-
Frontiers in Pharmacology 2024A growing population of individuals diagnosed with idiopathic pulmonary fibrosis (IPF) are receiving treatment with nintedanib and pirfenidone. The aim of our study was...
Risk of potential hepatotoxicity from pirfenidone or nintedanib in patients with idiopathic pulmonary fibrosis: results of a retrospective analysis of a large insurance database in Taiwan.
A growing population of individuals diagnosed with idiopathic pulmonary fibrosis (IPF) are receiving treatment with nintedanib and pirfenidone. The aim of our study was to assess the incidence of drug-induced liver injury (DILI) associated with the use of pirfenidone and nintedanib in patients with IPF in Taiwan. We collected a cohort of adult patients diagnosed with IPF between 2017 and 2020. The research outcomes involved assessing the incidence of DILI in patients treated with nintedanib or pirfenidone. Poisson regression analysis was employed to estimate incidence rates, with and without adjustments for covariates, to calculate and present both unadjusted and adjusted incidence rate ratios (IRRs). The risk of DILI was greater in patients who received nintedanib than in those who received pirfenidone during the 1-year follow-up. Patients treated with nintedanib exhibited a heightened risk of DILI based on inpatient diagnoses using specific codes after adjusting for variables such as gender, age group, comorbidities and concomitant medications, with an adjusted incidence rate ratio (aIRR) of 3.62 (95% confidence interval (CI) 1.11-11.78). Similarly, the risk of DILI was elevated in patients treated with nintedanib according to a per-protocol Poisson regression analysis of outcomes identified from inpatient diagnoses using specific codes. This was observed after adjusting for variables including gender, age group, comorbidities, and concomitant medications, with an aIRR of 3.60 (95% CI 1.11-11.72). Data from postmarketing surveillance in Taiwan indicate that patients who received nintedanib have a greater risk of DILI than do those who received pirfenidone.
PubMed: 38384288
DOI: 10.3389/fphar.2024.1309712 -
Ecotoxicology and Environmental Safety Mar 2024Silica nanoparticle (SiNP) exposure induces severe pulmonary inflammation and fibrosis, but the pathogenesis remains unclear, and effective therapies are currently...
Silica-induced macrophage pyroptosis propels pulmonary fibrosis through coordinated activation of relaxin and osteoclast differentiation signaling to reprogram fibroblasts.
Silica nanoparticle (SiNP) exposure induces severe pulmonary inflammation and fibrosis, but the pathogenesis remains unclear, and effective therapies are currently lacking. To explore the mechanism underlying SiNPs-induced pulmonary fibrosis, we constructed in vivo silica exposure animal models and in vitro models of silica-induced macrophage pyroptosis and fibroblast transdifferentiation. We found that SiNP exposure elicits upregulation of pulmonary proteins associated with pyroptosis, including NLRP3, ASC, IL-1β, and GSDMD, while the immunofluorescence staining co-localized NLRP3 and GSDMD with macrophage-specific biomarker F4/80 in silica-exposed lung tissues. However, the NLRP3 inhibitor MCC950 and classical anti-fibrosis drug pirfenidone (PFD) were found to be able to alleviate silica-induced collagen deposition in the lungs. In in vitro studies, we exposed the fibroblast to a conditioned medium from silica-induced pyroptotic macrophages and found enhanced expression of α-SMA, suggesting increased transdifferentiation of fibroblast to myofibroblast. In line with in vivo studies, the combined treatment of MCC950 and PFD was demonstrated to inhibit the expression of α-SMA and attenuate fibroblast transdifferentiation. Mechanistically, we adopted high throughput RNA sequencing on fibroblast with different treatments and found activated signaling of relaxin and osteoclast differentiation pathways, where the expression of the dysregulated genes in these two pathways was examined and found to be consistently altered both in vitro and in vivo. Collectively, our study demonstrates that SiNP exposure induces macrophage pyroptosis, which subsequently causes fibroblast transdifferentiation to myofibroblasts, in which the relaxin and osteoclast differentiation signaling pathways play crucial roles. These findings may provide valuable references for developing new therapies for pulmonary fibrosis.
Topics: Animals; Pulmonary Fibrosis; NLR Family, Pyrin Domain-Containing 3 Protein; Silicon Dioxide; Relaxin; Pyroptosis; Osteoclasts; Fibroblasts; Fibrosis; Macrophages
PubMed: 38377782
DOI: 10.1016/j.ecoenv.2024.116106 -
Mediators of Inflammation 2024As an interstitial fibrosis disease characterized by diffuse alveolitis and structural alveolar disorders, idiopathic pulmonary fibrosis (IPF) has high lethality but...
As an interstitial fibrosis disease characterized by diffuse alveolitis and structural alveolar disorders, idiopathic pulmonary fibrosis (IPF) has high lethality but lacks limited therapeutic drugs. A hospital preparation used for the treatment of viral pneumonia, Qingfei Tongluo mixture (QFTL), is rumored to have protective effects against inflammatory and respiratory disease. This study aims to confirm whether it has a therapeutic effect on bleomycin-induced IPF in rats and to elucidate its mechanism of action. Male SD rats were randomly divided into the following groups: control, model, CQ + QFTL (84 mg/kg chloroquine (CQ) + 3.64 g/kg QFTL), QFTL-L, M, H (3.64, 7.28, and 14.56 g/kg, respectively) and pirfenidone (PFD 420 mg/kg). After induction modeling and drug intervention, blood samples and lung tissue were collected for further detection. Body weight and lung coefficient were examined, combined with hematoxylin and eosin (H&E) and Masson staining to observe lung tissue lesions. The enzyme-linked immunosorbent assay (ELISA) and the hydroxyproline (HYP) assay kit were used to detect changes in proinflammatory factors (transforming growth factor- (TGF-), tumor necrosis factor- (TNF-), and interleukin-1 (IL-1)) and HYP. Immunohistochemistry and Western blotting were performed to observe changes in proteins related to pulmonary fibrosis (-smooth muscle actin (-SMA) and matrix metalloproteinase 12 (MMP12)) and autophagy (P62 and mechanistic target of rapamycin (mTOR)). Treatment with QFTL significantly improved the adverse effects of bleomycin on body weight, lung coefficient, and pathological changes. Then, QFTL reduced bleomycin-induced increases in proinflammatory mediators and HYP. The expression changes of pulmonary fibrosis and autophagy marker proteins are attenuated by QFTL. Furthermore, the autophagy inhibitor CQ significantly reversed the downward trend in HYP levels and -SMA protein expression, which QFTL improved in BLM-induced pulmonary fibrosis rats. In conclusion, QFTL could effectively attenuate bleomycin-induced inflammation and pulmonary fibrosis through mTOR-dependent autophagy in rats. Therefore, QFTL has the potential to be an alternative treatment for IPF in clinical practice.
Topics: Rats; Male; Animals; Pulmonary Fibrosis; Bleomycin; Rats, Sprague-Dawley; Lung; Pneumonia; TOR Serine-Threonine Kinases; Body Weight; Transforming Growth Factor beta1; Drugs, Chinese Herbal
PubMed: 38361765
DOI: 10.1155/2024/5573353 -
BioRxiv : the Preprint Server For... Jan 2024Growing evidence from animal models indicates that the myocardium hosts a population of B cells that play a role in the development of cardiomyopathy. However, there is...
INTRODUCTION
Growing evidence from animal models indicates that the myocardium hosts a population of B cells that play a role in the development of cardiomyopathy. However, there is minimal data on human myocardial B cells in the context of cardiomyopathy.
METHODS
We integrated single-cell and single-nuclei datasets from 45 healthy human hearts, 70 hearts with dilated cardiomyopathy (DCM), and 8 hearts with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). Interactions between B cells and other cell types were investigated using the CellChat Package. Differential gene expression analysis comparing B cells across conditions was performed using DESeq2. Pathway analysis was performed using Ingenuity, KEGG, and GO pathways analysis.
RESULTS
We identified 1,100 B cells, including naive B cells and plasma cells. B cells showed an extensive network of interactions within the healthy myocardium that included outgoing signaling to macrophages, T cells, endothelial cells, and pericytes, and incoming signaling from endothelial cells, pericytes, and fibroblasts. This niche relied on ECM-receptor, contact, and paracrine interaction; and changed significantly in the context of cardiomyopathy, displaying disease-specific features. Differential gene expression analysis showed that in the context of DCM both naive and plasma B cells upregulated several pathways related to immune activation, including upregulation of oxidative phosphorylation, upregulation of leukocyte extravasation, and, in naive B cells, antigen presentation.
DISCUSSION
The human myocardium contains naive B cells and plasma cells, integrated into a diverse and dynamic niche that has distinctive features in healthy myocardium, DCM, and ARVC. Naive myocardial-associated B cells likely contribute to the pathogenesis of human DCM.
PubMed: 38293212
DOI: 10.1101/2023.09.21.558902 -
Alternative Therapies in Health and... Jan 2024This study aimed to evaluate the therapeutic impact of pirfenidone in patients with nonspecific interstitial pneumonia (NSIP) secondary to Sjögren's syndrome, comparing...
OBJECTIVE
This study aimed to evaluate the therapeutic impact of pirfenidone in patients with nonspecific interstitial pneumonia (NSIP) secondary to Sjögren's syndrome, comparing its effectiveness against conventional treatments.
METHODS
A controlled clinical trial was conducted on a cohort of patients diagnosed with primary Sjögren's syndrome complicated by interstitial lung disease. The study included a total of 120 patients, divided equally into two groups: a control group comprising 60 patients and an observation group with another 60 patients. Random assignment placed patients in either a control group receiving hydroxychloroquine and prednisone or an observation group supplemented with pirfenidone. Pulmonary function parameters, Warrick scores from high-resolution CT scans, and Leicester Cough Quality of Life Questionnaire (LCQ) scores were assessed before and after treatment. Adverse reactions were monitored for treatment safety.
RESULTS
Before treatment, no statistically significant differences in pulmonary function indicators (FVC%, FEV1%, DLco%) were observed between the groups (P > .05). Post-treatment, both groups showed significant improvements in these parameters (P < .05). Importantly, the observation group demonstrated superior improvements in pulmonary function compared to the control group (P < .05). Warrick's scores improved significantly in both groups after treatment, with the observation group achieving a more substantial reduction in scores compared to the control group (P < .05). LCQ scores showed no significant differences between the groups before treatment (P > .05). However, after treatment, both groups exhibited significant improvements, with the observation group consistently scoring higher (P < .05). Safety assessments revealed a slightly higher incidence of adverse reactions, including neurosensory abnormality and drowsiness, in the observation group compared to the control group.
CONCLUSIONS
This study suggests that adding pirfenidone to the treatment regimen for NSIP secondary to Sjögren's syndrome leads to significant improvements in pulmonary function, high-resolution CT scores, and quality of life compared to conventional treatments.
PubMed: 38290451
DOI: No ID Found -
The Clinical Respiratory Journal Jan 2024The aim of the study is to observe the anti-inflammatory and antioxidative stress effects of metformin on bleomycin (BLM)-induced pulmonary fibrosis in mice.
BACKGROUND
The aim of the study is to observe the anti-inflammatory and antioxidative stress effects of metformin on bleomycin (BLM)-induced pulmonary fibrosis in mice.
METHODS
Mice with BLM-induced pulmonary fibrosis were treated with pirfenidone, metformin, pirfenidone plus metformin and the NADPH oxidase 4 (NOX4) inhibitor diphenyleneiodonium chloride (DPI). Pathological changes and hydroxyproline (HPO) levels were examined in the lung tissue of mice with pulmonary fibrosis. Superoxide dismutase (SOD) activity and malonaldehyde (MDA) levels in lung tissue were determined.
RESULTS
Compared with pirfenidone, pirfenidone plus metformin could reduce alveolar damage and collagen fibre deposition and alleviate BLM-induced pulmonary fibrosis. Lung HPO levels were significantly lower in the PFD + MET group than in the BLM group (p < 0.05). SOD levels in the lungs of mice were increased in the PFD + MET group than in the BLM group (p < 0.05). Metformin and pirfenidone plus metformin can reduce MDA levels (p < 0.05). Pirfenidone plus metformin could reduce HPO levels, increase SOD levels, and reduce MDA levels in the lungs of mice. There was a significant correlation between the HPO level and the Ashcroft score (r = 0.520, p < 0.001).
CONCLUSION
Metformin enhanced the antifibrotic effects of pirfenidone on BLM-treated mice. Moreover, these findings provide an experimental basis for examining whether metformin can improve the antifibrotic effects of pirfenidone on patients with idiopathic pulmonary fibrosis (IPF). It has broad therapeutic prospects for patients with IPF.
Topics: Humans; Mice; Animals; Metformin; Lung; Idiopathic Pulmonary Fibrosis; Superoxide Dismutase; Mice, Inbred C57BL; Pyridones
PubMed: 38286745
DOI: 10.1111/crj.13731 -
BMC Pulmonary Medicine Jan 2024Randomized controlled trials(RCTs) of multiple drugs for Idiopathic pulmonary fibrosis(IPF) have been reported and achieved a certain degree of efficacy, however, the... (Meta-Analysis)
Meta-Analysis
A comprehensive comparison of the safety and efficacy of drugs in the treatment of idiopathic pulmonary fibrosis: a network meta-analysis based on randomized controlled trials.
OBJECTIVE
Randomized controlled trials(RCTs) of multiple drugs for Idiopathic pulmonary fibrosis(IPF) have been reported and achieved a certain degree of efficacy, however, the difference in safety and efficacy of them for IPF is not yet well understood. The aim of this network meta-analysis is to assess their safety and efficacy in the treatment of IPF and differences in this safety and efficacy comprehensively.
METHODS
The PubMed, EMbase, CENTRAL and MEDLINE were retrieved to find out the RCTs of drugs in the treatment of IPF. The retrieval date is from construction to November 10, 2022. Stata 14.0 and RevMan 5.3 was used for statistical analysis.
REGISTRATION NUMBER
CRD42023385689.
RESULTS
Twenty-four studies with a total of 6208 patients were finally included, including RCTs of 13 drugs. The results of safety showed that there' s no difference in the incidence of SAEs of 13 drugs treated with IPF compared to placebo (P>0.05), and it's also found that Warfarin had a higher all-cause mortality for IPF than placebo (OR = 5.63, 95% CI [1.54 to 20.55]). SUCRA' s scatterplot showed that Pirfenidone, Nintedanib, Sildenafil and Imatinib were lower than placebo, and Warfarin, Ambrisentan and N-acetylcysteine were higher than placebo. The results of effectiveness showed that Nintedanib (MD = -0.08, 95% CI [-0.12 to -0.04]) improved FVC (L)absolute change from baseline in patients better than placebo, and Nintedanib (OR=1.81, 95% CI [1.23 to 2.66]), Pirfenidone (OR=1.85, 95%CI [1.26 to 2.71]) and Pamrevlumab (OR=4.11, 95% CI [1.25 to 13.58]) improved the proportion of patients with a decline in FVC ≥10% predicted better than placebo. SUCRA' s scatterplot showed that Pamrevlumab, Pirfenidone and Nintedanib were lower than placebo, and Warfarin and Ambrisentan were higher than placebo.
CONCLUSION
Compared with other drugs, Nintedanib and Pirfenidone can significantly slow the decline of lung function in patients with IPF, and the safety is higher. Therefore, they can be further promoted in clinical practice. Warfarin and Ambrisentan shouldn't be used clinically for IPF as the safety and efficacy of them are poor compared to other drugs and placebo. Pamrevlumab may become important drugs for the treatment of IPF in the future.
Topics: Humans; Warfarin; Network Meta-Analysis; Treatment Outcome; Randomized Controlled Trials as Topic; Idiopathic Pulmonary Fibrosis; Pyridones; Phenylpropionates; Pyridazines
PubMed: 38281037
DOI: 10.1186/s12890-024-02861-w -
Journal of Translational Medicine Jan 2024Idiopathic pulmonary fibrosis (IPF) is a globally prevalent, progressive disease with limited treatment options and poor prognosis. Because of its irreversible disease... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a globally prevalent, progressive disease with limited treatment options and poor prognosis. Because of its irreversible disease progression, IPF affects the quality and length of life of patients and imposes a significant burden on their families and social healthcare services. The use of the antifibrotic drugs pirfenidone and nintedanib can slow the progression of the disease to some extent, but it does not have a reverse effect on the prognosis. The option of lung transplantion is also limited owing to contraindications to transplantation, possible complications after transplantation, and the risk of death. Therefore, the discovery of new, effective treatment methods is an urgent need. Over recent years, various studies have been undertaken to investigate the relationship between interstitial pneumonia and lung cancer, suggesting that some immune checkpoints in IPF are similar to those in tumors. Immune checkpoints are a class of immunosuppressive molecules that are essential for maintaining autoimmune tolerance and regulating the duration and magnitude of immune responses in peripheral tissues. They can prevent normal tissues from being damaged and destroyed by the immune response. While current studies have focused on PD-1/PD-L1 and CTLA-4, PD-1/PD-L1 may be the only effective immune checkpoint IPF treatment. This review discusses the application of PD-1/PD-L1 checkpoint in IPF, with the aim of finding a new direction for IPF treatment.
Topics: Humans; Programmed Cell Death 1 Receptor; B7-H1 Antigen; Idiopathic Pulmonary Fibrosis; Contraindications; Immune Tolerance
PubMed: 38263193
DOI: 10.1186/s12967-024-04884-7 -
Journal of Personalized Medicine Dec 2023Pulmonary fibrosis, a critical outcome of chronic inflammatory diseases, has gained prominence in the context of post-coronavirus (post-COVID-19) complications. This... (Review)
Review
Pulmonary fibrosis, a critical outcome of chronic inflammatory diseases, has gained prominence in the context of post-coronavirus (post-COVID-19) complications. This review delves into the multifaceted landscape of post-COVID-19 pulmonary fibrosis, elucidating the intricate molecular mechanisms underlying its pathogenesis and highlighting promising therapeutic avenues. Examining the aftermath of severe acute respiratory syndrome-2 (SARS-CoV-2) infection, the review reveals key signaling pathways implicated in the fibrotic cascade. Drawing parallels with previous coronavirus outbreaks enhances our understanding of the distinctive features of post-COVID-19 fibrosis. Antifibrotic drugs, like pirfenidone and nintedanib, take center stage; their mechanisms of action and potential applications in post-COVID-19 cases are thoroughly explored. Beyond the established treatments, this review investigates emerging therapeutic modalities, including anti-interleukin agents, immunosuppressants, and experimental compounds, like buloxybutide, saracatinib, sirolimus, and resveratrol. Emphasizing the critical importance of early intervention, this review highlights the dynamic nature of post-COVID-19 pulmonary fibrosis research. In conclusion, the synthesis of current knowledge offers a foundation for advancing our approaches to the prevention and treatment of these consequential sequelae of COVID-19.
PubMed: 38248752
DOI: 10.3390/jpm14010051 -
Cells Jan 2024Wound repair in the retina is a complex mechanism, and a deeper understanding of it is necessary for the development of effective treatments to slow down or even prevent...
Wound repair in the retina is a complex mechanism, and a deeper understanding of it is necessary for the development of effective treatments to slow down or even prevent degenerative processes leading to photoreceptor loss. In this study, we harnessed a laser-induced retinal degeneration model (532-nm laser photocoagulation with 300 μm spot size, 60 ms duration and 60 mV pulse), enabling a profound molecular elucidation and a comprehensive, prolonged observation of the wound healing sequence in a murine laser-induced degeneration model (C57BL/6J mice, 6-12 weeks) until day 49 post-laser. Our observations included the expression of specific extracellular matrix proteins and myofibroblast activity, along with an analysis of gene expression related to extracellular matrix and adhesion molecules through RNA measurements. Furthermore, the administration of pirfenidone (10 mg/kg via drinking water), an anti-inflammatory and anti-fibrotic compound, was used to modulate scar formation after laser treatment. Our data revealed upregulated collagen expression in late regenerative phases and sustained inflammation in the damaged tissue. Notably, treatment with pirfenidone was found to mitigate scar tissue formation, effectively downregulating collagen production and diminishing the presence of inflammatory markers. However, it did not lead to the regeneration of the photoreceptor layer.
Topics: Animals; Mice; Mice, Inbred C57BL; Cicatrix; Retina; Extracellular Matrix; Inflammation; Eye Injuries; Collagen; Pyridones
PubMed: 38247855
DOI: 10.3390/cells13020164