that both SIRT-1 and SIRT-3 could be considered as potential biomarkers of IPF, whereas SIRT-6 and SIRT-7 were not associated with IPF.

TRIOBP modulates β-catenin signaling by regulation of miR-29b in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal and devastating lung disease of unknown etiology, described as the result of multiple cycles of epithelial cell injury and fibroblast activation. Despite this impressive increase in understanding, a therapy that reverses this form of fibrosis remains elusive. In our previous study, we found that miR-29b has a therapeutic effect on pulmonary fibrosis. However, its anti-fibrotic mechanism is not yet clear. Recently, our study identified that F-Actin Binding Protein (TRIOBP) is one of the target genes of miR-29b and found that deficiency of TRIOBP increases resistance to lung fibrosis in vivo. TRIOBP knockdown inhibited the proliferation of epithelial cells and attenuated the activation of fibroblasts. In addition, deficiency of Trio Rho Guanine Nucleotide Exchange Factor (TRIO) in epithelial cells and fibroblasts decreases susceptibility to lung fibrosis. TRIOBP interacting with TRIO promoted abnormal epithelial–mesenchymal crosstalk and modulated the nucleocytoplasmic translocation of β-catenin. We concluded that the miR-29b‒TRIOBP–TRIO–β-catenin axis might be a key anti-fibrotic axis in IPF to regulate lung regeneration and fibrosis, which may provide a promising treatment strategy for lung fibrosis.Graphical

ACSS3 regulates the metabolic homeostasis of epithelial cells and alleviates pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease of unknown etiology. The emerging evidence demonstrates that metabolic homeostatic imbalance caused by repetitive injuries of the alveolar epithelium is the potential pathogenesis of IPF. Proteomic analysis identified that Acetyl-CoA synthetase short chain family member 3 (ACSS3) expression was decreased in IPF patients and mice with bleomycin-induced fibrosis. ACSS3 participated in lipid and carbohydrate metabolism. Increased expression of ACSS3 downregulated carnitine palmitoyltransferase 1A (CPT-1A) and resulted in the accumulation of lipid droplets, while enhanced glycolysis which led to an increase in extracellular lactic acid levels in A549 cells. ACSS3 increases the production of succinyl-CoA through propionic acid metabolism, and decreases the generation of acetyl-CoA and ATP in alveolar epithelial cells. Overexpression of Acss3 inhibited the excessive deposition of ECM and attenuated the ground-glass opacity which determined by micro-CT in vivo. In a nutshell, our findings demonstrate that ACSS3 decreased the fatty acid oxidation through CPT1A deficiency and enhanced anaerobic glycolysis, this metabolic reprogramming deactivate the alveolar epithelial cells by lessen mitochondrial fission and fusion, increase of ROS production, suppression of mitophagy, promotion of apoptosis, suggesting that ACSS3 might be potential therapeutic target in pulmonary fibrosis.

Genome-wide DNA methylation analysis of Astragalus and Danshen on the intervention of myofibroblast activation in idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF), a chronic progressive interstitial lung disease of unknown etiology, is characterized by continuous damage to alveolar epithelial cells, abnormal repair of alveolar tissue, and alveolar wall scar formation. Currently, the recommended treatment for IPF in Western medicine is relatively limited. In contrast, traditional Chinese medicine and compound prescriptions show advantages in the diagnosis and treatment of IPF, which can be attributed to their multi-channel and multi-target characteristics and minimal side-effects. The purpose of this study was to further corroborate the effectiveness and significance of the traditional Chinese medications Astragalus and Danshen in IPF treatment.MethodsWe performed whole-genome methylation analysis on nine rat lung tissue samples to determine the epigenetic variation between IPF and non-fibrotic lungs using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses and quantitative reverse transcription polymerase chain reactions.ResultsWe identified differentially methylated regions and 105 associated key functional genes in samples related to IPF and Chinese medicine treatment. Based on the methylation levels and gene expression profiles between the Chinese medicine intervention and pulmonary fibrosis model groups, we speculated that Astragalus and Salvia miltiorrhiza (traditionally known as Danshen) act on the Isl1, forkhead box O3, and Sonic hedgehog genes via regulation at transcriptional and epigenetic levels during IPF.ConclusionsThese findings provide novel insights into the epigenetic regulation of IPF, indicate the effectiveness of Astragalus and Danshen in treating IPF, and suggest several promising therapeutic targets for preventing and treating IPF.

Macrophage Implication in IPF: Updates on Immune, Epigenetic, and Metabolic Pathways.

Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease of unknown etiology with a poor prognosis. It is a chronic and progressive disease that has a distinct radiological and pathological pattern from common interstitial pneumonia. The use of immunosuppressive medication was shown to be completely ineffective in clinical trials, resulting in years of neglect of the immune component. However, recent developments in fundamental and translational science demonstrate that immune cells play a significant regulatory role in IPF, and macrophages appear to be among the most crucial. These highly plastic cells generate multiple growth factors and mediators that highly affect the initiation and progression of IPF. In this review, we will provide an update on the role of macrophages in IPF through a systemic discussion of various regulatory mechanisms involving immune receptors, cytokines, metabolism, and epigenetics.

Alvespimycin Exhibits Potential Anti-TGF-β Signaling in the Setting of a Proteasome Activator in Rats with Bleomycin-Induced Pulmonary Fibrosis: A Promising Novel Approach.

Idiopathic pulmonary fibrosis (IPF) is an irreversible and life-threatening lung disease of unknown etiology presenting only a few treatment options. TGF-β signaling orchestrates a cascade of events driving pulmonary fibrosis (PF). Notably, recent research has affirmed the augmentation of TGF-β receptor (TβR) signaling via HSP90 activation. HSP90, a molecular chaperone, adeptly stabilizes and folds TβRs, thus intricately regulating TGF-β1 signaling. Our investigation illuminated the impact of alvespimycin, an HSP90 inhibitor, on TGF-β-mediated transcriptional responses by inducing destabilization of TβRs. This outcome stems from the explicit interaction of TβR subtypes I and II with HSP90, where they are clients of this cellular chaperone. It is worth noting that regulation of proteasome-dependent degradation of TβRs is a critical standpoint in the termination of TGF-β signal transduction. Oleuropein, the principal bioactive compound found in Olea europaea, is acknowledged for its role as a proteasome activator. In this study, our aim was to explore the efficacy of a combined therapy involving oleuropein and alvespimycin for the treatment of PF. We employed a PF rat model that was induced by intratracheal bleomycin infusion. The application of this dual therapy yielded a noteworthy impediment to the undesired activation of TGF-β/mothers against decapentaplegic homologs 2 and 3 (SMAD2/3) signaling. Consequently, this novel combination showcased improvements in both lung tissue structure and function while also effectively restraining key fibrosis markers such as PDGF-BB, TIMP-1, ACTA2, col1a1, and hydroxyproline. On a mechanistic level, our findings unveiled that the antifibrotic impact of this combination therapy likely stemmed from the enhanced degradation of both TβRI and TβRII. In conclusion, the utilization of proteasomal activators in conjunction with HSP90 inhibitors ushers in a promising frontier for the management of PF.

Myeloid-specific deletion of activating transcription factor 6 alpha increases CD11b+ macrophage subpopulations and aggravates lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease of unknown etiology. The accumulation of macrophages is associated with disease pathogenesis. The unfolded protein response (UPR) has been linked to macrophage activation in pulmonary fibrosis. To date, the impact of activating transcription factor 6 alpha (ATF6α), one of the UPR mediators, on the composition and function of pulmonary macrophage subpopulations during lung injury and fibrogenesis is not fully understood. We began by examining the expression of Atf6α in IPF patients' lung single-cell RNA sequencing dataset, archived surgical lung specimens, and CD14+ circulating monocytes. To assess the impact of ATF6α on pulmonary macrophage composition and pro-fibrotic function during tissue remodeling, we conducted an in vivo myeloid-specific deletion of Atf6α. Flow cytometric assessments of pulmonary macrophages were carried out in C57BL/6 and myeloid specific ATF6α-deficient mice in the context of bleomycin-induced lung injury. Our results demonstrated that Atf6α mRNA was expressed in pro-fibrotic macrophages found in the lung of a patient with IPF and in CD14+ circulating monocytes obtained from blood of a patient with IPF. After bleomycin administration, the myeloid-specific deletion of Atf6α altered the pulmonary macrophage composition, expanding CD11b+ subpopulations with dual polarized CD38+ CD206+ expressing macrophages. Compositional changes were associated with an aggravation of fibrogenesis including increased myofibroblast and collagen deposition. A further mechanistic ex vivo investigation revealed that ATF6α was required for CHOP induction and the death of bone marrow-derived macrophages. Overall, our findings suggest a detrimental role for the ATF6α-deficient CD11b+ macrophages which had altered function during lung injury and fibrosis.

Identification of immune biomarkers associated with basement membranes in idiopathic pulmonary fibrosis and their pan-cancer analysis.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease of unknown etiology, characterized by diffuse alveolitis and alveolar structural damage. Due to the short median survival time and poor prognosis of IPF, it is particularly urgent to find new IPF biomarkers. Previous studies have shown that basement membranes (BMs) are associated with the development of IPF and tumor metastasis. However, there is still a lack of research on BMs-related genes in IPF. Therefore, we investigated the expression level of BMs genes in IPF and control groups, and explored their potential as biomarkers for IPF diagnosis. In this study, the GSE32537 and GSE53845 datasets were used as training sets, while the GSE24206, GSE10667 and GSE101286 datasets were used as validation sets. In the training set, seven immune biomarkers related to BMs were selected by differential expression analysis, machine learning algorithm (LASSO, SVM-RFE, Randomforest) and ssGSEA analysis. Further ROC analysis confirmed that seven BMs-related genes played an important role in IPF. Finally, four immune-related Hub genes (COL14A1, COL17A1, ITGA10, MMP7) were screened out. Then we created a logistic regression model of immune-related hub genes (IHGs) and used a nomogram to predict IPF risk. The nomogram model was evaluated to have good reliability and validity, and ROC analysis showed that the AUC value of IHGs was 0.941 in the training set and 0.917 in the validation set. Pan-cancer analysis showed that IHGs were associated with prognosis, immune cell infiltration, TME, and drug sensitivity in 33 cancers, suggesting that IHGs may be potential targets for intervention in human diseases including IPF and cancer.

Exogenous Thymosin Beta 4 Suppresses IPF-Lung Cancer in Mice: Possibly Associated with Its Inhibitory Effect on the JAK2/STAT3 Signaling Pathway.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease of unknown etiology. At present, the mortality rate of the deadly disease is still very high, while the existing treatments only delay the progression of the disease and improve the quality of life of patients. Lung cancer (LC) is the most fatal disease in the world. In recent years, IPF has been considered to be an independent risk factor for the development of LC. The incidence of lung cancer is increased in the patients with IPF and the mortality is also significantly increased in the patients inflicted with the two diseases. In this study, we evaluated an animal model of pulmonary fibrosis complicated with LC by implanting LC cells orthotopically into the lungs of mice several days after bleomycin induction of the pulmonary fibrosis in the same mice. In vivo studies with the model showed that exogenous recombinant human thymosin beta 4 (exo-rhTβ4) alleviated the impairment of lung function and severity of damage of the alveolar structure by the pulmonary fibrosis and inhibited the proliferation of LC tumor growth. In addition, in vitro studies showed that exo-rhTβ4 inhibited the proliferation and migration of A549 and Mlg cells. Furthermore, our results also showed that rhTβ4 could effectively inhibit the JAK2-STAT3 signaling pathway and this might exert an anti-IPF-LC effect. The establishment of the IPF-LC animal model will be helpful for the development of drugs for the treatment of IPF-LC. Exogenous rhTβ4 can be potentially used for the treatment of IPF and LC.

Early Diagnosis and Treatment of Idiopathic Pulmonary Fibrosis: A Narrative Review.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial lung disease of unknown aetiology. Patients typically present with symptoms of chronic dyspnoea and cough over a period of months to years. IPF has a poor prognosis, with an average life expectancy of 3-5years from diagnosis if left untreated. Two anti-fibrotic medications (nintedanib and pirfenidone) have been approved for the treatment of IPF. These drugs slow disease progression by reducing decline in lung function. Early diagnosis is crucial to ensure timely treatment selection and improve outcomes. High-resolution computed tomography (HRCT) plays a major role in the diagnosis of IPF. In this narrative review, we discuss the importance of early diagnosis, awareness among primary care physicians, lung cancer screening programmes and early IPF detection, and barriers to accessing anti-fibrotic medications.

Roles of lipid metabolism and its regulatory mechanism in idiopathic pulmonary fibrosis: A Review.

Idiopathic pulmonary fibrosis is a progressive lung disease of unknown etiology characterized by distorted distal lung architecture, inflammation, and fibrosis. Several lung cell types, including alveolar epithelial cells and fibroblasts, have been implicated in the development and progression of fibrosis. However, the pathogenesis of idiopathic pulmonary fibrosis is still incompletely understood. The latest research has found that dysregulation of lipid metabolism plays an important role in idiopathic pulmonary fibrosis. The changes in the synthesis and activity of fatty acids, cholesterol and other lipids seriously affect the regenerative function of alveolar epithelial cells and promote the transformation of fibroblasts into myofibroblasts. Mitochondrial function is the key to regulating the metabolic needs of a variety of cells, including alveolar epithelial cells. Sirtuins located in mitochondria are essential to maintain mitochondrial function and cellular metabolic homeostasis. Sirtuins can maintain normal lipid metabolism by regulating respiratory enzyme activity, resisting oxidative stress, and protecting mitochondrial function. In this review, we aimed to discuss the difference between normal and idiopathic pulmonary fibrosis lungs in terms of lipid metabolism. Additionally, we highlight recent breakthroughs on the effect of abnormal lipid metabolism on idiopathic pulmonary fibrosis, including the effects of sirtuins. Idiopathic pulmonary fibrosis has its high mortality and limited therapeutic options; therefore, we believe that this review will help to develop a new therapeutic direction from the aspect of lipid metabolism in idiopathic pulmonary fibrosis.

Visualization of the individual blood microbiome to study the etiology of sarcoidosis

IntroductionSingle microbial pathogens or host-microbiome dysbiosis are the causes of lung diseases with suspected infectious etiology. Metagenome sequencing provides an overview of the microbiome content. Due to the rarity of most granulomatous lung diseases collecting large systematic datasets is challenging. Thus, single-patient data often can only be summarized visually. ObjectiveTo increase the information gain from a single-case metagenome analysis we suggest a quantitative and qualitative approach. ResultsThe 16S metagenomic results of 7 patients with pulmonary sarcoidosis were compared with those of 22 healthy individuals. From lysed blood, total microbial DNA was extracted and sequenced. Cleaned data reads were identified taxonomically using Kraken 2 software. Individual metagenomic data were visualized with a Sankey diagram, Krona chart, and a heat-map. We identified five genera that were exclusively present or significantly enhanced in patients with sarcoidosis - Veillonella, Prevotella, Cutibacterium, Corynebacterium, and Streptococcus. ConclusionsOur approach can characterize the blood microbiome composition and diversity in rare diseases at an individual level. Investigation of the blood microbiome in patients with granulomatous lung diseases of unknown etiology, such as sarcoidosis could enhance our comprehension of their origin and pathogenesis and potentially uncover novel personalized therapeutics.

Pharmacological inhibition of MDM4 alleviates pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology with no cure. A better understanding of the disease processes and identification of druggable targets will benefit the development of effective therapies for IPF. We previously reported that MDM4 promoted lung fibrosis through the MDM4-p53-dependent pathway. However, it remained unclear whether targeting this pathway would have any therapeutic potential. In this study, we evaluated the efficacy of XI-011, a small molecular inhibitor of MDM4, for treating lung fibrosis. We found that XI-011 significantly reduced MDM4 expression and increased the expression of total and acetylated p53 in primary human myofibroblasts and a murine fibrotic model. XI-011 treatment resulted in the resolution of lung fibrosis in mice with no notable impact on normal fibroblast death or the morphology of healthy lungs. Based on these findings, we propose that XI-011 might be a promising therapeutic drug candidate for treating pulmonary fibrosis.

Combination of esomeprazole and pirfenidone enhances antifibrotic efficacy in vitro and in a mouse model of TGFβ-induced lung fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. Currently, pirfenidone and nintedanib are the only FDA-approved drugs for the treatment of IPF and are now the standard of care. This is a significant step in slowing down the progression of the disease. However, the drugs are unable to stop or reverse established fibrosis. Several retrospective clinical studies indicate that proton pump inhibitors (PPIs; FDA-approved to treat gastroesophageal reflux) are associated with favorable outcomes in patients with IPF, and emerging preclinical studies report that PPIs possess antifibrotic activity. In this study, we evaluated the antifibrotic efficacy of the PPI esomeprazole when combined with pirfenidone in vitro and in vivo. In cell culture studies of IPF lung fibroblasts, we assessed the effect of the combination on several fibrosis-related biological processes including TGFβ-induced cell proliferation, cell migration, cell contraction, and collagen production. In an in vivo study, we used mouse model of TGFβ-induced lung fibrosis to evaluate the antifibrotic efficacy of esomeprazole/pirfenidone combination. We also performed computational studies to understand the molecular mechanisms by which esomeprazole and/or pirfenidone regulate lung fibrosis. We found that esomeprazole significantly enhanced the anti-proliferative effect of pirfenidone and favorably modulated TGFβ-induced cell migration and contraction of collagen gels. We also found that the combination significantly suppressed collagen production in response to TGFβ in comparison to pirfenidone monotherapy. In addition, our animal study demonstrated that the combination therapy effectively inhibited the differentiation of lung fibroblasts into alpha smooth muscle actin (αSMA)-expressing myofibroblasts to attenuate the progression of lung fibrosis. Finally, our bioinformatics study of cells treated with esomeprazole or pirfenidone revealed that the drugs target several extracellular matrix (ECM) related pathways with esomeprazole preferentially targeting collagen family members while pirfenidone targets the keratins. In conclusion, our cell biological, computational, and in vivo studies show that the PPI esomeprazole enhances the antifibrotic efficacy of pirfenidone through complementary molecular mechanisms. This data supports the initiation of prospective clinical studies aimed at repurposing PPIs for the treatment of IPF and other fibrotic lung diseases where pirfenidone is prescribed.

Discovery of the novel Benzo[b]thiophene 1,1-dioxide derivatives as a potent STAT3 inhibitor against idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease of unknown aetiology with limited treatment options. Currently, only two drugs, nintedanib and pirfenidone, are approved for the clinical treatment of IPF, but their efficacies are not satisfactory. Previous studies have shown that STAT3 might be a promising therapeutic target for IPF. Here, we designed several series of compounds and finally synthesized a total of 48 novel compounds as potential STAT3 inhibitors. Notably, compound 10K was the most promising compound with excellent inhibitory activity against STAT3 phosphorylation. Subsequently, the anti-pulmonary fibrosis effect of 10K was further investigated by TGF-β1-stimulated in vitro cell assay and bleomycin (BLM)-induced pulmonary fibrosis animal models. Specifically, compound 10K inhibited the TGF-β1 induced fibrotic response and blocked the epithelial-mesenchymal transition (EMT) of A549 cells, and its inhibitory effect was significantly better than that of Stattic. In addition, after oral administration of 10K, the symptoms of IPF in the lung tissue in the prevention and treatment mouse models were significantly reversed, and the efficacy was comparable to that of nintedanib. Moreover, 10K improved BLM-induced imbalance of immune microenvironment in lung tissue. Taken together, these results suggest that 10K could be a potential STAT3 inhibitor for the treatment of IPF.

Idiopathic Pulmonary Fibrosis and Telomeres

Idiopathic pulmonary fibrosis is an interstitial lung disease of unknown etiology with a highly compromised prognosis and a significant mortality rate within a few years of diagnosis. Despite being idiopathic, it has been shown that telomeric shortening could play an important role in its etiopathogenesis. Mutations in telomere-related genes have been identified, but they are not always present despite telomere shortening. On the other hand, this telomeric shortening has been linked to a worse prognosis of the disease independently of other clinical factors, implying it may serve as a biomarker.

The impact of FVC/DLCO ratio on diagnosis of pulmonary hypertension and disease prognosis in idiopathic pulmonary fibrosis

Introduction: Idiopathic pulmonary fibrosis is a chronic progressive fibrotic lung disease of unknown etiology that occurs most commonly in older adults. The presence of pulmonary hypertension in Idiopathic pulmonary fibrosis is associated with poor prognosis and mortality. Literature suggests that the forced vital capacity to diffusion capacity of the lung for carbon monoxide ratio has a positive predictive value for the diagnosis of pulmonary hypertension. Therefore, this study aimed to investigate the impact of forced vital capacity to diffusion capacity of the lung for carbon monoxide ratio on the diagnosis of pulmonary hypertension and disease prognosis in Idiopathic pulmonary fibrosis patients. MATERIAL AND METHOD: Forty-eight patients diagnosed with Idiopathic pulmonary fibrosis were included in the study. Patient records, echocardiographic and spirometric data were retrospectively reviewed. Results: The average pulmonary arterial pressure was observed to be 32.8 (±9) mmHg, with the second-year follow-up pulmonary arterial pressure at 40.8 (±17.2) mmHg and the fourth-year follow-up pulmonary arterial pressure at 51 (±23.6) mmHg. In those diagnosed as pulmonary hypertension, the forced vital capacity to diffusion capacity of the lung for carbon monoxide ratio was initially 1.54 (±0.72). By the second year, it was 1.61 (±0.45), and by the fourth year, it was 1.87 (±0.8). It was found that the forced vital capacity to diffusion capacity of the lung for carbon monoxide ratio tended to increase when pulmonary artery pressure increased during the follow-up period. Conclusion: We found that low six- minute walking test distance was an important marker for the diagnosis of pulmonary hypertension in patients with idiopathic pulmonary fibrosis and that the presence of desaturation was also significantly associated with survival in pulmonary hypertension. Although we did not find it statistically significant, we found that both pulmonary arterial pressure and the the forced vital capacity to diffusion capacity of the lung for carbon monoxide ratio increased with progressive disease duration after diagnosis in patients with IPF. We believe that the the forced vital capacity to diffusion capacity of the lung for carbon monoxide ratio is an important marker for early detection of pulmonary hypertension and prognosis in idiopathic pulmonary fibrosis.