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Phytomedicine : International Journal... Jul 2024Silicosis presents a significant clinical challenges and economic burdens, with Traditional Chinese Medicine (TCM) emerging as a potential therapeutic avenue. However,...
BACKGROUND
Silicosis presents a significant clinical challenges and economic burdens, with Traditional Chinese Medicine (TCM) emerging as a potential therapeutic avenue. However, the precise effects and mechanisms of TCM in treating silicosis remain uncertain and subject to debate.
OBJECTIVE
The study aims to elucidate the therapeutic role and mechanisms of the Yang-Yin-Qing-Fei Decoction (YYQFD) and its key component, paeoniflorin, in silicosis using a murine model.
METHODS
Silicotic mice were treated with YYQFD, pirfenidone (PFD), or paeoniflorin. RAW264.7 cells and mouse lung fibroblasts (MLF) were stimulated with silica, matrix metalloproteinase-12 (MMP-12), or TGF-β1, followed by treatment with paeoniflorin, PFD, or relevant inhibitors. YYQFD constituents were characterized using High-Performance Liquid Chromatography (HPLC). Lung fibrosis severity was assessed via histopathological examination, micro-CT imaging, lung functions, and Western blot analysis. Transcriptome sequencing and bioinformatics analysis were employed to delineate the gene expression profile and target genes modulated by YYQFD in silicosis.
RESULTS
Treatment with YYQFD ameliorated silica-induced lung fibrosis. Transcriptome sequencing identified MMP-12 as a potential common target of YYQFD and PFD. Additionally, a potential pro-inflammatory role of MMP-12, regulated by silica-induced TLR4 signaling pathways, was revealed. Paeoniflorin, one of the most distinctive compounds in YYQFD, attenuated silica-induced MMP-12 increase and its derived inflammatory factors in macrophages through a direct binding effect. Notably, paeoniflorin treatment exerted anti-fibrotic effects by inhibiting MMP-12-derived inflammatory factors and TGF-β1-induced myofibroblast differentiation in silica-exposed mice.
CONCLUSIONS
This study underscores paeoniflorin as one of the most principal bioactive compounds in YYQFD, highlighting its capacity to attenuate lung inflammation driven by macrophage-derived MMP-12 and reduce lung fibrosis both in vivo and in vitro.
Topics: Animals; Male; Mice; Disease Models, Animal; Drugs, Chinese Herbal; Fibroblasts; Glucosides; Inflammation; Lung; Matrix Metalloproteinase 12; Mice, Inbred C57BL; Monoterpenes; Pulmonary Fibrosis; RAW 264.7 Cells; Silicosis
PubMed: 38669965
DOI: 10.1016/j.phymed.2024.155616 -
BMJ Open Respiratory Research Apr 2024Idiopathic pulmonary fibrosis (IPF) is a rare disorder associated with increased mortality and morbidity. There are currently two drugs approved for IPF but their safety... (Observational Study)
Observational Study
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a rare disorder associated with increased mortality and morbidity. There are currently two drugs approved for IPF but their safety and efficacy profile in real-world settings in Spain is not well understood.
METHODS
An observational, multicentre, prospective study was carried out among patients with IPF who started treatment with pirfenidone or nintedanib from 2015 to 2021. Data regarding clinical characteristics, drug adherence, safety profiles and clinical outcomes between these two drugs were collected.
RESULTS
232 patients were included in the analysis. There were no meaningful differences between both groups at baseline. Patients who started pirfenidone showed a decreased risk for treatment withdrawal compared with those starting nintedanib (HR 0.65 (95% CI 0.46 to 0.94; p=0.002)). Time to first adverse event and all-cause mortality was similar between study groups. Risk factors for withdrawal were female sex, diarrhoea and photosensitivity.
CONCLUSIONS
in this real-world study, both pirfenidone and nintedanib showed similar efficacy profiles. Pirfenidone was associated with less treatment discontinuations due to side effects.
Topics: Humans; Idiopathic Pulmonary Fibrosis; Female; Male; Spain; Pyridones; Prospective Studies; Aged; Indoles; Treatment Outcome; Middle Aged; Antifibrotic Agents; Medication Adherence; Aged, 80 and over
PubMed: 38663886
DOI: 10.1136/bmjresp-2023-001687 -
Advanced Healthcare Materials Apr 2024The intricate tumor microenvironment in triple-negative breast cancer (TNBC) hampers chemotherapy and immunotherapy efficacy due to dense extracellular matrix (ECM) by...
The intricate tumor microenvironment in triple-negative breast cancer (TNBC) hampers chemotherapy and immunotherapy efficacy due to dense extracellular matrix (ECM) by tumor-associated fibroblasts (TAFs). Nanoparticle-based therapies, especially "all-in-one" nanoparticles, have shown great potential in combined drug delivery strategies to reshape the tumor microenvironment and enhance therapeutic efficiency. However, these "all-in-one" nanoparticles suffer from limitations in targeting different target cells, uncontrollable dosing ratio, and disregarding the impact of delivery schedules. This study prepared cell membrane fusion liposomes (TAFsomes and CCMsomes) to load FDA-approved antifibrotic drug pirfenidone (PFD/TAFsomes) and antitumor drug doxorubicin (DOX/CCMsomes). These liposomes can specifically target TAFs cells and tumor cells, and combined administration can effectively inhibit TAFs activity, reshape the tumor microenvironment (TME), and significantly enhance the tumor chemotherapy efficacy. Combined drug delivery defeats "all-in-one" liposomes (DOX/PFD/Liposomes, DOX/PFD/TAFsomes, and DOX/PFD/CCMsomes) by flexibly adjusting the drug delivery ratio. Moreover, an asynchronous delivery strategy that optimizes the administration schedule not only further improves the therapeutic effect, but also amplifies the effectiveness of α-PD-L1 immunotherapy by modulating the tumor immune microenvironment. This delivery strategy provides a personalized treatment approach with clinical translation potential, providing new ideas for enhancing the therapeutic effect against solid tumors such as TNBC.
PubMed: 38657266
DOI: 10.1002/adhm.202400219 -
Heliyon Apr 2024At the beginning of 21st century, reclassification of fibrosing interstitial lung diseases (ILD) scored academic concerning, and then propelled development. Decade...
BACKGROUND
At the beginning of 21st century, reclassification of fibrosing interstitial lung diseases (ILD) scored academic concerning, and then propelled development. Decade before, pifenidone and nintedanib were approved for idiopathic pulmonary fibrosis, but no more drugs are yet available. To evaluate the development traits of pirfenidone and nintedanib in fibrosing ILD, including the influential country, institution, authors, keywords, and the major problems or the priorities of the field emerge and evolve, bibliometric analysis was used to summarize and draw scientific knowledge maps.
METHODS
We confined the words to "pirfenidone", "nintedanib", "pulmonary fibrosis", and "lung disease, interstitial". Publications were retrieved from the Web of Science Core Collection on February 24, 2024 with the search strategies. Citespace and VOSviewer were adopted for bibliometric analysis.
RESULTS
For the knowledge map of pirfenidone, a total of 4359 authors from 279 institutions in 58 countries/regions contributed to 538 studies. The United States and Italy are way ahead. Genentech Inc and the University of Turin are the institutions with the strongest influence. AM J RESP CRIT CARE is the maximized influential periodical. Raghu G was the most frequently co-cited scholar. keywords cluster demonstrated that vital capacity, safety, outcome, effectiveness, acute exacerbation, pathway, cell, collagen were the hotspots. The burst timeline of hotspots and references revealed academic transitions of pirfenidone-related studies. About the knowledge map of nintedanib, 3297 authors from 238 institutions in 47 countries/regions published 374 studies. Japan, the United States, and Italy are the most productive countries. Boehringer Ingelheim is the overriding productive institution. New ENGL J MED have important roles in reporting milestones of nintedanib. Richeldi L carried numerous capital publications to support the anti-fibrotic effect of nintedanib. From the network of co-occurrence keywords, idiopathic pulmonary fibrosis, efficacy, and safety were the hotspots. Nintedanib for systemic sclerosis-related ILD and progressive pulmonary fibrosis is the hotspot with sharp evolution recently.
CONCLUSIONS
We summarized and showed developmental alterations of pirfenidone and nintedanib in fibrosing ILD through bibliographic index-based analysis. Our findings showed just dozen years sharp development period of pirfenidone and nintedanib in ILD, and identifies potential partners for interested researchers. The burst of hotspots demonstrated the evolvement of research priorities and major problems, and we observed the transition of keywords from experimental terms like mouse, bleomycin, cell, pathway, collagen, gene expression, to clinical terms including efficacy, safety, survival, acute exacerbation, and progressive pulmonary fibrosis. In the future, exploration about disparity models of drug administration, differences between early and later initiate anti-fibrotic therapy, both short-term and long-term efficacy of pirfenidone and nintedanib in fibrosing ILD, specifically in connective disease associate ILD would be emphatically concerned by pulmonologists.
PubMed: 38655311
DOI: 10.1016/j.heliyon.2024.e29266 -
Science Progress 2024Idiopathic pulmonary fibrosis is a chronic and progressive interstitial lung disease with a poor prognosis. Idiopathic pulmonary fibrosis is characterized by repeated... (Review)
Review
Idiopathic pulmonary fibrosis is a chronic and progressive interstitial lung disease with a poor prognosis. Idiopathic pulmonary fibrosis is characterized by repeated alveolar epithelial damage leading to abnormal repair. The intercellular microenvironment is disturbed, leading to continuous activation of fibroblasts and myofibroblasts, deposition of extracellular matrix, and ultimately fibrosis. Moreover, pulmonary fibrosis was also found as a COVID-19 complication. Currently, two drugs, pirfenidone and nintedanib, are approved for clinical therapy worldwide. However, they can merely slow the disease's progression rather than rescue it. These two drugs have other limitations, such as lack of efficacy, adverse effects, and poor pharmacokinetics. Consequently, a growing number of molecular therapies have been actively developed. Treatment options for IPF are becoming increasingly available. This article reviews the research platform, including cell and animal models involved in molecular therapy studies of idiopathic pulmonary fibrosis as well as the promising therapeutic targets and their development progress during clinical trials. The former includes patient case/control studies, cell models, and animal models. The latter includes transforming growth factor-beta, vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, lysophosphatidic acid, interleukin-13, Rho-associated coiled-coil forming protein kinase family, and Janus kinases/signal transducers and activators of transcription pathway. We mainly focused on the therapeutic targets that have not only entered clinical trials but were publicly published with their clinical outcomes. Moreover, this work provides an outlook on some promising targets for further validation of their possibilities to cure the disease.
Topics: Idiopathic Pulmonary Fibrosis; Humans; Animals; Molecular Targeted Therapy; Pyridones; Indoles; COVID-19; Disease Models, Animal
PubMed: 38651330
DOI: 10.1177/00368504241247402 -
JAMA May 2024Interstitial lung disease (ILD) consists of a group of pulmonary disorders characterized by inflammation and/or fibrosis of the lung parenchyma associated with... (Review)
Review
IMPORTANCE
Interstitial lung disease (ILD) consists of a group of pulmonary disorders characterized by inflammation and/or fibrosis of the lung parenchyma associated with progressive dyspnea that frequently results in end-stage respiratory failure. In the US, ILD affects approximately 650 000 people and causes approximately 25 000 to 30 000 deaths per year.
OBSERVATIONS
The most common forms of ILD are idiopathic pulmonary fibrosis (IPF), which accounts for approximately one-third of all cases of ILD, hypersensitivity pneumonitis, accounting for 15% of ILD cases, and connective tissue disease (CTD), accounting for 25% of ILD cases. ILD typically presents with dyspnea on exertion. Approximately 30% of patients with ILD report cough. Thoracic computed tomography is approximately 91% sensitive and 71% specific for diagnosing subtypes of ILDs such as IPF. Physiologic assessment provides important prognostic information. A 5% decline in forced vital capacity (FVC) over 12 months is associated with an approximately 2-fold increase in mortality compared with no change in FVC. Antifibrotic therapy with nintedanib or pirfenidone slows annual FVC decline by approximately 44% to 57% in individuals with IPF, scleroderma associated ILD, and in those with progressive pulmonary fibrosis of any cause. For connective tissue disease-associated ILD, immunomodulatory therapy, such as tocilizumab, rituximab, and mycophenolate mofetil, may slow decline or even improve FVC at 12-month follow-up. Structured exercise therapy reduces symptoms and improves 6-minute walk test distance in individuals with dyspnea. Oxygen reduces symptoms and improves quality of life in individuals with ILD who desaturate below 88% on a 6-minute walk test. Lung transplant may improve symptoms and resolve respiratory failure in patients with end-stage ILD. After lung transplant, patients with ILD have a median survival of 5.2 to 6.7 years compared with a median survival of less than 2 years in patients with advanced ILD who do not undergo lung transplant. Up to 85% of individuals with end-stage fibrotic ILD develop pulmonary hypertension. In these patients, treatment with inhaled treprostinil improves walking distance and respiratory symptoms.
CONCLUSIONS AND RELEVANCE
Interstitial lung disease typically presents with dyspnea on exertion and can progress to respiratory failure. First-line therapy includes nintedanib or pirfenidone for IPF and mycophenolate mofetil for ILD due to connective tissue disease. Lung transplant should be considered for patients with advanced ILD. In patients with ILD, exercise training improves 6-minute walk test distance and quality of life.
Topics: Humans; Antifibrotic Agents; Connective Tissue Diseases; Dyspnea; Idiopathic Pulmonary Fibrosis; Indoles; Lung Diseases, Interstitial; Lung Transplantation; Prognosis; Pyridones; Respiratory System Agents; United States; Vital Capacity
PubMed: 38648021
DOI: 10.1001/jama.2024.3669 -
Lung Jun 2024Lung fibrosis is a chronic lung disease with a high mortality rate with only two approved drugs (pirfenidone and nintedanib) to attenuate its progression. To date, there...
BACKGROUND
Lung fibrosis is a chronic lung disease with a high mortality rate with only two approved drugs (pirfenidone and nintedanib) to attenuate its progression. To date, there are no reliable biomarkers to assess fibrosis development and/or treatment effects for these two drugs. Osteoprotegerin (OPG) is used as a serum marker to diagnose liver fibrosis and we have previously shown it associates with lung fibrosis as well.
METHODS
Here we used murine and human precision-cut lung slices to investigate the regulation of OPG in lung tissue to elucidate whether it tracks with (early) fibrosis development and responds to antifibrotic treatment to assess its potential use as a biomarker.
RESULTS
OPG mRNA expression in murine lung slices was higher after treatment with profibrotic cytokines TGFβ1 or IL13, and closely correlated with Fn and PAI1 mRNA expression. More OPG protein was released from fibrotic human lung slices than from the control human slices and from TGFβ1 and IL13-stimulated murine lung slices compared to control murine slices. This OPG release was inhibited when murine slices were treated with pirfenidone or nintedanib. OPG release from human fibrotic lung slices was inhibited by pirfenidone treatment.
CONCLUSION
OPG can already be detected during the early stages of fibrosis development and responds, both in early- and late-stage fibrosis, to treatment with antifibrotic drugs currently on the market for lung fibrosis. Therefore, OPG should be further investigated as a potential biomarker for lung fibrosis and a potential surrogate marker for treatment effect.
Topics: Animals; Osteoprotegerin; Humans; Indoles; Biomarkers; Transforming Growth Factor beta1; Lung; Pulmonary Fibrosis; Pyridones; Mice; Antifibrotic Agents; Mice, Inbred C57BL; Male; RNA, Messenger
PubMed: 38642135
DOI: 10.1007/s00408-024-00691-5 -
BMC Pulmonary Medicine Apr 2024Dyspnea impairs quality of life (QOL) in patients with fibrotic hypersensitivity pneumonitis (FHP). The Living with Pulmonary Fibrosis questionnaire (L-PF) assesses...
BACKGROUND
Dyspnea impairs quality of life (QOL) in patients with fibrotic hypersensitivity pneumonitis (FHP). The Living with Pulmonary Fibrosis questionnaire (L-PF) assesses symptoms, their impacts and PF-related QOL in patients with any form of PF. Its scores have not undergone validation analyses in an FHP cohort.
METHODS
We used data from the Pirfenidone in FHP trial to examine reliability, validity and responsiveness of the L-PF-35 Dyspnea domain score (Dyspnea) and to estimate its meaningful within-patient change (MWPC) threshold for worsening. Lack of suitable anchors precluded conducting analyses for other L-PF-35 scores.
RESULTS
At baseline, Dyspnea's internal consistency (Cronbach's coefficient alpha) was 0.85; there were significant correlations with all four anchors (University of California San Diego Shortness of Breath Questionnaire scores r = 0.81, St. George's Activity domain score r = 0.82, percent predicted forced vital capacity r = 0.37, and percent predicted diffusing capacity of the lung for carbon monoxide r = 0.37). Dyspnea was significantly different between anchor subgroups (e.g., lowest percent predicted forced vital capacity (FVC%) vs. highest, 33.5 ± 18.5 vs. 11.1 ± 9.8, p = 0.01). There were significant correlations between changes in Dyspnea and changes in anchor scores at all trial time points. Longitudinal models further confirmed responsiveness. The MWPC threshold estimate for worsening was 6.6 points (range 5-8).
CONCLUSION
The L-PF-35 Dyspnea domain appears to possess acceptable psychometric properties for assessing dyspnea in patients with FHP. Because instrument validation is never accomplished with one study, additional research is needed to build on the foundation these analyses provide.
TRIAL REGISTRATION
The data for the analyses presented in this manuscript were generated in a trial registered on ClinicalTrials.gov; the identifier was NCT02958917.
Topics: Humans; Quality of Life; Reproducibility of Results; Lung; Dyspnea; Surveys and Questionnaires; Alveolitis, Extrinsic Allergic
PubMed: 38641768
DOI: 10.1186/s12890-024-02991-1 -
Medicine Apr 2024Immune checkpoint inhibitor pneumonitis (ICIP) is thought to be a self-limiting disease; however, an effective treatment option does not currently exist. This study...
Immune checkpoint inhibitor pneumonitis (ICIP) is thought to be a self-limiting disease; however, an effective treatment option does not currently exist. This study aimed to determine the clinical efficacy of combination therapy with glucocorticoids and pirfenidone for ICIP related to programmed cell death protein-1 (PD-1) inhibitors. We conducted a retrospective analysis of 45 patients with advanced non-small cell lung cancer who developed ICIP following PD-1 inhibitor and albumin-bound paclitaxel or carboplatin treatment at our hospital. The PD-1 inhibitor was discontinued, and glucocorticoids were used alone or in combination with pirfenidone to treat ICIP. The relevant clinical data of these patients were collected and analyzed. Compared with the glucocorticoid alone group, the glucocorticoid-pirfenidone group showed significant improvement in forced vital capacity (FVC), carbon monoxide diffusing capacity [%], peripheral capillary oxygen saturation, and 6-minute walk distance (P < .05). There were benefits with respect to the St. George's Respiratory Questionnaire score and the recurrence rate of ICIP, but there was no significant difference between the 2 groups (P > .05). Adding pirfenidone to glucocorticoid treatment was shown to be safe and may be more beneficial than glucocorticoids alone for improving pulmonary interstitial lesions, reversing ICIP, and preventing its recurrence.
Topics: Humans; Retrospective Studies; Immune Checkpoint Inhibitors; Idiopathic Pulmonary Fibrosis; Glucocorticoids; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Treatment Outcome; Pyridones; Pneumonia
PubMed: 38640289
DOI: 10.1097/MD.0000000000037808 -
Scientific Reports Apr 2024Pirfenidone (PFD), one acceptable medication for treating idiopathic pulmonary fibrosis (IPF), is not well tolerated by patients at full doses. Hence, employing of some...
Pirfenidone (PFD), one acceptable medication for treating idiopathic pulmonary fibrosis (IPF), is not well tolerated by patients at full doses. Hence, employing of some approaches such as combination therapy may be applicable for increasing therapeutic efficacy of PFD. Losartan (LOS), an angiotensin II receptor antagonist, could be a suitable candidate for combination therapy because of its stabilizing effect on the pulmonary function of IPF patients. Therefore, this study aimed to investigate the effects of LOS in combination with PFD on bleomycin (BLM)-induced lung fibrosis in rats. BLM-exposed rats were treated with LOS alone or in combination with PFD. The edema, pathological changes, level of transforming growth factor-β (TGF-β1), collagen content, and oxidative stress parameters were assessed in the lung tissues. Following BLM exposure, the inflammatory response, collagen levels, and antioxidant markers in rat lung tissues were significantly improved by PFD, and these effects were improved by combination with LOS. The findings of this in vivo study suggest that the combined administration of PFD and LOS may provide more potent protection against IPF than single therapy through boosting its anti-inflammatory, anti-fibrotic, and anti-oxidant effects. These results hold promise in developing a more effective therapeutic strategy for treating of lung fibrosis.
Topics: Humans; Rats; Animals; Losartan; Bleomycin; Lung; Idiopathic Pulmonary Fibrosis; Antioxidants; Transforming Growth Factor beta1; Collagen; Pyridones
PubMed: 38622264
DOI: 10.1038/s41598-024-59395-8