Effect Of Nintedanib Research Articles

Polymeric Polylactic Acid-Glycolic Acid-Based Nanoparticles Deliver Nintedanib Across the Blood-Brain Barrier to Inhibit Glioblastoma Growth.

The aim of this study was to investigate the inhibitory effect of nintedanib (BIBF) on glioblastoma (GBM) cells and its mechanism of action and to optimize a drug delivery strategy to overcome the limitations posed by the blood-brain barrier (BBB). We analyzed the inhibition of GBM cell lines following BIBF treatment and explored its effect on the autophagy pathway. The cytotoxicity of BIBF was assessed using the CCK-8 assay, and further techniques such as transmission electron microscopy, Western blotting (WB), and flow cytometry were employed to demonstrate that BIBF could block the autophagic pathway by inhibiting the fusion of autophagosomes and lysosomes, ultimately limiting the proliferation of GBM cells. Molecular docking and surface plasmon resonance (SPR) experiments indicated that BIBF specifically binds to the autophagy-associated protein VPS18, interfering with its function and inhibiting the normal progression of autophagy. However, the application of BIBF in GBM therapy is limited due to restricted drug penetration across the BBB. Therefore, this study utilized poly-lactic-co-glycolic acid (PLGA) nanocarriers as a drug delivery system to significantly enhance the delivery efficiency of BIBF in vivo. In vitro cellular experiments and in vivo animal model validation demonstrated that PLGA-BIBF NPs effectively overcame the limitations of the BBB, significantly enhanced the antitumor activity of BIBF, and improved therapeutic efficacy in a GBM BALB/c-Nude model. This study demonstrated that BIBF exerted significant inhibitory effects on GBM cells by binding to VPS18 and inhibiting the autophagy pathway. Combined with the PLGA nanocarrier delivery system, the blood-brain barrier permeability and anti-tumor effect of BIBF were significantly enhanced. Targeting the BIBF-VPS18 pathway and optimizing drug delivery through nanotechnology may represent a new strategy for GBM treatment, providing innovative clinical treatment ideas and a theoretical basis for patients with GBM.

Reduced tracheal stenosing effect of nintedanib in a patient with scarred posttraumatic tracheal stenosis and airflow limitation- A case report

Reduced tracheal stenosing effect of nintedanib in a patient with scarred posttraumatic tracheal stenosis and airflow limitation- A case report

Real-World Safety, Tolerability and Effectiveness of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis: Final Report of Post-marketing Surveillance in Japan.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial pneumonia, which is characterised by progressive worsening of dyspnoea and lung function. Nintedanib treatment is recommended to slow IPF disease progression. The aim of this post-marketing surveillance (PMS) study was to evaluate the safety and effectiveness of nintedanib over 24months in patients with IPF in a real-world setting in Japan. This prospective, non-interventional, all-case PMS study of nintedanib included Japanese patients with IPF who started nintedanib between 7 October 2015 and 2 May 2023. The primary outcome was to determine the proportion of patients with adverse drug reactions (ADRs), and the secondary outcome was the adjusted absolute change from baseline in forced vital capacity (FVC) at 24months. In total, 5717 patients from 1013 institutions were included in the safety analysis (mean±standard deviation age 71.7±8.1years, 78.1% male, 70.8% current or former smokers). Most patients (83.9%) had initiated nintedanib at a dose of 150mg capsules twice daily. At 24months, 2841 patients (64.8%) had discontinued nintedanib, mainly due to adverse events (44.0%), ADRs (24.1%) or insufficient effectiveness (5.7%). The most common ADRs were diarrhoea (35.5%), hepatic function abnormal (14.4%), decreased appetite (9.9%), liver disorders (7.8%) and nausea (5.8%). The adjusted absolute mean change in FVC from baseline to 24months was-212.3mL (95% confidence interval-235.3,-189.3). This is the largest prospective study to investigate patients with IPF who were treated with nintedanib. The safety and effectiveness of nintedanib treatment in this real-world setting of Japanese patients with IPF was similar to that reported in previous studies. Nintedanib effectively slowed the progression of IPF. No new safety concerns were identified, and the need for appropriate management of hepatic disorders and diarrhoea (as per the approved product information) was confirmed. ClinicalTrials.gov (NCT02607722)/European Union electronic register of Post-Authorisation Studies (EUPAS10891).

Nintedanib in Rheumatoid Arthritis-Related Interstitial Lung Disease: Real-World Safety Profile and Risk of Side Effects and Discontinuation.

Some concerns remain about the safety of nintedanib in patients with rheumatoid arthritis-related interstitial lung disease (RA-ILD), such as in the presence of comorbidities or in combination with biologic, targeted synthetic, and/or conventional synthetic disease-modifying antirheumatic drugs (DMARDs). In this multicenter study, we retrospectively evaluated the safety of nintedanib in a real-world population of patients with RA-ILD from the Italian Group for the Study of Early Arthritis (GISEA) registry and the possible role of comorbidities and DMARDs on drug safety and withdrawal. Our secondary aim was to investigate the causes of nintedanib discontinuation. Sixty-five patients treated with nintedanib in accordance with the current therapeutic indications were enrolled in the study. Nintedanib was prescribed in combination with DMARDs and/or steroids in 62 patients (95.4%). The 12-month retention rate of nintedanib was 76.7% and the drug was effective in about 80% of patients with ≥ 6 months of follow-up. Adverse events (AEs) were recorded in 36 subjects (55.3%), and these were mainly gastroenteric. Thirty-one subjects required a reduction of the nintedanib dose; among them, a transient or permanent reduction of the daily dose of nintedanib allowed the continuation of the treatment in 22, whereas 15 (23.1%) withdrew from the drug. All reductions and discontinuations were owing to treatment-related AEs. Comorbidities were significantly associated with side effects in multivariate analysis, whereas AEs due to nintedanib were the main cause of discontinuation. Combination therapy with DMARDs did not reduce the safety and effectiveness of nintedanib, and AEs were the main cause of drug withdrawal or dose reduction, mainly owing to comorbidities.

Multiscale computational model predicts how environmental changes and treatments affect microvascular remodeling in fibrotic disease.

Investigating the molecular, cellular, and tissue-level changes caused by disease, and the effects of pharmacological treatments across these biological scales, necessitates the use of multiscale computational modeling in combination with experimentation. Many diseases dynamically alter the tissue microenvironment in ways that trigger microvascular network remodeling, which leads to the expansion or regression of microvessel networks. When microvessels undergo remodeling in idiopathic pulmonary fibrosis (IPF), functional gas exchange is impaired and lung function declines. We integrated a multiscale computational model with independent experiments to investigate how combinations of biomechanical and biochemical cues in IPF alter cell fate decisions leading to microvascular remodeling. Our computational model predicted that extracellular matrix (ECM) stiffening reduced microvessel area, which was accompanied by physical uncoupling of endothelial cell (EC) and pericytes, the cells that comprise microvessels. Nintedanib, an Food and Drug Administration-approved drug for treating IPF, was predicted to further potentiate microvessel regression by decreasing the percentage of quiescent pericytes while increasing the percentage of pericytes undergoing pericyte-myofibroblast transition in high ECM stiffnesses. Importantly, the model suggested that YAP/TAZ inhibition may overcome the deleterious effects of nintedanib by promoting EC-pericyte coupling and maintaining microvessel homeostasis. Overall, our combination of computational and experimental modeling can predict and explain how cell decisions affect tissue changes during disease and in response to treatments.

Aberrant Activation of Wound-Healing Programs within the Metastatic Niche Facilitates Lung Colonization by Osteosarcoma Cells.

Lung metastasis is responsible for nearly all deaths caused by osteosarcoma, the most common pediatric bone tumor. How malignant bone cells coerce the lung microenvironment to support metastatic growth is unclear. The purpose of this study is to identify metastasis-specific therapeutic vulnerabilities by delineating the cellular and molecular mechanisms underlying osteosarcoma lung metastatic niche formation. Using single-cell RNA sequencing, we characterized genome- and tissue-wide molecular changes induced within lung tissues by disseminated osteosarcoma cells in both immunocompetent murine models of metastasis and patient samples. We confirmed transcriptomic findings at the protein level and determined spatial relationships with multiparameter immunofluorescence and spatial transcriptomics. Based on these findings, we evaluated the ability of nintedanib, a kinase inhibitor used to treat patients with pulmonary fibrosis, to impair metastasis progression in both immunocompetent murine osteosarcoma and immunodeficient human xenograft models. Single-nucleus and spatial transcriptomics were used to perform molecular pharmacodynamic studies that define the effects of nintedanib on tumor and nontumor cells within the metastatic microenvironment. Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. Single-cell RNA sequencing demonstrated that the surrounding lung stroma adopts a chronic, nonresolving wound-healing phenotype similar to that seen in other models of lung injury. Accordingly, the metastasis-associated lung demonstrated marked fibrosis, likely because of the accumulation of pathogenic, profibrotic, partially differentiated epithelial intermediates and macrophages. Our data demonstrated that nintedanib prevented metastatic progression in multiple murine and human xenograft models by inhibiting osteosarcoma-induced fibrosis. Fibrosis represents a targetable vulnerability to block the progression of osteosarcoma lung metastasis. Our data support a model wherein interactions between osteosarcoma cells and epithelial cells create a prometastatic niche by inducing tumor deposition of extracellular matrix proteins such as fibronectin that is disrupted by the antifibrotic tyrosine kinase inhibitor (TKI) nintedanib. Our data shed light on the non-cell-autonomous effects of TKIs on metastasis and provide a roadmap for using single-cell and spatial transcriptomics to define the mechanism of action of TKI on metastases in animal models.

Design of a randomised controlled hybrid trial of nintedanib in patients with progressive myositis-associated interstitial lung disease.

The Myositis Interstitial Lung Disease Nintedanib Trial (MINT) is a hybrid trial, which is enrolling patients both at local sites and remotely via a decentralised site. The trial will investigate the efficacy and safety of nintedanib in patients with progressive myositis-associated interstitial lung disease (MA-ILD). MINT is an exploratory, prospective randomised placebo-controlled trial. Eligible patients will have myositis and evidence of fibrosing ILD on high-resolution computed tomography (HRCT), be taking standard of care medications for myositis, and meet criteria for ILD progression within the prior 24months based on decline in FVC, worsened fibrosis on HRCT, and/or worsened dyspnoea. Patients will be randomised 1:1 to receive nintedanib 150mg twice daily or placebo for 12weeks then open-label nintedanib for 12weeks. Patients will be enrolled at local sites and a decentralised site. Most study visits will be completed remotely using telemedicine or digital health technologies. The primary endpoint is the change in Living with Pulmonary Fibrosis (L-PF) questionnaire dyspnoea domain score at week 12. Other endpoints include changes in other L-PF questionnaire domains, lung function, imaging, and physical activity, and assessment of adverse events. Data collected using remote versus clinic enrolment, and using home versus clinic spirometry, will be compared. MINT is an innovative, hybrid trial that will evaluate the effects of nintedanib on symptoms, quality of life, and ILD progression in patients with progressive MA-ILD and provide valuable information on the utility of decentralised recruitment and remote data collection in clinical trials. Clinicaltrials.gov NCT05799755 (date of registration: 05/04/2023).

Neutrophil extracellular traps as immunofibrotic mediators in RA-ILD; pilot evaluation of the nintedanib therapy.

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a significant pulmonary complication of RA. This study tried to elucidate the mechanisms enhancing inflammation and causing lung injury in RA-ILD, focusing on the role of neutrophil extracellular traps (NETs). The study also investigated the potential benefits of nintedanib in advanced disease. Nine RA-ILD patients and nine healthy controls were included in the study. Inflammatory markers in patients' circulation were evaluated with immunoassays. The formation of NETs was examined using a citrullinated histone H3 (CitH3) ELISA and cell immunofluorescence. Inflammatory proteins expressed in neutrophils/NETs were studied with real-time qPCR and NET ELISA. To assess the effect of nintedanib, an intracellular tyrosine kinase inhibitor with antifibrotic properties, in RA-ILD a paired study was conducted in five patients before treatment administration and 16 weeks later. The soluble terminal complement complex sC5b-9 and the levels of CitH3 were significantly elevated in patients with RA-ILD, compared to healthy controls. In addition, neutrophils isolated from RA-ILD patients released NETs enriched with tissue factor and interleukin-17A. Inflammatory NETs had a dynamic role, increasing the fibrotic potential of human pulmonary fibroblasts (HPFs). On the other hand, nintedanib treatment decreased NETs and sC5b-9 levels in RA-ILD patients. The findings propose an interplay between circulating NETs and HPFs, establishing the immunofibrotic aspects of RA-ILD. They also support the effectiveness of nintedanib in reducing key pathological processes of the disease. Further research is needed to fully understand these mechanisms and optimize treatment strategies for RA-ILD.

Short- and long-term clinical outcomes of nintedanib therapy in IPF patients with different phenotypes: A retrospective registry-based study

BackgroundThere is a lack of data on the long-term effect of nintedanib on survival in specific groups of idiopathic pulmonary fibrosis (IPF) patients with different phenotypes. We investigated the outcomes of nintedanib therapy in an observational study of a large multicentre real-world cohort of IPF patients with various initial characteristics. MethodsThe analysis included IPF patients treated with nintedanib (NIN) and IPF patients not receiving antifibrotic treatment (NAF) enrolled for the EMPIRE registry in 2015–2020. The patients were stratified according to their initial FVC predicted, dyspnoea, UIP pattern and age. All-cause mortality and annual rate of FVC decline were the main endpoints. Cox proportional hazards model for survival assessment and linear mixed-effects model for FVC decline modelling were used. ResultsA total of 869 NIN patients and 691 NAF patients were eligible for the analysis. The annual FVC decline rate was significantly different (adjusted values −0.053 l/yr vs −0.122 l/yr; p = 0.001). The adjusted hazard ratio (HR) for mortality was 0.40 (95 % CI 0.3 to 0.53, p < 0.001). The most significant effect of nintedanib was demonstrated in patients with impaired lung function, i.e., with an FVC predicted to be less than 80 % and a NYHA II to IV. Nintedanib therapy also reduced the difference in survival between men and women. ConclusionsModelling confirmed that NIN therapy reduced differences in OS between patients with better and worse initial conditions and prognosis. Our results indicate that NIN is particularly beneficial for patients with advanced IPF and more severe phenotypes. Trial registrationEMPIRE was registered as a non-interventional post-registration study at the State Institute for Drug Control of the Czech Republic under ID 1412080000 on December 8, 2014.

Effects of nintedanib on circulating biomarkers of idiopathic pulmonary fibrosis.

Biomarkers that change in response to nintedanib in subjects with idiopathic pulmonary fibrosis (IPF) would be valuable. We investigated the effects of nintedanib on circulating biomarkers in subjects with IPF in the INMARK trial. Subjects with IPF were randomised 1:2 to receive nintedanib 150 mg twice daily or placebo for 12 weeks, after which all patients received open-label nintedanib for 40 weeks. Fold changes in adjusted mean levels of circulating biomarkers were analysed using a linear mixed model for repeated measures. 346 subjects were treated (116 randomised to nintedanib, 230 to placebo). Surfactant protein D (SP-D) and cancer antigen 125 (CA-125), markers of epithelial injury, decreased in subjects treated with nintedanib versus placebo. Fold changes from baseline in SP-D at week 12 corresponded to a 4% decrease and 3% increase in the nintedanib and placebo groups, respectively (ratio 0.94, 95% CI 0.89-0.99; p=0.024). Fold changes in CA-125 at week 12 corresponded to a 22% decrease and 4% increase in the nintedanib and placebo groups, respectively (ratio 0.75, 95% CI 0.71-0.81; p<0.0001). A mediation analysis suggested that 42.1% of the effect of nintedanib on change in forced vital capacity over 12 weeks was attributable to the change in CA-125. A small increase in C3A (collagen 3 degraded by ADAMTS-1/4/8) and a small decrease in C3M (collagen 3 degraded by matrix metalloproteinase-9), markers of extracellular matrix turnover, were observed in subjects treated with nintedanib versus placebo. Effects of nintedanib on circulating markers of epithelial dysfunction and collagen degradation, most notably CA-125, were observed in patients with IPF.

Renewable Therapy Potential of Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells for Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a rare chronic respiratory disease characterized by progressive fibrotic changes in lung tissue of unknown origin, resulting in severe decline in lung function and poor prognosis with a median survival of 3 to 5 years. Current pharmacological therapies, including nintedanib and pirfenidone, aim to slow disease progression but are limited by side effects and lack of efficacy in reversing established fibrosis. This literature review explores emerging therapeutic approaches for IPF using data from PubMed, Google Scholar, and ScienceDirect databases. The review highlights mesenchymal stem cell (MSC) therapy, specifically allogeneic bone marrow-derived MSCs, as a promising option. MSC therapy demonstrates superior efficacy in improving forced vital capacity (FVC) by 3.7%, surpassing the effects of nintedanib (3.3%) and pirfenidone (-4.8%), while exhibiting minimal adverse effects. The findings underscore the potential of MSC therapy as a renewable treatment option for IPF, suggesting a paradigm shift towards addressing both disease progression and lung function restoration in affected individuals.

The effect of nintedanib on health-related quality of life in Japanese patients with progressive fibrosing interstitial lung diseases: A subset analysis of the INBUILD trial

BackgroundIn previous Japanese subgroup/subset analyses of the global INBUILD trial, nintedanib reduced the annual rate of forced vital capacity (FVC) decline and the risk of disease progression in patients with progressive fibrosing interstitial lung diseases (PF-ILDs). This exploratory subset analysis assessed the effect of nintedanib on symptoms and impacts of pulmonary fibrosis in Japanese patients with PF-ILDs, including those with usual interstitial pneumonia (UIP)-like fibrotic pattern on high-resolution computed tomography (HRCT). MethodsThis analysis included Japanese patients who received at least one dose of study treatment in the randomized, double-blind, placebo-controlled INBUILD trial. The Living with Pulmonary Fibrosis (L-PF) questionnaire was used to assess pulmonary fibrosis symptoms and impacts (higher scores indicated greater impairment) at baseline and weeks 12–52. ResultsIn total, 108 Japanese patients (nintedanib: n = 52; placebo: n = 56) were included; 84 patients had UIP-like fibrotic pattern on HRCT. In the total Japanese subgroup and in those with UIP-like fibrotic pattern, numerically greater increases in L-PF total, symptoms total, symptoms fatigue domain, and impacts scores were observed in the placebo group than in the nintedanib group at all timepoints, starting from week 12. A numerically greater increase in the symptoms dyspnea domain score was observed with placebo versus nintedanib starting from week 36. Throughout the study, the symptoms cough domain score increased in the placebo group but decreased in the nintedanib group. ConclusionsOur findings demonstrate that nintedanib has the potential to reduce the worsening of symptoms and impacts of pulmonary fibrosis in Japanese patients with PF-ILDs.

Bibliometric analysis of the pirfenidone and nintedanib in interstitial lung diseases

BackgroundAt 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. MethodsWe 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. ResultsFor 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. ConclusionsWe 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.

Pirfenidone and nintedanib attenuates pulmonary artery endothelial and smooth muscle cells transformations induced by IL-11

Idiopathic pulmonary fibrosis (IPF) associated to pulmonary hypertension (PH) portends a poor prognosis, characterized by lung parenchyma fibrosis and pulmonary artery remodeling. Serum and parenchyma levels of Interleukin 11 (IL-11) are elevated in IPF-PH patients and contributes to pulmonary artery remodeling and PH. However, the effect of current approved therapies against IPF in pulmonary artery remodeling induced by IL-11 is unknown. The aim of this study is to analyze the effects of nintedanib and pirfenidone on pulmonary artery endothelial and smooth muscle cell remodeling induced by IL-11 in vitro. Our results show that nintedanib (NTD) and pirfenidone (PFD) ameliorates endothelial to mesenchymal transition (EnMT), pulmonary artery smooth muscle cell to myofibroblast-like transformation and pulmonary remodeling in precision lung cut slices. This study provided also evidence of the inhibitory effect of PFD and NTD on IL-11-induced endothelial and muscle cells proliferation and senescence. The inhibitory effect of these drugs on monocyte arrest and angiogenesis was also studied. Finally, we observed that IL-11 induced canonical signal transducer and activator of transcription 3 (STAT3) and non-canonical mitogen-activated protein kinase 1/2 (ERK1/2) phosphorylation, but, PFD and NTD only inhibited ERK1/2 phosphorylation. Therefore, this study provided evidence of the inhibitory effect of NTD and PFD on markers of pulmonary artery remodeling induced by IL-11.

Nintedanib downregulates the profibrotic M2 phenotype in cultured monocyte-derived macrophages obtained from systemic sclerosis patients affected by interstitial lung disease

BackgroundSystemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by vasculopathy and progressive fibrosis of skin and several internal organs, including lungs. Macrophages are the main cells involved in the immune-inflammatory damage of skin and lungs, and alternatively activated (M2) macrophages seem to have a profibrotic role through the release of profibrotic cytokines (IL10) and growth factors (TGFβ1). Nintedanib is a tyrosine kinase inhibitor targeting several fibrotic mediators and it is approved for the treatment of SSc-related interstitial lung disease (ILD). The study aimed to evaluate the effect of nintedanib in downregulating the profibrotic M2 phenotype in cultured monocyte-derived macrophages (MDMs) obtained from SSc-ILD patients.MethodsFourteen SSc patients, fulfilling the 2013 ACR/EULAR criteria for SSc, 10 SSc patients affected by ILD (SSc-ILD pts), 4 SSc patients non affected by ILD (SSc pts no-ILD), and 5 voluntary healthy subjects (HSs), were recruited at the Division of Clinical Rheumatology-University of Genova, after obtaining Ethical Committee approval and patients’ informed consent. Monocytes were isolated from peripheral blood, differentiated into MDMs, and then maintained in growth medium without any treatment (untreated cells), or treated with nintedanib (0.1 and 1µM) for 3, 16, and 24 h. Gene expression of macrophage scavenger receptors (CD204, CD163), mannose receptor-1 (CD206), Mer tyrosine kinase (MerTK), identifying M2 macrophages, together with TGFβ1 and IL10, were evaluated by quantitative real-time polymerase chain reaction. Protein synthesis was investigated by Western blotting and the level of active TGFβ1 was evaluated by ELISA. Statistical analysis was carried out using non-parametric Wilcoxon test.ResultsCultured untreated SSc-ILD MDMs showed a significant increased protein synthesis of CD206 (p < 0.05), CD204, and MerTK (p < 0.01), together with a significant upregulation of the gene expression of MerTK and TGFβ1 (p < 0.05; p < 0.01) compared to HS-MDMs. Moreover, the protein synthesis of CD206 and MerTK and the gene expression of TGFβ1 were significantly higher in cultured untreated MDMs from SSc-ILD pts compared to MDMs without ILD (p < 0.05; p < 0.01). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly downregulated the gene expression and protein synthesis of CD204, CD206, CD163 (p < 0.05), and MerTK (p < 0.01) compared to untreated cells after 24 h of treatment. Limited to MerTK and IL10, both nintedanib concentrations significantly downregulated their gene expression already after 16 h of treatment (p < 0.05). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly reduced the release of active TGFβ1 after 24 h of treatment (p < 0.05 vs. untreated cells).ConclusionsIn cultured MDMs from SSc-ILD pts, nintedanib seems to downregulate the profibrotic M2 phenotype through the significant reduction of gene expression and protein synthesis of M2 cell surface markers, together with the significant reduction of TGFβ1 release, and notably MerTK, a tyrosine kinase receptor involved in lung fibrosis.

Aberrant TIMP-1 production in tumor-associated fibroblasts drives the selective benefits of nintedanib in lung adenocarcinoma.

The fibrotic tumor microenvironment is a pivotal therapeutic target. Nintedanib, a clinically approved multikinase antifibrotic inhibitor, is effective against lung adenocarcinoma (ADC) but not squamous cell carcinoma (SCC). Previous studies have implicated the secretome of tumor-associated fibroblasts (TAFs) in the selective effects of nintedanib in ADC, but the driving factor(s) remained unidentified. Here we examined the role of tissue inhibitor of metalloproteinase-1 (TIMP-1), a tumor-promoting cytokine overproduced in ADC-TAFs. To this aim, we combined genetic approaches with invitro and invivo preclinical models based on patient-derived TAFs. Nintedanib reduced TIMP-1 production more efficiently in ADC-TAFs than SCC-TAFs through a SMAD3-dependent mechanism. Cell culture experiments indicated that silencing TIMP1 in ADC-TAFs abolished the therapeutic effects of nintedanib on cancer cell growth and invasion, which were otherwise enhanced by the TAF secretome. Consistently, co-injecting ADC cells with TIMP1-knockdown ADC-TAFs into immunocompromised mice elicited a less effective reduction of tumor growth and invasion under nintedanib treatment compared to tumors bearing unmodified fibroblasts. Our results unveil a key mechanism underlying the selective mode of action of nintedanib in ADC based on the excessive production of TIMP-1 in ADC-TAFs. We further pinpoint reduced SMAD3 expression and consequent limited TIMP-1 production in SCC-TAFs as key for the resistance of SCC to nintedanib. These observations strongly support the emerging role of TIMP-1 as a critical regulator of therapy response in solid tumors.

Effects of Nintedanib on the Lungs via NLRP3 in a Model of Lipopolysaccharide-induced Acute Lung Injury in Rats

Effects of Nintedanib on the Lungs via NLRP3 in a Model of Lipopolysaccharide-induced Acute Lung Injury in Rats

Proteomic study on nintedanib in gastric cancer cells.

Gastric cancer is a very common gastrointestinal tumor with a high mortality rate. Nintedanib has been shown to significantly reduce tumor cell proliferation and increase apoptosis in gastric cancer cells in vitro. However, its systemic action mechanism on gastric cancer cells remains unclear. A high-throughput proteomic approach should help identify the potential mechanisms and targets of nintedanib on gastric cancer cells. The effects of nintedanib on the biological behavior of gastric cancer cells were evaluated. A cytotoxic proliferation assay was performed to estimate the half maximal inhibitory concentration (IC50). AGS cells were divided into control, and nintedanib-treated groups (5 µM, 48 h), and differential protein expression was investigated using tandem mass tags (TMT) proteomics. The molecular mechanisms of these differentially expressed proteins and their network interactions were then analyzed using bioinformatics, and potential nintedanib targets were identified. This study identified 845 differentially expressed proteins in the nintedanib-treated group (compared to the control group), comprising 526 up-regulated and 319 down-regulated proteins. Bioinformatics analysis revealed that the differentially expressed proteins were primarily enriched in biological pathways for branched-chain amino acid metabolism, steroid biosynthesis, propionate metabolism, fatty acid metabolism, lysosome, peroxisome, and ferroptosis. Key driver analysis revealed that proteins, such as enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (EHHADH), isocitrate dehydrogenase 1 (IDH1), acyl-CoA oxidase 1 (ACOX1), acyl-CoA oxidase 2 (ACOX2), acyl-CoA oxidase 3 (ACOX3), and acetyl-CoA acyltransferase 1 (ACAA1) could be linked with nintedanib action. Nintedanib inhibits the proliferation, invasion, and metastasis of gastric cancer cells. The crossover pathways and protein networks predicted by proteomics should provide more detailed molecular information enabling the use of nintedanib against gastric cancer.

A Comparison of the Effectiveness of Nintedanib and Pirfenidone in Treating Idiopathic Pulmonary Fibrosis: A Systematic Review.

Idiopathic pulmonary fibrosis (IPF), which shares a radiographic pattern with the usual interstitial pneumonia (UIP), is a specific form of chronic and progressive interstitial lung disorder resulting in persistent fibrosis and impaired lung function. Most of the patients suffer from dyspnea which adversely affects health-related quality of life (HRQOL). The underlying etiology of the disease is not yet understood, but research done on the subject reveals that aberrant repair mechanisms and dysregulated immune responses may be the cause.It can affect any age group but predominantly affects patients who are above 50 years of age. It has been observed that in addition to age, the reasons are also related to smoking, pollution, and inhalation of harmful elements. As the cause of IPF is still unknown and there is no cure yet, presently, it is treated to delay lung function loss with antifibrotic medications, nintedanib, and pirfenidone. However, both nintedanib and perfenidone have side effects which affect different patients in different ways and with different levels of severity, thereby making the treatment even more challenging for medical practitioners. The present systematic review aims at studying the efficacy of pirfenidone and nintedanib in relieving symptoms and in extending survival in patients. A detailed search was done in relevant articles listed in PubMed, ScienceDirect, and the New England Journal of Medicine between 2018 and 2023. It was observed that the most accepted way of measuring the progression of IPF is the evaluation of pulmonary function by assessing the forced vital capacity (FVC). Several studies have shown that the decline in FVC over a period of 6-12 months is directly associated with a higher mortality rate. The outcomes were similar in both male and female irrespective of age, gender, and ethnicity. However, some patients being treated with pirfenidone and nintedanib experienced various side-effects which were mainly gastrointestinal like diarrhea, dyspepsia, and vomiting. In the case of pirfenidone, some patients also experienced photosensitivity and skin rashes. In cases where the side-effects are extremely severe and are more threatening than the disease itself, the treatment has to be discontinued. The survival rate in patients with IPF is marked by a median of 3-5 yearsthat is even lower than many cancers; hence, the treatment should be started as soon as the disease is detected. However, further research is needed to establish the etiology of IPF and to establish treatments that can stop its progression.

Key learnings from the INBUILD trial in patients with progressive pulmonary fibrosis.

In a patient with interstitial lung disease (ILD) of known or unknown etiology other than idiopathic pulmonary fibrosis (IPF), progressive pulmonary fibrosis (PPF) is defined by worsening lung fibrosis on high-resolution computed tomography (HRCT), decline in lung function, and/or deterioration in symptoms. The INBUILD trial involved 663 patients with PPF who were randomized to receive nintedanib or placebo. The median exposure to trial medication was approximately 19 months. The INBUILD trial provided valuable learnings about the course of PPF and the efficacy and safety of nintedanib. The relative effect of nintedanib on reducing the rate of forced vital capacity decline was consistent across subgroups based on ILD diagnosis, HRCT pattern, and disease severity at baseline, and between patients who were and were not taking glucocorticoids or disease-modifying anti-rheumatic drugs and/or glucocorticoids at baseline. The adverse events most frequently associated with nintedanib were gastrointestinal, particularly diarrhea, but nintedanib was discontinued in only a minority of cases. The results of the INBUILD trial highlight the importance of prompt detection and treatment of PPF and the utility of nintedanib as a treatment option.