ESL attenuates BLM-induced IPF in mice: Dual mediation of the TLR4/NF-κB and TGF-ß1/PI3K/Akt/FOXO3a pathways.

BACKGROUNDS: Idiopathic pulmonary fibrosis (IPF) is a persistent and advanced pulmonary ailment. The roles of innate immunity and adaptive immunity are pivotal in the evolution of IPF. An ill-adjusted interaction between epithelial cells and immune cells is responsible for initiating the epithelial-mesenchymal transition (EMT) process and sustaining chronic inflammation, thereby fostering fibrosis progression. The intricacy of IPF pathogenesis has hindered the availability of efficacious agents. Elephantopus scaber Linn. (ESL) is a canonical Chinese medicine with significant immunoregulatory effects, and its aqueous extract has been proven to attenuate IPF symptoms in bleomycin (BLM)-induced mice. However, the underlying mechanism through which ESL relieves IPF remains unclear. AIM: To validate whether ESL reverses IPF by mediating the immune response and EMT. METHODS: Ultra-performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) and UPLC were used to identify the components and determine the concentrations of the specific compounds in the ESL. Network pharmacology and molecular docking were applied to predict the potential mechanism underlying the anti-IPF effect of ESL. BLM-induced IPF mice were used to validate the anti-IPF effect of ESL, and lung tissue was collected to test putative pathways involved in inflammation and EMT via immunohistochemistry (ICH), real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting. RESULTS: Sixty-one compounds were identified, and thirteen main ingredients were quantified in the ESL. In silico experiments predicted that the IPF-mediated reversal of adverse effects by ESL would be related to interruption of the Toll-like receptor 4 (TLR4)/nuclear factor-k-gene binding (NF-ĸB) inflammatory pathway and the transforming growth factor-beta l (TGF-ß1)/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/forkhead box O3 (FOXO3a) fibrosis pathway. In vivo experiments showed that ESL alleviates BLM-induced lung inflammation and fibrosis by reducing neutrophil aggregation and fibroblast foci, similar to the effects of the positive control drug pirfenidone (PFD). ESL markedly inhibited the transcription of TNF-α, IL-1ß, and IL-6, which are downstream genes of the NF-κB signaling pathway. Furthermore, the protein levels of TLR4 and p-NF-κB were correspondingly inhibited in response to ESL treatment. Additionally, ESL reverses BLM-induced changes in the expression of EMT-related biological characteristic indicators (collagen I [COLIA1], E-cadherin, and alpha smooth muscle actin [α-SMA]) at the messenger ribonucleic acid (mRNA) level and markedly inhibits the expression of EMT-related upstream proteins (TGF-ß1, p-PI3K, p-Akt, and p-FOXO3a). CONCLUSION: Our research suggested that ESL attenuates BLM-induced IPF through mediating the EMT process via the TGF-ß1/PI3K/Akt/FOXO3a signaling pathway and inhibiting inflammation through the TLR4/NF-κB signaling pathway, highlighting that ESL can serve as an immunoregulator for relieving the abnormal immune response and reversing the EMT in IPF.

[Interstitial lung diseases : From imaging to treatment]. / Interstitielle Lungenerkrankungen : Vom Bild zur Therapie.

BACKGROUND: The role of radiology in the diagnosis of interstitial lung diseases (ILDs) has evolved over time, in part replacing histology. Radiology now represents a pillar of diagnostics and monitoring in ILDs. OBJECTIVE: To what extent does radiology influence diagnostics and treatment in ILDs? MATERIALS AND METHODS: A literature review was conducted, and current findings were discussed in the context of clinical data. RESULTS: Radiology plays a crucial role in the diagnosis of ILDs. Within the framework of the multidisciplinary conference, it provides specific CT patterns such as usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), and organizing pneumonia (OP), or helps in identifying cystic lung diseases. Multicompartment diseases can be detected, and pulmonary hypertension or extrapulmonary involvement of the respective diseases can be suspected. Progressive pulmonary fibrosis requires radiologic assessment as one of the required criteria. Interstitial lung abnormalities are usually detected by radiological studies performed for an unrelated indication. CONCLUSION: Radiology plays an important role within the multidisciplinary conference to determine both diagnosis and treatment with antifibrotic or anti-inflammatory drugs, or a combination of both.

Discovery of novel pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione (PBD) derivatives as selective HDAC6 inhibitors for the efficient treatment of idiopathic pulmonary fibrosis (IPF) in vitro and in vivo.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by a progressive fibrotic phenotype. Immunohistochemical studies on HDAC6 overexpression in IPF lung tissues confirmed that IPF is associated with aberrant HDAC6 activity. We herein developed a series of novel HDAC6 inhibitors that can be used as potential pharmacological tools for IPF treatment. The best-performing derivative H10 showed good selectivity for multiple isoforms of the HDAC family. The structural analysis and structure-activity relationship studies of H10 will contribute to optimizing the binding mode of the new molecules. The pharmacological mechanism of H10 to inhibit pulmonary fibrosis was validated, and its ability to inhibit the IPF phenotype was also demonstrated. Moreover, H10 showed satisfactory metabolic stability. The efficacy of H10 was also determined in a mouse model of bleomycin-induced pulmonary fibrosis. The results highlighted in this paper may provide a reference for the identification of new drug molecules for the treatment of IPF.

Cell-Based Therapy for Fibrosing Interstitial Lung Diseases, Current Status, and Potential Applications of iPSC-Derived Cells.

Fibrosing interstitial lung diseases (FILDs), e.g., due to idiopathic pulmonary fibrosis (IPF), are chronic progressive diseases with a poor prognosis. The management of these diseases is challenging and focuses mainly on the suppression of progression with anti-fibrotic drugs. Therefore, novel FILD treatments are needed. In recent years, cell-based therapy with various stem cells has been investigated for FILD, and the use of mesenchymal stem cells (MSCs) has been widely reported and clinical studies are also ongoing. Induced pluripotent stem cells (iPSCs) have also been reported to have an anti-fibrotic effect in FILD; however, these have not been as well studied as MSCs in terms of the mechanisms and side effects. While MSCs show a potent anti-fibrotic effect, the possibility of quality differences between donors and a stable supply in the case of donor shortage or reduced proliferative capacity after cell passaging needs to be considered. The application of iPSC-derived cells has the potential to overcome these problems and may lead to consistent quality of the cell product and stable product supply. This review provides an overview of iPSCs and FILD, followed by the current status of cell-based therapy for FILD, and then discusses the possibilities and perspectives of FILD therapy with iPSC-derived cells.

Pursuing Clinical Predictors and Biomarkers for Progression in ILD: Analysis of the Pulmonary Fibrosis Foundation (PFF) Registry.

INTRODUCTION: Pulmonary fibrosis is a characteristic of various interstitial lung diseases (ILDs) with differing etiologies. Clinical trials in progressive pulmonary fibrosis (PPF) enroll patients based on previously described clinical criteria for past progression, which include a clinical practice guideline for PPF classification and inclusion criteria from the INBUILD trial. In this study, we compared the ability of past FVC (forced vital capacity) progression and baseline biomarker levels to predict future progression in a cohort of patients from the PFF Patient Registry. METHODS: Biomarkers previously associated with pathobiology and/or progression in pulmonary fibrosis were selected to reflect cellular senescence (telomere length), pulmonary epithelium (SP-D, RAGE), myeloid activation (CXCL13, YKL40, CCL18, OPN) and fibroblast activation (POSTN, COMP, PROC3). RESULTS: PFF or INBUILD-like clinical criteria was used to separate patients into past progressor and non-past progressor groups, and neither clinical criterion appeared to enrich for patients with greater future lung function decline. All baseline biomarkers measured were differentially expressed in patient groups compared to healthy controls. Baseline levels of SP-D and POSTN showed the highest correlations with FVC slope over one year, though correlations were low. CONCLUSIONS: Our findings provide further evidence that prior decline in lung function may not predict future disease progression for ILD patients, and elevate the need for molecular definitions of a progressive phenotype. Across ILD subtypes, certain shared pathobiologies may be present based on the molecular profile of certain biomarker groups observed. In particular, SP-D may be a common marker of pulmonary injury and future lung function decline across ILDs.

A Case of Tension Pneumomediastinum Treated With Mediastinal Drainage Using a Semi-flexible Fiberscope via a Subxiphoid Approach.

Tension pneumomediastinum with hemodynamic failure is a rare but life-threatening condition. Rapid decompression of the mediastinum by drainage is essential to save the patient's life. This report presents a case of tension pneumomediastinum that developed during conservative management of a pneumomediastinum associated with idiopathic pulmonary fibrosis. Endoscopically guided mediastinal drainage was successfully performed in the emergency situation of tension pneumomediastinum. Using the semi-flexible fiberscope inserted through a subxiphoid approach, the drainage catheter was easily and safely placed at the appropriate site in the mediastinum. Good mediastinal decompression was achieved, and the patient was out of this critical condition.

Patients with idiopathic pulmonary fibrosis and refractory cough have traction bronchiectasis and distorted airway architecture: a retrospective case review study.

Cough is a common and important sign/symptom in patients with idiopathic pulmonary fibrosis (IPF). However, there have been few reports focusing on cough, and the exact mechanisms for cough in patients with IPF have remained unclear. The objective of this study was to investigate the clinical features of IPF patients with refractory cough and to clarify mechanisms for cough in these patients. We retrospectively reviewed the files of patients with the diagnosis of IPF at Kanazawa University Hospital and compared the clinical features of IPF patients with refractory cough with the clinical features of IPF patients without refractory cough. Among a total of 23 patients with IPF, 10 patients (43.5%) had chronic cough. Of the ten patients, seven patients had concomitant conditions that could lead to cough. Of these seven patients, the cough of four patients was resolved after treatment of their concomitant condition. Finally, among the 23 patients there were 6 (26.1%) with refractory cough associated with IPF. Significant differences were seen between the following clinical features of IPF patients with or without refractory cough, respectively, as follows: lower body mass index (BMI; 18.8±2.5 vs. 22.8±2.5 kg/m2, P<0.01), lower forced vital capacity (FVC; 77.5%±30.4% predicted vs. 99.9%±0.53% predicted, P=0.046), and presence of traction bronchiectasis and distorted airway architecture on high-resolution computed tomography (HRCT; 83.3% vs. 11.8%, P<0.01). The difference between the proportions of patients with or without refractory cough with capsaicin cough sensitivity was not significant. Mechanical stress on the airways due to traction bronchiectasis and distorted airway architecture is a possible mechanism for cough in IPF patients.

Genetic association between smoking and DLCO in idiopathic pulmonary fibrosis patients.

BACKGROUND: Observational 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. METHODS: Large-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. RESULTS: A 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]. CONCLUSIONS: Our 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.

Kefir peptides mitigate bleomycin-induced pulmonary fibrosis in mice through modulating oxidative stress, inflammation and gut microbiota.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and life-threatening lung disease with high mortality rates. The limited availability of effective drugs for IPF treatment, coupled with concerns regarding adverse effects and restricted responsiveness, underscores the need for alternative approaches. Kefir peptides (KPs) have demonstrated antioxidative, anti-inflammatory, and antifibrotic properties, along with the capability to modulate gut microbiota. This study aims to investigate the impact of KPs on bleomycin-induced pulmonary fibrosis. METHODS: Mice were treated with KPs for four days, followed by intratracheal injection of bleomycin for 21 days. Comprehensive assessments included pulmonary functional tests, micro-computed tomography (µ-CT), in vivo image analysis using MMPsense750, evaluation of inflammation- and fibrosis-related gene expression in lung tissue, and histopathological examinations. Furthermore, a detailed investigation of the gut microbiota community was performed using full-length 16 S rRNA sequencing in control mice, bleomycin-induced fibrotic mice, and KPs-pretreated fibrotic mice. RESULTS: In KPs-pretreated bleomycin-induced lung fibrotic mice, notable outcomes included the absence of significant bodyweight loss, enhanced pulmonary functions, restored lung tissue architecture, and diminished thickening of inter-alveolar septa, as elucidated by morphological and histopathological analyses. Concurrently, a reduction in the expression levels of oxidative biomarkers, inflammatory factors, and fibrotic indicators was observed. Moreover, 16 S rRNA sequencing demonstrated that KPs pretreatment induced alterations in the relative abundances of gut microbiota, notably affecting Barnesiella_intestinihominis, Kineothrix_alysoides, and Clostridium_viride. CONCLUSIONS: Kefir peptides exerted preventive effects, protecting mice against bleomycin-induced lung oxidative stress, inflammation, and fibrosis. These effects are likely linked to modifications in the gut microbiota community. The findings highlight the therapeutic potential of KPs in mitigating pulmonary fibrosis and advocate for additional exploration in clinical settings.

HOXA5-induced lncRNA DNM3OS promotes human embryo lung fibroblast fibrosis via recruiting EZH2 to epigenetically suppress TSC2 expression.

Background: Idiopathic pulmonary fibrosis (IPF) is an unrepairable disease that results in lung dysfunction and decreased quality of life. Prevention of pulmonary fibrosis is challenging, while its pathogenesis remains largely unknown. Herein, we investigated the effect and mechanism of long non-coding RNA (lncRNA) DNM3OS/Antisense RNA in the pathogenesis of pulmonary fibrosis. Methods: EdU (5-ethynyl-2'-deoxyuridine) and wound healing assays were employed to evaluate the role of DNM3OS on cell proliferation and migration. Western blot detected the proteins expressions of alpha-smooth muscle actin (α-SMA), vimentin, and fibronectin. The interactions among genes were evaluated by RNA pull-down, luciferase reporter, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP) and chromatin Isolation by RNA purification (ChIRP) assays. Results: DNM3OS was upregulated by transforming growth factor beta 1 (TGF-ß1) in a dose- and time-dependent manner. DNM3OS knockdown repressed the growth and migration of lung fibroblast, and fibrotic gene expression (CoL1α1, CoL3α1, α-SMA, vimentin, and fibronectin), while suppression of TSC2 accelerated the above process. DNM3OS recruited EZH2 to the promoter region of TSC2, increased the occupancy of EZH2 and H3K27me3, and thereby suppressed the expression of TSC2. HOXA5 promoted the transcription of DNM3OS. Conclusions: HOXA5-induced DNM3OS promoted the proliferation, migration, and expression of fibrosis-related genes in human embryo lung fibroblast via recruiting EZH2 to epigenetically suppress the expression of TSC2.

A narrative review of the role of HDAC6 in idiopathic pulmonary fibrosis.

Background and Objective: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible condition characterized by the deposition of extracellular matrix resulting from repetitive damage to the alveolar epithelium. These injuries, along with dysregulated wound repair and fibroblast dysfunction, lead to continuous tissue remodeling and fibrosis, eventually resulting in end-stage pulmonary fibrosis. Currently, there is no specific pharmacological treatment available for IPF. The role of inflammation in the development of IPF is still a topic of debate, and it is sometimes considered incidental to fibrosis. Over the past decade, macrophages have emerged as significant contributors to the pathogenesis of fibrosis. M1 macrophages are responsible for wound healing following alveolar epithelial injury, while M2 macrophages are involved in resolving wound repair and terminating the inflammatory response in the lungs. Various studies provide evidence that M2-like macrophages contribute to the abnormal fibrogenesis. In recent years, there has been growing interest in understanding macrophage polarization and its role in the development of pulmonary fibrosis. Histone deacetylase 6 (HDAC6), a member of the HDAC family with two functional deacetylase structural domains and a ubiquitin-binding zinc finger structural domain (ZnF-BUZ), plays a crucial role in pulmonary fibrosis. This article explores the role of HDAC6 in pulmonary fibrosis and evaluates its potential as a treatment approach for IPF. Methods: PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, China Biomedical Literature Service System (CBMdisc) and Web of Science were searched to obtain researches, published in English and Chinese, until July 2023. The search was performed using specific keywords such as Histone deacetylase 6, HDAC6, Idiopathic pulmonary fibrosis, IPF, fibrosis. Key Content and Findings: HDAC6 has diverse effects on physiological processes, including the NLRP3 inflammasome, epithelial-mesenchymal transition, the TGFß-PI3K-AKT pathway, macrophage polarization and TGF-ß-Smad signaling pathway, due to its unique structure. HDAC6 has been found to enhance the inflammatory response and fibrosis of lung tissues, contributing to the development of IPF. Conclusions: In the future, HDAC6 inhibitors are expected to play a crucial role in the treatment of fibrotic disorders and should be studied further deserves to pursue in future research.

The impact of respiratory reactance in oscillometry on survival in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. Pulmonary function tests (PFTs) aid in evaluating the disease status of IPF. The clinical significance of oscillometry measurements in interstitial lung diseases has recently been reported. Our previous study showed that respiratory reactance (Xrs) measured by oscillometry reflected disease severity and predicted subsequent lung capacity decline in patients with IPF. However, the direct impact of Xrs on survival needs to be determined, and there are currently no reference values in oscillometry to predict prognosis. Therefore, this study aimed to investigate the association between oscillometry measurements, particularly Xrs, and survival in patients with IPF and to determine the cutoff values of Xrs that predict 3-year survival. METHODS: We analyzed the relationship between the measured values of PFT and oscillometry derived from 178 patients with IPF. Univariate and multivariate Cox proportional hazards analyses were performed to investigate the relationships between clinical indices at the time of the first oscillometry and survival. We performed the time-dependent receiver operating characteristic (ROC) curve analysis to set the optimized cutoff values of Xrs for 3-year survival prediction. We examined the discriminating power of cutoff values of Xrs on survival using the Kaplan-Meier method and the log-rank test. RESULTS: Xrs components, especially in the inspiratory phase (In), significantly correlated with the PFT values. In the multivariate analyses, Xrs (all of reactance at 5 Hz [X5], resonant frequency [Fres], and low-frequency reactance area [ALX] in the inspiratory phase) had a significant impact on survival (X5, p = 0.003; Fres, p = 0.016; ALX, p = 0.003) independent of age, sex, and other prognostic factors derived from the univariate analysis. The area under the ROC curve was 0.765, 0.759, and 0.766 for X5 In, Fres In, and ALX In, with cutoff values determined at - 0.98, 10.67, and 5.32, respectively. We found significant differences in survival after dividing patients using each of the cutoff values of Xrs. CONCLUSIONS: In patients with IPF, Xrs measured by oscillometry significantly impacted survival. We also determined the cutoff values of Xrs to discriminate patients with poor prognoses.

Functional Progression after Dose Suspension or Discontinuation of Nintedanib in Idiopathic Pulmonary Fibrosis: A Real-Life Multicentre Study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with rapidly progressive evolution and an unfavorable outcome. Nintedanib (NTD) is an antifibrotic drug that has been shown to be effective in slowing down the progression of the disease. The aim of our study was to examine the efficacy, especially in terms of the functional decline, and the safety profile of NTD in patients treated with the recommended dose and subjects who reduced or suspended the therapy due to the occurrence of adverse reactions. METHODS: We conducted a real-life retrospective study based on the experience of NTD use in two centers between 2015 and 2022. Clinical data were evaluated at baseline, at 6 and 12 months after the NTD introduction in the whole population and in subgroups of patients who continued the full-dose treatment, at a reduced dosage, and at the discontinuation of treatment. The following data were recorded: the demographic features, IPF clinical features, NTD therapeutic dosage, tolerability and adverse events, pulmonary function tests (PFTs), the duration of treatment upon discontinuation, and the causes of interruption. RESULTS: There were 54 IPF patients who were included (29.6% females, with a median (IQR) age at baseline of 75 (69.0-79.0) years). Twelve months after the introduction of the NTD therapy, 20 (37%) patients were still taking the full dose, 11 (20.4%) had reduced it to 200 mg daily, and 15 (27.8%) had stopped treatment. Gastrointestinal intolerance predominantly led to the dose reduction (13.0%) and treatment cessation (20.4%). There were two deaths within the initial 6 months (3.7%) and seven (13.0%) within 12 months. Compared to the baseline, the results of the PFTs remained stable at 6 and 12 months for the entire NTD-treated population, except for a significant decline in the DLCO (% predicted value) at both 6 (38.0 ± 17.8 vs. 43.0 ± 26.0; p = 0.041) and 12 months (41.5 ± 15.3 vs. 44.0 ± 26.8; p = 0.048). The patients who continued treatment at the full dose or a reduced dosage showed no significant differences in the FVC and the DLCO at 12 months. Conversely, those discontinuing the NTD exhibited a statistically significant decline in the FVC (% predicted value) at 12 months compared to the baseline (55.0 ± 13.5 vs. 70.0 ± 23.0; p = 0.035). CONCLUSIONS: This study highlights the functional decline of the FVC at 12 months after the NTD initiation among patients discontinuing therapy but not among those reducing their dosage.

Osteopontin: an essential regulatory protein in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic lung disease characterized by abnormal proliferation and activation of fibroblasts, excessive accumulation of extracellular matrix (ECM), inflammatory damage, and disrupted alveolar structure. Despite its increasing morbidity and mortality rates, effective clinical treatments for IPF remain elusive. Osteopontin (OPN), a multifunctional ECM protein found in various tissues, has been implicated in numerous biological processes such as bone remodeling, innate immunity, acute and chronic inflammation, and cancer. Recent studies have highlighted the pivotal role of OPN in the pathogenesis of IPF. This review aims to delve into the involvement of OPN in the inflammatory response, ECM deposition, and epithelial-mesenchymal transition (EMT) during IPF, and intends to lay a solid theoretical groundwork for the development of therapeutic strategies for IPF.

Pathogenesis of Idiopathic Pulmonary Fibrosis and Modulating Effect of Chinese Medicine： A Review / 中国实验方剂学杂志

Idiopathic pulmonary fibrosis （IPF）， as a progressive lung disease， has a poor prognosis and no reliable and effective therapies. IPF is mainly treated by organ transplantation and administration of chemical drugs， which are ineffective and induce side effects， failing to meet the clinical needs. Therefore， developing safer and more effective drugs has become an urgent task， which necessitates clear understanding of the pathogenesis of IPF. The available studies about the pathogenesis of IPF mainly focus on macrophage polarization， epithelial-mesenchymal transition （EMT）， oxidative stress， and autophagy， while few studies systematically explain the principles and links of the pathogeneses. According to the traditional Chinese medicine theory， Qi deficiency and blood stasis and Qi-Yang deficiency are the key pathogeneses of IPF. Therefore， the Chinese medicines or compound prescriptions with the effects of replenishing Qi and activating blood， warming Yang and tonifying Qi， and eliminating stasis and resolving phlegm are often used to treat IPF. Modern pharmacological studies have shown that such medicines play a positive role in inhibiting macrophage polarization， restoring redox balance， inhibiting EMT， and regulating cell autophagy. However， few studies report how Chinese medicines regulate the pathways in the treatment of IPF. By reviewing the latest articles in this field， we elaborate on the pathogenesis of IPF and provide a comprehensive overview of the mechanism of the active ingredients or compound prescriptions of Chinese medicines in regulating IPF. Combining the pathogenesis of IPF with the modulating effects of Chinese medicines， we focus on exploring systemic treatment options for IPF， with a view to providing new ideas for the in-depth study of IPF and the research and development of related drugs.

ZLN005 improves the protective effect of mitochondrial function on alveolar epithelial cell aging by upregulating PGC-1α.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal pulmonary interstitial disease that usually occurs in the elderly. The senescence of alveolar epithelial cells (AECs) is an important mechanism of IPF. The AECs of patients with IPF have lower expression of peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α), which has been shown to play an important role in maintaining mitochondrial morphology and energy metabolism. This study sought to explore the mechanism by which ZLN005 improves mitochondrial function by upregulating PGC-1α to protect AECs from aging. Methods: Western blot was used to detect the expression of PGC-1α, mitochondrial synthesis protein nuclear respiratory factor-1 (NRF-1), and p21WAF1 in the lung tissue of the IPF patients and the mice with bleomycin (BLM)-induced pulmonary fibrosis. A549 cells and mice AEC2 cells were treated with hydrogen peroxide (H2O2) to construct cell senescence models. Cell senescence was detected by senescence-associated beta-galactosidase staining. The mitochondrial respiratory function was measured, including the adenosine triphosphate (ATP) generation, reactive oxygen species (ROS) level, changes in cell membrane potential, and energy metabolism. Using lentivirus as a vector and using gene editing technology to over express (upPGC-1α) and knockdown PGC-1α (shPGC-1α) in the A549 cells. The PGC-1α agonist ZLN005 was used to pretreat the A549 and shPGC-1α A549 cells, and cell aging and mitochondrial respiratory function were observed. Results: The Western blot and immunofluorescence assays showed that the expression of PGC-1α and NRF-1 was decreased in the lung tissues of the IPF patients and BLM-induced mice pulmonary fibrosis model, while the expression of p21WAF1 was increased. The results of the immunofluorescence and mitochondrial function experiments also indicated that the expression of PGC-1α and mitochondrial synthesis protein NRF-1 were decreased in the senescent cells. Further, the mitochondrial morphology was abnormal and the mitochondrial function was impaired. PGC-1α was involved in the AEC senescence by regulating mitochondrial morphology and function. Treatment with the agonist of PGC-1α (i.e., ZLN005) blocked the H2O2-induced cell senescence by enhancing the expression of PGC-1α. Conclusions: These results provide preliminary insights into the potential clinical application of ZLN005 as a novel therapeutic agent for the treatment of IPF.

Safety and tolerability of combination treatment with pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis: a systematic review and meta-analysis.

Background: The role of combination treatments with two antifibrotic agents, pirfenidone and nintedanib, has been not established in idiopathic pulmonary fibrosis (IPF). This study was performed to investigate the safety and tolerability of combination antifibrotic treatment in patients with IPF. Methods: We conducted a proportional meta-analysis and searched PubMed, EMBASE, and the Cochrane Central Register for relevant clinical trials. The primary outcome was the proportion of discontinuation of combination treatment over the treatment period. We also examined the pooled proportions of serious and any adverse drug reactions (ADRs). Results: Four clinical trials involving 191 patients were analyzed. In pooled estimates, 29% of patients discontinued treatment during the study period [95% confidence interval (CI): 17-41%, I2=65.42%]. The pooled proportions of serious and any ADRs were 10% (95% CI: 1-19%; I2=79.13%) and 82% (95% CI: 75-90%; I2=39.20%), respectively. During the follow-up period, gastrointestinal symptoms were the most frequent ADR. Acute exacerbation (AE) of IPF was reported in 7.0% of patients. Conclusions: Our findings showed relatively frequent incidence of discontinuation and ADRs for combination therapy in IPF. Further large-scale, randomized, controlled trials are needed to support our results because of the methodological limitations of the included trials and a scarcity of trials for analysis.

Combining single-cell RNA sequencing data and transcriptomic data to unravel potential mechanisms and signature genes of the progression of idiopathic pulmonary fibrosis to lung adenocarcinoma and predict therapeutic agents.

Patients with idiopathic pulmonary fibrosis (IPF) have a significantly higher prevalence of lung adenocarcinoma (LUAD) than normal subjects, although the underlying association is unclear. The raw data involved were obtained from the Gene Expression Omnibus (GEO) database. Differential expression analysis and weighted gene co-expression network analysis were used to screen for differentially expressed genes (DEGs) and modular signature genes (MSGs). Genes intersecting DEGs and MSGs were considered hub genes for IPF and LUAD. Machine learning algorithms were applied to capture epithelial cell-derived signature genes (EDSGs) shared. External cohort data were exploited to validate the robustness of EDSGs. Immunohistochemical staining and K-M plots were used to denote the prognostic value of EDSGs in LUAD. Based on EDSGs, we constructed a TF-gene-miRNA regulatory network. Molecular docking can validate the strength of action between candidate drugs and EDSGs. Epithelial cells, 650 DEGs, and 1773 MSGs were shared by IPF and LUAD. As for 379 hub genes, we performed pathway and functional enrichment analysis. By analyzing sc-RNA seq data, we identified 1234 marker genes of IPF epithelial cell-derived and 1481 of LUAD. And these genes shared 8 items with 379 hub genes. Through the machine learning algorithms, we further fished TRIM2, S100A14, CYP4B1, LMO7, and SFN. The ROC curves emphasized the significance of EDSGs in predicting the onset of LUAD and IPF. The TF-gene-miRNA network revealed regulatory relationships behind EDSGs. Finally, we predicted appropriate therapeutic agents. Our study preliminarily identified potential mechanisms between IPF and LUAD, which will inform subsequent studies.

A Curious Case of Biopsy-Proven Usual Interstitial Pneumonia.

Usual interstitial pneumonia (UIP) refers to a combination of radiologic and histologic findings, which include patchy interstitial fibrosis with fibroblastic foci and dense acellular collagen that causes architectural distortion due to scarring and honeycomb change with alternating areas of normal lungs. The UIP pattern is not a synonymous term with idiopathic pulmonary fibrosis (IPF). IPF is diagnosed when an etiologic workup has been performed, deemed to be unrevealing, with a radiologic or histologic UIP pattern. While the 2018 American Thoracic Society (ATS)/European Respiratory Society (ERS) guideline categories of UIP help eliminate the need for surgical lung biopsy (SLB) in two categories, i.e., "definite UIP" and "probable UIP," when characterizing a patient in the other categories, clinicians should wary about prolonging SLB in patients to determine the fibrosis pattern. Changes in the treatment and overall prognosis of patients can occur due to SLB confirming a UIP pattern on histology. Here, we report the case of a patient with an indeterminate UIP pattern on high-resolution computed tomography (HRCT) with histopathologic diagnosis of UIP on SLB. With no underlying identifiable cause for the UIP pattern, the patient was diagnosed and managed as IPF, ultimately requiring lung transplantation. This case highlights the importance of pursuing surgical lung biopsy in patients with indeterminate UIP on HRCT scanning to facilitate prompt treatment and guide further management.

Identification and Validation of Genes Exhibiting Dynamic Alterations in Response to Bleomycin-Induced Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) carries a high mortality rate and has a poor prognosis. The pathogenesis of pulmonary fibrosis (PF) is highly related to dysregulation of multiple RNAs. This study aims to identify and validate dysregulated RNAs that exhibited dynamic alterations in response to bleomycin (BLM)-induced PF. The results will provide therapeutic targets for patients suffering from IPF. Whole transcriptomic profiles of BLM-induced PF were obtained through high-throughput RNA sequencing. miRNA profiling was downloaded from GSE45789 database in the Gene Expression Omnibus (GEO). We identified the differentially expressed RNAs (DERNAs) that exhibited dynamic alterations in response to BLM-induced PF. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analysis were conducted to discovery regulatory processes of PF. Weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) analysis, and co-expression analysis were performed to identify key genes and pathogenic pattern during the progression of PF. MiRanda, miRcode, and TargetScan were utilized to predict target relationships in the potential competing endogenous RNA (ceRNA) network. The results were verified by qRT-PCR analysis. In the context of BLM-induced PF, this study identified a total of 167 differentially expressed messenger RNAs (DEmRNAs), 115 differentially expressed long non-coding RNAs (DElncRNAs), 45 differentially expressed circular RNAs (DEcircRNAs), and 87 differentially expressed microRNAs (DEmiRNAs). These RNA molecules showed dynamic alterations in response to BLM-induced PF. These DEmRNAs exhibited a predominant association with the biological processes pertaining to the organization of extracellular matrix. A regulatory network was built in PF, encompassing 31 DEmRNAs, 18 DE lncRNAs, 13 DEcircRNAs, and 13 DEmiRNAs. Several DERNA molecules were subjected to validate using additional BLM-induced PF model. The outcomes of this validation process shown a strong correlation with the results obtained from RNA sequencing analysis. The GSE213001 dataset was utilized to validate the expression levels and diagnostic efficacy of four specific hub mRNAs (CCDC80, CLU, COL5A1, and COL6A3) in individuals diagnosed with PF. In this study, we identified and validated several RNA molecules that exhibited dynamic alternations in response to BLM-induced PF. These dysregulated RNAs participated in the pathogenesis of PF and can be used as therapeutic targets for early-stage IPF. Although more work must be done to confirm the results, our study may provide directions for future studies.