Front Immunol. 2023 Aug 23;14:1215450. doi: 10.3389/fimmu.2023.1215450. eCollection 2023.

ABSTRACT

OBJECTIVES: This study aims to assess the efficacy of tofacitinib (TOF) plus iguratimod (IGU) in rheumatoid arthritis (RA) with usual interstitial pneumonia (UIP) (RA-UIP).

METHODS: This was a prospective observational cohort, single-center study. Data from 78 RA-UIP patients treated with TOF plus IGU, IGU plus conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), and csDMARDs were analyzed. Clinically relevant responses in RA activity assessment, pulmonary function tests (PFTs), and high-resolution computed tomography (HRCT) assessment at baseline and follow-up were compared between groups to evaluate the efficacy of TOF plus IGU.

RESULTS: A total of 78 patients were followed up for at least 6 months after treatment. There were significant changes in sedimentation rate (ESR), C reactive protein (CRP), and disease activity score (DAS) 28-CRP during the follow-up within each treatment group, but there was no statistically significant difference between the two groups. After 6 months of TOF plus IGU treatment, forced vital capacity (FVC)% (84.7 ± 14.7 vs. 90.7 ± 15.4) and HRCT fibrosis score (7.3 ± 3.4 vs. 7.0 ± 5.6) showed a significant improvement compared to the csDMARDs group (P = 0.031, P = 0.015). The TOF plus IGU-treated patients had a significantly higher regression and lower deterioration than the csDMARDs-treated patients (P = 0.026, P = 0.026) and had a significantly higher response (regression + stability), with overall response rates of 66.7% (16/24) vs. 35.7% (10/28) (P = 0.027), respectively.

CONCLUSION: Our results indicate that TOF plus IGU can simultaneously relieve RA and RA-UIP and be better than the csDMARDs with a higher response rate in RA-UIP, which may be a potential choice for "dual treat-to-target".

PMID:37680626 | PMC:PMC10482028 | DOI:10.3389/fimmu.2023.1215450

Eur J Med Chem. 2023 Aug 25;260:115762. doi: 10.1016/j.ejmech.2023.115762. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the most common fibrotic form of idiopathic diffuse lung disease. Due to limited treatment options, IPF patients suffer from poor survival. About ten years ago, Pirfenidone (Shionogi, 2008; InterMune, 2011) and Nintedanib (Boehringer Ingelheim, 2014) were approved, greatly changing the direction of IPF drug design. However, limited efficacy and side effects indicate that neither can reverse the process of IPF. With insights into the occurrence of IPF, novel targets and agents have been proposed, which have fundamentally changed the treatment of IPF. With the next-generation agents, targeting pro-fibrotic pathways in the epithelial-injury model offers a promising approach. Besides, several next-generation IPF drugs have entered phase II/III clinical trials with encouraging results. Due to the rising IPF treatment requirements, there is an urgent need to completely summarize the mechanisms, targets, problems, and drug design strategies over the past ten years. In this review, we summarize known mechanisms, target types, drug design, and novel technologies of IPF drug discovery, aiming to provide insights into the future development and clinical application of next-generation IPF drugs.

PMID:37683364 | DOI:10.1016/j.ejmech.2023.115762

Cells. 2023 Sep 1;12(17):2193. doi: 10.3390/cells12172193.

ABSTRACT

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.

PMID:37681924 | DOI:10.3390/cells12172193

Mol Ther Nucleic Acids. 2023 Aug 18;33:898-907. doi: 10.1016/j.omtn.2023.08.014. eCollection 2023 Sep 12.

ABSTRACT

MicroRNAs are attractive therapeutic targets in many diseases, including chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Among microRNA inhibitors antimiRs have been proven successful in lowering aberrant microRNA levels in the clinic. We present a set of antimiRs targeting miR-34a, which has been shown to be dysregulated in chronic lung diseases. The tool compounds were taken up by a bronchial epithelial cell line and primary human bronchial epithelial cells, followed by efficient knockdown of miR-34a. Similar results were observed in 3D differentiated primary human bronchial epithelial cells cultured at the air-liquid interface. Varying chemical properties of antimiRs had significant impact on cellular uptake and potency, resulting in effective tool compounds for use in lung-relevant cellular systems. This report demonstrates gymnotic antimiR uptake and activity in 3D epithelial cell culture after apical administration, mimicking inhalation conditions.

PMID:37680982 | PMC:PMC10480572 | DOI:10.1016/j.omtn.2023.08.014

Drug Des Devel Ther. 2023 Sep 2;17:2679-2690. doi: 10.2147/DDDT.S415453. eCollection 2023.

ABSTRACT

Due to the complex mechanism and limited treatments available for pulmonary fibrosis, the development of targeted drugs or inhibitors based on their molecular mechanisms remains an important strategy for prevention and treatment. In this paper, the downstream signaling pathways mediated by VEGFR and LPAR1 in pulmonary cells and the role of these pathways in pulmonary fibrosis, as well as the current status of drug research on the targets of LPAR1 and VEGFR2, are described. The mechanism by which these two pathways regulate vascular leakage and collagen deposition leading to the development of pulmonary fibrosis are analyzed, and the mutual promotion of the two pathways is discussed. Here we propose the development of drugs that simultaneously target LPAR1 and VEGFR2, and discuss the important considerations in targeting and safety.

PMID:37680863 | PMC:PMC10482219 | DOI:10.2147/DDDT.S415453

Sci Rep. 2023 Sep 7;13(1):14706. doi: 10.1038/s41598-023-41933-5.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that lacks effective treatment modalities. Once patients are diagnosed with IPF, their median survival is approximately 3-5 years. PPARγ is an important target for the prevention and treatment of pulmonary fibrosis. Asarinin is a lignan compound that can be extracted from food plant Asarum heterotropoides. In this study, we investigated the therapeutic effects of asarinin in a pulmonary fibrosis model constructed using bleomycin in mice and explored the underlying mechanisms. Intraperitoneal administration of asarinin to mice with pulmonary fibrosis showed that asarinin effectively attenuated pulmonary fibrosis, and this effect was significantly inhibited by the PPARγ inhibitor GW9662. Asarinin inhibited TGF-β1-induced fibroblast-to-myofibroblast transition in vitro, while GW9662 and PPARγ gene silencing significantly inhibited this effect. In addition, asarinin inhibited not only the canonical Smad pathway of TGF-β but also the non-canonical AKT and MAPK pathways by activating PPARγ. Our study demonstrates that asarinin can be used as a therapeutic agent for pulmonary fibrosis, and that PPARγ is its key target.

PMID:37679587 | DOI:10.1038/s41598-023-41933-5

Eur Respir J. 2023 Sep 7:2301299. doi: 10.1183/13993003.01299-2023. Online ahead of print.

NO ABSTRACT

PMID:37678948 | DOI:10.1183/13993003.01299-2023

Ann Am Thorac Soc. 2023 Sep 7. doi: 10.1513/AnnalsATS.202303-208OC. Online ahead of print.

ABSTRACT

RATIONALE: Hypoxemia in fibrotic interstitial lung disease (ILD) indicates disease progression and is of prognostic significance. The onset of hypoxemia signifies disease progression and predicts mortality in fibrotic interstitial lung diseases (ILD). Accurately predicting new-onset exertional and resting hypoxemia prompts appropriate patient discussion and timely consideration of home oxygen.

OBJECTIVE: We derived and externally validated a risk prediction tool for both new-onset exertional and resting hypoxemia.

METHODS: This study used ILD registries from Canada for the derivation cohort and from Australia and United States for the validation cohort. New-onset exertional and resting hypoxemia were defined as nadir SpO2 <88% during 6-minute walk tests, resting SpO2 <88%, or the initiation of ambulatory or continuous oxygen. Candidate predictors included patient demographics, ILD subtypes, and pulmonary function. Time-varying Cox regression was used to identify the top performing prediction model according to Akaike information criterion and clinical usability. Model performance was assessed using Harrell's C-index and goodness-of-fit (GoF) likelihood ratio test. A categorized risk prediction tool was developed.

RESULTS: The best-performing prediction model for both new-onset exertional and resting hypoxemia included age, body mass index, a diagnosis of idiopathic pulmonary fibrosis, and percent-predicted forced vital capacity and diffusing capacity of carbon monoxide. The risk prediction tool exhibited good performance for exertional hypoxemia (C-index=0.70, GoF=0.85) and resting hypoxemia (C-index=0.77, GoF=0.27) in the derivation cohort, with similar performance in the validation cohort except calibration for resting hypoxemia (GoF=0.001).

CONCLUSIONS: This clinically applicable risk prediction tool predicted new-onset exertional and resting hypoxemia at six months in the derivation cohort and a diverse validation cohort. Suboptimal GoF in the validation cohort likely reflected overestimation of hypoxemia risk and indicated that the model is not flawed due to underestimation of hypoxemia.

PMID:37676933 | DOI:10.1513/AnnalsATS.202303-208OC

JCI Insight. 2023 Sep 7:e173374. doi: 10.1172/jci.insight.173374. Online ahead of print.

ABSTRACT

A hallmark of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases is dysregulated repair of the alveolar epithelium. The Hippo pathway effector transcription factors YAP and TAZ are implicated as essential for type 1 and type 2 alveolar epithelial cell (AT1 and AT2) differentiation in the developing lung, yet aberrant activation of YAP/TAZ is a prominent feature of the dysregulated alveolar epithelium in IPF. In these studies, we sought to define the functional role of YAP/TAZ activity during alveolar regeneration. We demonstrated that Yap and Taz are normally activated in AT2 cells shortly after injury, and deletion of Yap/Taz in AT2 cells led to pathologic alveolar remodeling, failure of AT2 to AT1 cell differentiation, increased collagen deposition, exaggerated neutrophilic inflammation, and increased mortality following injury induced by a single dose of bleomycin. Loss of Yap/Taz activity prior to a LPS injury prevented AT1 cell regeneration, led to intra-alveolar collagen deposition, and resulted in persistent innate inflammation. Together these findings established that AT2 cell Yap/Taz activity is essential for functional alveolar epithelial repair and prevention of fibrotic remodeling.

PMID:37676731 | DOI:10.1172/jci.insight.173374

Respirology. 2023 Sep 6. doi: 10.1111/resp.14594. Online ahead of print.

NO ABSTRACT

PMID:37673421 | DOI:10.1111/resp.14594

Life Sci. 2023 Sep 4:122071. doi: 10.1016/j.lfs.2023.122071. Online ahead of print.

ABSTRACT

AIMS: Idiopathic pulmonary fibrosis (IPF) is a severe pulmonary interstitial pneumonia. Our study focuses on the role of PLA2 enzyme in the IPF to explore a more effective diagnosis and treatment mechanism of IPF.

MAIN METHODS: Transcriptome data of IPF from GEO database and bleomycin-induced pulmonary fibrosis mice were analyzed to identify PLA2 enzyme and their metabolite, lysophosphatidylcholines 18:0, in IPF. Based on PLA2G2A and PLA2G2D / PLA2G2A-associated cell death genes (PCDs), the consensus clustering analysis was used to identify the subtypes of IPF and the correlation between PLA2G2A and prognosis was analyzed. The machine learning (ML) models and artificial neural network (ANN) model was used to validate the diagnostic accuracy of PLA2s and PCDs in diagnosing IPF. The gene and protein expression of NLRP3, GSDMD, and CASP-1 was estimated in recombinant PLA2G2A protein induced MLE-12 cells.

KEY FINDINGS: The expression of PLA2G2D, PLA2G2A, and LPC18 significantly changed in IPF. Furtherly, PLA2G2A has a significant correlation with poor patient prognosis, which could predict the 2 or 3-years mortality rates of IPF. Two subtypes of IPF patients, identified based on PCDs, showed significant different immunoinfiltration. Recombinant PLA2G2A protein could induce the pyrotosis in the MLE-12 cell. The generalized linear model and ANN model of PLA2s or PCDs accurate diagnosis IPF.

SIGNIFICANCE: PLA2G2A is the most robustly associated gene with IPF among the PLA2s, which demonstrates a potential in diagnosing and prognostic value in IPF, and provides a foundation for further understanding and breakthroughs in IPF diagnosis and treatment.

PMID:37673297 | DOI:10.1016/j.lfs.2023.122071

Acta Biochim Pol. 2023 Sep 6. doi: 10.18388/abp.2020_6459. Online ahead of print.

ABSTRACT

OBJECTIVE: This paper was to investigate the effect of circ_PWWP2A-mediated miR-27b-3p/GATA3 axis on idiopathic pulmonary fibrosis (IPF).

METHODS: circ_PWWP2A expression in lung fibroblasts MLg2908 induced by different concentrations of TGF-β was detected. The relationship between circ_PWWP2A or GATA3 and miR-27b-3p was analyzed by RNA immunoprecipitation and dual-luciferin reporter assay. The proliferation of MLg2908 cells was determined by MTT. GATA3, α-SMA, Collagen-I, and Collagen-III in cells were detected by RT-qPCR and Western blot. The rat model of IPF induced by bleomycin (BLM) was constructed and treated with circ_PWWP2A siRNA injection. HE and Masson staining were of utility to evaluate the pathological conditions of rat lung tissue, and circ_PWWP2A, miR-27b-3p, and GATA3 levels in lung tissues were detected by RT-qPCR. Immunohistochemistry was used to detect the staining of α-SMA, collagen I, and collagen III in the lung tissues of rats.

RESULTS: circ_PWWP2A in MLg2908 cells induced by TGF-β decreased in a concentration-dependent manner. MLg2908 cells transfected with circ_PWWP2A siRNA were induced by 5 ng/ml TGF-β, decreasing circ_PWWP2A and GATA3 levels, increasing miR-27b-3p expression, and suppressing cell proliferation. The targeting relationship between circ_PWWP2A and miR-27b-3p, as well as miR-27b-3p and GATA3, was confirmed. Depleting miR-27b-3p reduced the inhibitory effect of circ_PWWP2A down-regulation on the proliferation of TGF-β-treated MLg2908 cells, accompanied by increased expression of α-SMA, Collagen 1, and Collagen 3, and increased expression of GATA3. The in vivo results showed that BLM-induced fibrosis in rat lung tissue was obvious, accompanied by increased expression of circ_PWWP2A and GATA3, decreased expression of miR-27b-3p, and deepened staining of α-SMA, collagen I, and collagen III, but circ_PWWP2A siRNA could improve these phenomena.

CONCLUSION: Silencing circ_PWWP2A can inhibit the proliferation of lung fibroblasts induced by TGF-β through the miR-27b-3p/GATA3 axis, and reduce BLM-induced pulmonary fibrosis in rats, which may be a potential therapeutic target for IPF.

PMID:37672715 | DOI:10.18388/abp.2020_6459

Mol Med. 2023 Sep 5;29(1):119. doi: 10.1186/s10020-023-00719-1.

ABSTRACT

Small ubiquitin-like modifier mediated modification (SUMOylation) is a critical post-translational modification that has a broad spectrum of biological functions, including genome replication and repair, transcriptional regulation, protein stability, and cell cycle progression. Perturbation or deregulation of a SUMOylation and deSUMOylation status has emerged as a new pathophysiological feature of lung diseases. In this review, we highlighted the link between SUMO pathway and lung diseases, especially the sumoylated substrate such as C/EBPα in bronchopulmonary dysplasia (BDP), PPARγ in pneumonia, TFII-I in asthma, HDAC2 in chronic obstructive pulmonary disease (COPD), KLF15 in hypoxic pulmonary hypertension (HPH), SMAD3 in idiopathic pulmonary fibrosis (IPF), and YTHDF2 in cancer. By exploring the impact of SUMOylation in pulmonary diseases, we intend to shed light on its potential to inspire the development of innovative diagnostic and therapeutic strategies, holding promise for improving patient outcomes and overall respiratory health.

PMID:37670258 | DOI:10.1186/s10020-023-00719-1

J Digit Imaging. 2023 Sep 5. doi: 10.1007/s10278-023-00896-9. Online ahead of print.

ABSTRACT

The purpose of this study is to evaluate the accuracy and inter-observer agreement of a quantitative pulmonary surface irregularity (PSI) score on high-resolution chest CT (HRCT) for predicting transplant-free survival in patients with IPF. For this IRB-approved HIPAA-compliant retrospective single-center study, adult patients with IPF and HRCT imaging (N = 50) and an age- and gender-matched negative control group with normal HRCT imaging (N = 50) were identified. Four independent readers measured the PSI score in the midlungs on HRCT images using dedicated software while blinded to clinical data. A t-test was used to compare the PSI scores between negative control and IPF cohorts. In the IPF cohort, multivariate cox regression analysis was used to associate PSI score and clinical parameters with transplant-free survival. Inter-observer agreement for the PSI score was assessed by intraclass correlation coefficient (ICC). The technical failure rate of the midlung PSI score was 0% (0/100). The mean PSI score of 5.38 in the IPF cohort was significantly higher than 3.14 in the negative control cohort (p < .001). In the IPF cohort, patients with a high PSI score (≥ median) were 8 times more likely to die than patients with a low PSI score (HR: 8.36; 95%CI: 2.91-24.03; p < .001). In a multivariate model including age, gender, FVC, DLCO, and PSI score, only the PSI score was associated with transplant-free survival (HR:2.11 per unit increase; 95%CI: 0.26-3.51; p = .004). Inter-observer agreement for the PSI score among 4 readers was good (ICC: 0.88; 95%CI: 0.84-0.91). The PSI score had high accuracy and good inter-observer agreement on HRCT for predicting transplant-free survival in patients with IPF.

PMID:37670182 | DOI:10.1007/s10278-023-00896-9

Clin Transl Sci. 2023 Sep 4. doi: 10.1111/cts.13622. Online ahead of print.

ABSTRACT

Ziritaxestat, an autotaxin inhibitor, was under development for the treatment of idiopathic pulmonary fibrosis. It is a substrate of CYP3A4 and P-glycoprotein and a weak inhibitor of the CYP3A4 and OATP1B1 pathways. We developed a physiologically based pharmacokinetic (PBPK) network interaction model for ziritaxestat that incorporated its metabolic and transporter pathways, enabling prediction of its potential as a victim or perpetrator of drug-drug interactions (DDIs). Concurrently, we evaluated CYP3A4 autoinhibition, including time-dependent inhibition (TDI). In vitro information and clinical data from healthy volunteer studies were used for model building and validation. DDIs with rifampin, itraconazole, voriconazole, pravastatin, and rosuvastatin were predicted, followed by validation against a test dataset. DDIs of ziritaxestat as a victim or perpetrator were simulated using the final model. Predicted-to-observed DDI ratios for Cmax and AUC were within a 2-fold ratio for both the metabolic and transporter-mediated simulated DDIs. The predicted impact of autoinhibition/autoinduction or TDI of CYP3A4 was a 12% decrease in exposure. Model-based predictions for ziritaxestat as a victim of DDIs with a moderate CYP3A4 inhibitor (fluconazole) suggested a 2.6-fold increase in the AUC of ziritaxestat, while multiple doses of a strong inhibitor (voriconazole) would increase the AUC by 15-fold. Efavirenz would yield a 3-fold decrease in the AUC of ziritaxestat. As a perpetrator, ziritaxestat was predicted to increase the AUC of the CYP3A4 index substrate midazolam by 2.7-fold. An overarching PBPK model was developed that could predict DDI liability of ziritaxestat for both CYP3A4 and the transporter pathways.

PMID:37667518 | DOI:10.1111/cts.13622

Stem Cell Res Ther. 2023 Sep 4;14(1):234. doi: 10.1186/s13287-023-03449-7.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible lung disease characterized by pulmonary fibrosis and lung dysfunction, ultimately leading to respiratory failure. Many preclinical studies have investigated the therapeutic potential of stem cell-derived exosomes in this disease, particularly mesenchymal stem cell-derived exosomes. However, the effects of embryonic stem cell-derived exosomes in IPF remain unclear.

METHODS: We established a bleomycin (BLM)-induced pulmonary fibrosis mice model and administered human embryonic stem cell exosomes (hESC-exo) from the first day after BLM treatment. The effects of hESC-exo were assessed by pulmonary function tests, biochemical analysis, histochemistry, quantitative real-time polymerase chain reaction (qPCR), and western blot (WB). RNA-seq was used to screen for the potential therapeutic targets of hESC-exo in fibrotic lungs; the identified signaling axis was characterized using a luciferase assay, qPCR, and WB.

RESULTS: Results indicated hESC-exo administration notably alleviated inflammation, removed deposited collagen, and rescued alveolar architecture in the lungs of BLM-induced mice. In vivo and in vitro tests revealed that hESC-exo-derived miR-17-5p directly bound thrombospondin-2 (Thbs2) to regulate inflammation and fibrosis; thus, hESC-exo protected against BLM toxicity in the lungs via the miR-17-5p/Thbs2 axis.

CONCLUSION: These results suggest a promising new treatment for fibrosis-associated diseases.

PMID:37667335 | DOI:10.1186/s13287-023-03449-7

BMC Pulm Med. 2023 Sep 4;23(1):325. doi: 10.1186/s12890-023-02601-6.

ABSTRACT

BACKGROUND: Idiopathic 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.

METHODS: We 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.

RESULTS: We 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.

CONCLUSIONS: These 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.

PMID:37667288 | DOI:10.1186/s12890-023-02601-6

Sci Rep. 2023 Sep 4;13(1):10110. doi: 10.1038/s41598-023-36944-1.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic disease with an unclear etiology and no effective treatment. This study aims to elucidate the pathogenic mechanism networks involving multiple targets and pathways in IPF. Extracts and metabolites of Astragalus membranaceus (AM) and Radix paeoniae rubra (RPR), two well-known traditional Chinese medicines, have demonstrated therapeutic effects on IPF. However, the underlying mechanisms of AM and RPR remain unclear. Utilizing network pharmacology analysis, differentially expressed genes (DEGs) associated with IPF were obtained from the GEO database. Targets of AM and RPR were identified using the TCM Systems Pharmacology Database and Analysis Platform and SwissTargetPrediction. A protein-protein interaction (PPI) network was subsequently constructed and analyzed using the STRING database and Cytoscape software. Gene ontology enrichment analysis and kyoto encyclopedia of genes and genomes analysis were conducted using Metascape. Additionally, a component-target-pathway network and a Sankey diagram were employed to identify the main active components, and molecular docking was performed between these components and proteins encoded by key targets. Finally, in vivo studies were conducted based on network pharmacology. A total of 117 common targets between DEGs of IPF and drug targets were identified and included in the PPI network, in which AKT1, MAPK3, HSP90AA1, VEGFA, CASP3, JUN, HIF1A, CCND1, PTGS2, and MDM2 were predicted as key targets. These 117 targets were enriched in the PI3K-AKT pathway, HIF-1 signaling pathway, apoptosis, and microRNAs in cancer. Astragaloside III, (R)-Isomucronulatol, Astragaloside I, Paeoniflorin, and β-sitosterol were selected as the main active components. Docking scores ranged from - 4.7 to - 10.7 kcal/mol, indicating a strong binding affinity between the main active compounds and key targets. In vivo studies have indeed shown that AM and RPR can alleviate the pathological lung fibrotic damage caused by bleomycin treatment. The treatment with AM and RPR resulted in a reduction of mRNA levels for key targets AKT1, HSP90AA1, CASP3, MAPK3, and VEGFA. Additionally, the protein expression levels of AKT1, HSP90AA1, and VEGFA were also reduced. These results support the therapeutic potential of AM and RPR in ameliorating pulmonary fibrosis and provide insight into the molecular mechanisms involved in their therapeutic effects.

PMID:37666859 | DOI:10.1038/s41598-023-36944-1

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2023 Aug 25;40(4):632-637. doi: 10.7507/1001-5515.202206016.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive scar-forming disease with a high mortality rate that has received widespread attention. Epithelial mesenchymal transition (EMT) is an important part of the pulmonary fibrosis process, and changes in the biomechanical properties of lung tissue have an important impact on it. In this paper, we summarize the changes in the biomechanical microenvironment of lung tissue in IPF-EMT in recent years, and provide a systematic review on the effects of alterations in the mechanical microenvironment in pulmonary fibrosis on the process of EMT, the effects of mechanical factors on the behavior of alveolar epithelial cells in EMT and the biomechanical signaling in EMT, in order to provide new references for the research on the prevention and treatment of IPF.

PMID:37666752 | DOI:10.7507/1001-5515.202206016

J Cancer Res Clin Oncol. 2023 Sep 4. doi: 10.1007/s00432-023-05324-7. Online ahead of print.

ABSTRACT

BACKGROUND: An increasing number of cohort studies have indicated a correlation between lung diseases and esophageal cancer, but the exact causal relationship has not been definitively established. Therefore, the objective of this study is to assess the causal relationship between lung diseases and esophageal cancer.

METHODS: Single-nucleotide polymorphisms (SNPs) related to lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and idiopathic pulmonary fibrosis (IPF), along with outcomes data on esophageal cancer, were extracted from public genome-wide association studies (GWAS). A two-sample Mendelian randomization (MR) analysis was then performed using publicly available GWAS data to investigate the potential causal relationship. The effect estimates were primarily calculated using the fixed-effects inverse-variance-weighted method.

RESULTS: Totally, 81 SNPs related to asthma among 218,792 participants in GWAS. Based on the primary causal effects model using MR analyses with the inverse variance weighted (IVW) method, asthma was demonstrated a significantly related to the risk of esophageal cancer (OR 1.0006; 95% CI 1.0003-1.0010, p = 0.001), while COPD (OR 1.0306; 95% CI 0.9504-1.1176, p = 0.466), lung cancer (OR 1.0003, 95% CI 0.9998-1.0008, p = 0.305), as well as IPF (OR 0.9999, 95% CI 0.9998-1.0000, p = 0.147), showed no significant correlation with esophageal cancer.

CONCLUSIONS: The two-sample MR analysis conducted in this study revealed a positive causal relationship between asthma and esophageal cancer. In contrast, esophageal cancer demonstrated no significant correlation with COPD, lung cancer, or IPF. Further large-sample prospective studies are needed to validate these findings and to provide appropriate recommendations regarding esophageal cancer screening among patients with asthma.

PMID:37665406 | DOI:10.1007/s00432-023-05324-7