nintedanib and Pulmonary-Fibrosis

Lung injury in severe COVID-19 pneumonia can rapidly evolve to established pulmonary fibrosis, with prognostic implications in the acute phase of the disease and long-lasting impact on the quality of life of COVID-19 survivors. This is an emerging medical need, and it has been hypothesized that antifibrotic treatments could have a role in ameliorating the fibrotic process in the lungs of these patients.. The safety and efficacy of available antifibrotic drugs (nintedanib and pirfenidone) and novel promising agents are being assessed in several ongoing clinical trials that were performed either in critically ill patients admitted to intensive care, or in discharged patients presenting fibrotic sequalae from COVID-19. Literature search was performed using Medline and Clinicaltrials.org databases (2001-2021).. Despite the strong rationale support the use of antifibrotic therapies in COVID-related fibrosis, there are several uncertainties regarding the timing for their introduction and the real risks/benefits ratio of antifibrotic treatment in the acute and the chronic phases of the disease. The findings of ongoing clinical trials and the long-term observation of longitudinal cohorts will eventually clarify the best management approach for these patients.

Topics: Animals; Antifibrotic Agents; COVID-19; Critical Illness; Humans; Indoles; Pulmonary Fibrosis; Pyridones

Research questions To compare the efficacy of nintedanib and pirfenidone in the treatment of progressive pulmonary fibrosis; and to compare the efficacy of anti-fibrotic therapy (grouping nintedanib and pirfenidone together) in patients with IPF versus patients with progressive lung fibrosis not classified as IPF.. A search of databases including MEDLINE, EMBASE, PubMed, and clinicaltrials.gov was conducted. Studies were included if they were randomised controlled trials of pirfenidone or nintedanib in adult patients with IPF or non-IPF patients, and with extractable data on mortality or decline in forced vital capacity (FVC). Random effects meta-analyses were performed on changes in FVC and where possible on mortality in the selected studies.. 13 trials of antifibrotic therapy were pooled in a meta-analysis (with pirfenidone and nintedanib considered together as anti-fibrotic therapy). The change in FVC was expressed as a standardised difference to allow pooling of percentage and absolute changes. The mean effect size in the IPF studies was - 0.305 (SE 0.043) (p < 0.001) and in the non-IPF studies the figures were - 0.307 (SE 0.063) (p < 0.001). There was no evidence of any difference between the two groups for standardised rate of FVC decline (p = 0.979). Pooling IPF and non-IPF showed a significant reduction in mortality, with mean risk ratio of 07.01 in favour of antifibrotic therapy (p = 0.008). A separate analysis restricted to non-IPF did not show a significant reduction in mortality (risk ratio 0.908 (0.547 to 1.508), p = 0.71.. Anti-fibrotic therapy offers protection against the rate of decline in FVC in progressive lung fibrosis, with similar efficacy shown between the two anti-fibrotic agents currently in clinical use. There was no significant difference in efficacy of antifibrotic therapy whether the underlying condition was IPF or non-IPF with progressive fibrosis, supporting the hypothesis of a common pathogenesis. The data in this analysis was insufficient to be confident about a reduction in mortality in non-IPF with anti-fibrotic therapy. Trial Registration PROSPERO, registration number CRD42021266046.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antifibrotic Agents; Cause of Death; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Pulmonary Fibrosis; Pyridones; Treatment Outcome

Since December 2019, coronavirus disease (COVID-19) has rapidly swept the world. So far, more than 30 million people have been infected and nearly one million have died. Although the world is still in the stage of COVID-19 pandemic, the treatment of new cases and critically ill patients is the focus of the current work. However, COVID-19 patients lead to pulmonary fibrosis, such a serious threat to the prognosis of complications were also worthy of our attention. First of all, we proposed the possible mechanism of pulmonary fibrosis caused by SARS-CoV-2, based on the published data of COVID-19 ((i) Direct evidence: pulmonary fibrosis was found in autopsy and pulmonary puncture pathology. (ii) Indirect evidence: increased levels of fibrosis-related cytokines[transforming growth factor [TGF]- β, tumor necrosis factor [TNF]- α, interleukin [IL]-6, etc] in peripheral blood of severe patients.) What is more, we summarized the role of three fibrosis-related signaling pathways (TGF- β signal pathway, WNT signal pathway and YAP/TAZ signal pathway) in pulmonary fibrosis. Finally, we suggested the therapeutic value of two drugs (pirfenidone and nintedanib) for idiopathic pulmonary fibrosis in COVID-19-induced pulmonary fibrosis.

Topics: Anti-Inflammatory Agents, Non-Steroidal; COVID-19; Humans; Indoles; Lung; Patient Discharge; Pulmonary Fibrosis; Pyridones; Severity of Illness Index; Signal Transduction

A significant proportion - up to 40 % - of patients suffering from fibrosing interstitial pneumonia will acquire a progressive phenotype which shares genetic and pathogenic mechanisms, as well a clinical behavior similar to those of idiopathic pulmonary fibrosis (IPF). It therefore makes sense to suggest that molecules with antifibrotic properties such as pirfenidone and nintedanib could be effective in patients with progressive fibrosing interstitial lung disease as they are in patients with IPF. The first studies published on this topic show encouraging results which however have to be confirmed on a larger scale.. Un pourcentage important – jusqu’à 40 % – de patients qui présentent une pneumopathie interstitielle fibrosante va acquérir un phénotype progressif qui partage, avec la fibrose pulmonaire idiopathique (FPI), des mécanismes génétiques et pathogéniques ainsi qu’un comportement clinique relativement similaires. Il est donc logique de penser que des molécules dotées de propriétés antifibrotiques comme la pirfénidone et le nintédanib pourraient être efficaces chez les patients avec pneumopathie interstitielle fibrosante progressive comme elles le sont chez ceux avec FPI. Les premières études publiées sur le sujet montrent des résultats encourageants qui doivent toutefois être confirmés à plus large échelle.

Topics: Humans; Idiopathic Pulmonary Fibrosis; Indoles; Lung; Pulmonary Fibrosis; Pyridones

Progressive fibrosing interstitial lung disease (PF-ILD) has been redefined as a new clinical syndrome that shares similar genetics, pathophysiology, and natural history to idiopathic pulmonary fibrosis (IPF). IPF is the most common form of idiopathic interstitial pneumonias, which is progressive in nature and is associated with significant mortality. Therapies targeting an inflammatory and/or immune response have not been consistently effective or well tolerated in patients with IPF. The two antifibrotic drugs approved for IPF treatment, nintedanib and pirfenidone, have been shown to reduce lung function decline in PF-ILD. Novel uses of antifibrotic therapy are emerging due to a paucity of evidence-based treatments for multiple ILD subtypes. In this review, we describe the current body of knowledge on antifibrotic therapy and immunomodulators in PF-ILD, drawing from experience in IPF where appropriate.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Disease Progression; Humans; Idiopathic Pulmonary Fibrosis; Immunologic Factors; Immunosuppressive Agents; Indoles; Lung Diseases, Interstitial; Protein Kinase Inhibitors; Pulmonary Fibrosis; Pyridones; Vital Capacity

Pulmonary fibrosis is a progressive chronic inflammatory disease with a poor clinical outcome. Although pirfenidone and nintedanib have been approved by FDA to treat idiopathic pulmonary fibrosis (IPF), these drugs can only slow the progression of IPF. Autophagy plays an important role in the pathogenesis of pulmonary fibrosis. Whether the autophagic flux is blocked or not is directly related to the development direction of pulmonary fibrosis. Defining how autophagy activity regulates the pathogenesis of pulmonary fibrosis will greatly advance the progression of pulmonary fibrosis therapy.

Topics: Autophagy; Disease Progression; Humans; Indoles; Pulmonary Fibrosis; Pyridones

To provide an overview of recent studies that could be helpful in a better understanding of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and to facilitate the clinical management of this severe complication of RA.. The advances in deciphering the genetic architecture of RA-ILD support the hypothesis of RA-ILD as a complex disease with a complex phenotype encompassing at least the usual interstitial pneumonia (UIP) high-resolution CT pattern and non-UIP. Genetics studies have provided evidence for a shared genetic background in idiopathic pulmonary fibrosis (IPF) and RA-ILD, and more specifically RA-UIP, a disease with high morbidity and mortality. These findings support the rationale for common pathogenic pathways opening new avenues for future intervention in RA-ILD, notably with - drugs that proved active in IPF. In agreement, a recent controlled trial suggests efficacy of nintedanib, an antifibrotic drug, in patients with progressive lung fibrosis, including RA-ILD. However, there is a substantial gap in RA-ILD treatment, notably evaluating the effect of the RA treatments on the ILD course because of no controlled trial yet.. The phenotypical, environmental, and genetic similarities between IPF and RA-ILD have led to a better understanding of the underlying pathogenesis of RA-ILD. Despite the identification of several biomarkers and useful screening tools, several questions remain unanswered regarding the identification of patients with RA at increased risk of ILD and risk of progression. Other substantial gaps are the lack of recommendations for how high-risk patients should be screened and which specific therapeutic strategy should be initiated. International collaborative efforts are needed to address these issues and develop specific recommendations for RA-ILD.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Biomarkers; Disease Progression; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Lung Diseases, Interstitial; Phenotype; Prognosis; Protein Kinase Inhibitors; Pulmonary Fibrosis; Tomography, X-Ray Computed

Interstitial lung disease (ILD) is a common manifestation of systemic autoimmune diseases and a leading cause of death in these patients. A proportion of patients with autoimmune ILDs develop a progressive fibrosing form of ILD, characterized by increasing fibrosis on high-resolution computed tomography, worsening of lung function, and early mortality. Autoimmune disease-related ILDs have a variable clinical course and not all patients will require treatment, but all patients should be monitored for signs of progression. Apart from systemic sclerosis-associated ILD, the limited evidence to support the efficacy of immunosuppression as a treatment for ILDs is based mainly on small retrospective series and expert opinion. Non-clinical data suggest that there are commonalities in the mechanisms that drive progressive fibrosis in ILDs with an immunological trigger as in other forms of progressive fibrosing ILD. This suggests that nintedanib and pirfenidone, drugs known to slow disease progression in patients with idiopathic pulmonary fibrosis, may also slow the progression of ILD associated with systemic autoimmune diseases. In the SENSCIS® trial, nintedanib reduced the rate of ILD progression in patients with systemic sclerosis-associated ILD. The results of other large clinical trials will provide further insights into the role of anti-fibrotic therapies in the treatment of autoimmune disease-related ILDs.

Topics: Arthritis, Rheumatoid; Autoimmune Diseases; Clinical Trials as Topic; Disease Progression; Humans; Immunosuppression Therapy; Indoles; Kaplan-Meier Estimate; Lung; Lung Diseases, Interstitial; Phenotype; Pulmonary Fibrosis; Pyridones; Risk Factors; Tomography, X-Ray Computed

Patients with certain types of fibrosing interstitial lung disease (ILD) are at risk of developing a progressive phenotype characterised by self-sustaining fibrosis, decline in lung function, worsening quality of life, and early mortality. It has been proposed that such progressive fibrosing ILDs, which show commonalities in clinical behaviour and in the pathogenetic mechanisms that drive progressive fibrosis, may be "lumped" together for the purposes of clinical research and, potentially, for treatment. At present, no drugs are approved for the treatment of ILDs other than nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis. For other progressive fibrosing ILDs, the mainstay of drug therapy is immunosuppression. However, it is postulated that, once the response to lung injury in fibrosing ILDs has reached the stage at which fibrosis has become progressive and self-sustaining, targeted antifibrotic therapy would be required to slow disease progression. Nintedanib, an intracellular inhibitor of tyrosine kinases, has shown antifibrotic, anti-inflammatory and vascular remodelling effects in several non-clinical models of fibrosis, irrespective of the trigger for the injury. Ongoing clinical trials will provide insight into the role of antifibrotic treatment with nintedanib or pirfenidone in the management of fibrosing ILDs with a progressive phenotype.

Topics: Disease Progression; Health Status; Humans; Indoles; Lung; Lung Diseases, Interstitial; Phenotype; Pulmonary Fibrosis; Pyridones; Quality of Life; Respiratory System Agents; Risk Factors; Severity of Illness Index; Treatment Outcome

A proportion of patients with fibrosing interstitial lung diseases (ILDs) develop a progressive phenotype characterised by decline in lung function, worsening quality of life and early mortality. Other than idiopathic pulmonary fibrosis (IPF), there are no approved drugs for fibrosing ILDs and a poor evidence base to support current treatments. Fibrosing ILDs with a progressive phenotype show commonalities in clinical behaviour and in the pathogenic mechanisms that drive disease worsening. Nintedanib is an intracellular inhibitor of tyrosine kinases that has been approved for treatment of IPF and has recently been shown to reduce the rate of lung function decline in patients with ILD associated with systemic sclerosis (SSc-ILD).

Topics: Animals; Anti-Inflammatory Agents; Bleomycin; Disease Models, Animal; Disease Progression; Extracellular Matrix; Fibroblasts; Fibrosis; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Lung; Lung Diseases, Interstitial; Mice; Phenotype; Protein Kinase Inhibitors; Pulmonary Fibrosis; Scleroderma, Systemic

A proportion of patients with interstitial lung diseases (ILDs) are at risk of developing a progressive-fibrosing phenotype, which is associated with a deterioration in lung function and early mortality. In addition to idiopathic pulmonary fibrosis (IPF), fibrosing ILDs that may present a progressive phenotype include idiopathic nonspecific interstitial pneumonia, connective tissue disease-associated ILDs, hypersensitivity pneumonitis, unclassifiable idiopathic interstitial pneumonia, ILDs related to other occupational exposures and sarcoidosis. Corticosteroids and/or immunosuppressive therapies are sometimes prescribed to patients with these diseases. However, this treatment regimen may not be effective, adequate on its own or well tolerated, suggesting that there is a pressing need for efficacious and better tolerated therapies. Currently, the only approved treatments to slow disease progression in patients with IPF are nintedanib and pirfenidone. Similarities in pathobiological mechanisms leading to fibrosis between IPF and other ILDs that may present a progressive-fibrosing phenotype provide a rationale to suggest that nintedanib and pirfenidone may be therapeutic options for patients with the latter diseases.This review provides an overview of the therapeutic options currently available for patients with fibrosing ILDs, including fibrosing ILDs that may present a progressive phenotype, and explores the status of the randomised controlled trials that are underway to determine the efficacy and safety of nintedanib and pirfenidone.

Topics: Disease Progression; Humans; Indoles; Lung; Lung Diseases, Interstitial; Phenotype; Pulmonary Fibrosis; Pyridones; Risk Factors; Treatment Outcome

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive genetic disorder characterized by oculocutaneous albinism and a bleeding diathesis due to platelet dysfunction. More than 50% of cases worldwide are diagnosed on the Caribbean island of Puerto Rico. Genetic testing plays a growing role in diagnosis; however, not all patients with HPS have identified genetic mutations. In Puerto Rico, patients with HPS are often identified shortly after birth by their albinism, although the degree of hypopigmentation is highly variable. Ten subtypes have been described. Patients with HPS-1, HPS-2, and HPS-4 tend to develop pulmonary fibrosis in Puerto Rico; 100% of patients with HPS-1 develop HPS-PF. HPS-PF and idiopathic pulmonary fibrosis are considered similar entities (albeit with distinct causes) because both can show similar histological disease patterns. However, in contrast to idiopathic pulmonary fibrosis, HPS-PF manifests much earlier, often at 30-40 years of age. The progression of HPS-PF is characterized by the development of dyspnea and increasingly debilitating hypoxemia. No therapeutic interventions are currently approved by the U.S. Food and Drug Administration for the treatment of HPS and HPS-PF. However, the approval of two new antifibrotic drugs, pirfenidone and nintedanib, has prompted new interest in identifying drugs capable of reversing or halting the progression of HPS-PF. Thus, lung transplantation remains the only potentially life-prolonging treatment. At present, two clinical trials are recruiting patients with HPS-PF to identify biomarkers for disease progression. Advances in the diagnosis and management of these patients will require the establishment of multidisciplinary centers of excellence staffed by experts in this disease.

Topics: Animals; Biomarkers; Disease Progression; Hermanski-Pudlak Syndrome; Hispanic or Latino; Humans; Indoles; Lung Transplantation; Membrane Proteins; Mice; Mutation; Puerto Rico; Pulmonary Fibrosis; Pyridones; Randomized Controlled Trials as Topic; Tomography, X-Ray Computed

Novel compounds targeting various aspects of fibrogenesis have been developed consequent to the increasing knowledge of the pathogenetic mechanisms of the interstitial lung diseases (ILDs). The authors review the evolution of treatment approaches in the ILDs, informed by recent placebo-controlled trials, and discuss current clinical trials in which emerging pathogenetic mechanisms are targeted as novel therapeutic agents.. In idiopathic pulmonary fibrosis (IPF), recent randomised, placebo-controlled trials have tested the efficacy of new therapies, and although primary end points have not been met in most, treatment effects have been observed. The demonstration of harmful effects from widely used IPF therapies has been equally important. Pirfenidone and nintedanib are emerging agents that exert pleiotropic effects, reflective of the multiple mechanistic pathways of IPF. Treatment may necessitate a similarly multifaceted approach using combination regimens of antifibrotic and antioxidant agents in order to be effective. In other ILDs, including systemic sclerosis, other connective tissue diseases and pulmonary sarcoidosis, the inflammatory/fibrotic model remains appropriate. Studies in systemic sclerosis have provided 'proof of concept' data for immunosuppressive therapy in the prevention of disease progression but there is a continuing need for controlled clinical trials in the more prevalent ILDs.. In IPF, significant treatment effects have been reported with pirfenidone, nintedanib and N-acetylcysteine. Combinations of these pleiotropic agents, along with future monotherapies, in 'oncological regimens' may hold the key to more effective IPF treatment. In disorders other than IPF, there is an ongoing need for the controlled evaluation of traditional anti-inflammatory and immunosuppressive therapies. 'Cohort enrichment' (the selective recruitment of patients most likely to progress) holds the key to the identification of worthwhile treatment benefits.

Topics: Acetylcysteine; Anti-Inflammatory Agents, Non-Steroidal; Humans; Idiopathic Interstitial Pneumonias; Immunosuppressive Agents; Indoles; Lung Diseases, Interstitial; Pulmonary Fibrosis; Pyridones; Randomized Controlled Trials as Topic; Sarcoidosis, Pulmonary; Scleroderma, Systemic; Treatment Outcome

Although pulmonary fibrosis secondary to COVID-19 infection is uncommon, it can lead to problems if not treated effectively in the early period. This study aimed to compare the effects of treatment with nintedanib and pirfenidone in patients with COVID-19-related fibrosis.. Thirty patients who presented to the post-COVID outpatient clinic between May 2021 and April 2022 with a history of COVID-19 pneumonia and exhibited persistent cough, dyspnea, exertional dyspnea, and low oxygen saturation at least 12 weeks after diagnosis were included. The patients were randomized to receive off-label treatment with nintedanib or pirfenidone and were followed up for 12 weeks.. After 12 weeks of treatment, all pulmonary function test (PFT) parameters, 6MWT distance, and oxygen saturation were increased compared to baseline in both the pirfenidone group and nintedanib groups, while heart rate and radiological score levels were decreased (p<0.05 for all). The changes in 6MWT distance and oxygen saturation were significantly greater in the nintedanib group than in the pirfenidone group (p=0.02 and 0.005, respectively). Adverse drug effects were more frequent with nintedanib than pirfenidone, with the most common being diarrhea, nausea, and vomiting.. In patients with interstitial fibrosis after COVID-19 pneumonia, both nintedanib and pirfenidone were observed to be effective in improving radiological score and PFT parameters. Nintedanib was more effective than pirfenidone in increasing exercise capacity and saturation values but caused more adverse drug effects.

Topics: Adult; Aged; Antifibrotic Agents; Female; Follow-Up Studies; Humans; Male; Middle Aged; Post-Acute COVID-19 Syndrome; Prospective Studies; Pulmonary Fibrosis; Pyridones; Treatment Outcome

Some patients with rheumatoid arthritis develop interstitial lung disease (RA-ILD) that develops into progressive pulmonary fibrosis. We assessed the efficacy and safety of nintedanib versus placebo in patients with progressive RA-ILD in the INBUILD trial.. The INBUILD trial enrolled patients with fibrosing ILD (reticular abnormality with traction bronchiectasis, with or without honeycombing) on high-resolution computed tomography of >10% extent. Patients had shown progression of pulmonary fibrosis within the prior 24 months, despite management in clinical practice. Subjects were randomised to receive nintedanib or placebo.. In the subgroup of 89 patients with RA-ILD, the rate of decline in FVC over 52 weeks was -82.6 mL/year in the nintedanib group versus -199.3 mL/year in the placebo group (difference 116.7 mL/year [95% CI 7.4, 226.1]; nominal p = 0.037). The most frequent adverse event was diarrhoea, which was reported in 61.9% and 27.7% of patients in the nintedanib and placebo groups, respectively, over the whole trial (median exposure: 17.4 months). Adverse events led to permanent discontinuation of trial drug in 23.8% and 17.0% of subjects in the nintedanib and placebo groups, respectively.. In the INBUILD trial, nintedanib slowed the decline in FVC in patients with progressive fibrosing RA-ILD, with adverse events that were largely manageable. The efficacy and safety of nintedanib in these patients were consistent with the overall trial population. A graphical abstract is available at: https://www.globalmedcomms.com/respiratory/INBUILD_RA-ILD . Key Points • In patients with rheumatoid arthritis and progressive pulmonary fibrosis, nintedanib reduced the rate of decline in forced vital capacity (mL/year) over 52 weeks by 59% compared with placebo. • The adverse event profile of nintedanib was consistent with that previously observed in patients with pulmonary fibrosis, characterised mainly by diarrhoea. • The effect of nintedanib on slowing decline in forced vital capacity, and its safety profile, appeared to be consistent between patients who were taking DMARDs and/or glucocorticoids at baseline and the overall population of patients with rheumatoid arthritis and progressive pulmonary fibrosis.

Topics: Diarrhea; Disease Progression; Humans; Lung Diseases, Interstitial; Protein Kinase Inhibitors; Pulmonary Fibrosis; Vital Capacity

For patients with connective tissue disease-associated interstitial lung disease (CTD-ILD), early medical intervention would be desirable. This study analyzed the real-world, single-center use of nintedanib for CTD-ILD patients.. Patients with CTD who received nintedanib from January 2020 to July 2022 were enrolled. Medical records review and stratified analyses of the collected data were conducted.. Reduction in the percentage of predicted forced vital capacity (%FVC) was seen in the elderly group (>70 years; P = .210), males (P = .027), the late group who started nintedanib >80 months after confirmation of an ILD disease activity (P = .03), the severe %DLco (diffusing capacity for carbon monoxide as a percentage of predicted) group (<40%; P = .20), the group who had extensive pulmonary fibrosis at the beginning of nintedanib (pulmonary fibrosis score >35%), and the low-dose group (nintedanib 50-100 mg/d; P = .40). %FVC did not decrease by >5% in the young group (<55 years), the early group who started nintedanib within 10 months after confirmation of an ILD disease activity, and the group whose pulmonary fibrosis score at the beginning of nintedanib was <35%.. It is important to diagnose ILD early and start antifibrotic drugs with proper timing for cases in need. It is better to start nintedanib early, especially for patients at risk (>70 years old, male, <40% DLco, and >35% areas of pulmonary fibrosis).

Topics: Aged; Connective Tissue Diseases; Humans; Lung Diseases, Interstitial; Male; Prognosis; Pulmonary Fibrosis; Vital Capacity

Synovial inflammation and fibrosis are important pathological changes associated with osteoarthritis (OA). Herein, we investigated if nintedanib, a drug specific for pulmonary fibrosis, plays a positive role in osteoarthritic synovial inflammation and fibrosis. We assessed the effect of nintedanib on osteoarthritic synovial inflammation and fibrosis in a mouse model of OA created by destabilization of the medial meniscus and a macrophage M1 polarization model created by stimulating RAW264.7 cells with lipopolysaccharide. Histological staining showed that daily gavage administration of nintedanib significantly alleviated articular cartilage degeneration, reduced the OARSI score, upregulated matrix metalloproteinase-13 and downregulated collagen II expression, and significantly reduced the synovial score and synovial fibrosis in a mouse OA model. In addition, immunofluorescence staining showed that nintedanib significantly decreased the number of M1 macrophages in the synovium of a mouse model of OA. In vitro results showed that nintedanib downregulated the phosphorylation levels of ERK, JNK, p38, PI3K, and AKT while inhibiting the expression of macrophage M1 polarization marker proteins (CD86, CD80, and iNOS). In conclusion, this study suggests that nintedanib is a potential candidate for OA treatment. The mechanisms of action of nintedanib include the inhibition of M1 polarization in OA synovial macrophages via the MAPK/PI3K-AKT pathway, inhibition of synovial inflammation and fibrosis, and reduction of articular cartilage degeneration.

Topics: Animals; Disease Models, Animal; Inflammation; Macrophages; Mice; Osteoarthritis; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pulmonary Fibrosis

Lung fibrosis (LF) is a chronic progressive, incurable, and debilitating condition of the lung, which is associated with different lung disease. Treatment options are still sparse. Nintedanib, an oral tyrosine kinase inhibitor, significantly slows the LF progression. However, there is a strong need of further research and the development of novel therapies. In this study, we used a correlative set-up that combines X-ray based lung function (XLF) with microCT and whole body plethysmography (WBP) for a comprehensive functional and structural evaluation of lung fibrosis (LF) as well as for monitoring response to orally administered Nintedanib in the mouse model of bleomycin induced LF. The decline in lung function as early as one week after intratracheal bleomycin instillation was reliably detected by XLF, revealing the lowest decay rate in the LF mice compared to healthy ones. Simultaneously performed microCT and WBP measurements corroborated XLF findings by exhibiting reduced lung volume [Formula: see text] and tidal volume [Formula: see text]. In LF mice XLF also revealed profound improvement in lung function one week after Nintedanib treatment. This positive response to Nintedanib therapy was further substantiated by microCT and WBP measurements which also showed significantly improved [Formula: see text] and [Formula: see text] in the Nintedanib treated mice. By comparing the XLF data to structural features assessing the extent of fibrosis obtained by ex-vivo high-resolution synchrotron radiation-based imaging and classical histology we demonstrate that: (1) a simple low dose x-ray measurement like XLF is sensitive enough to pick up treatment response, (2) Nintedanib treatment successfully improved lung function in a bleomycin induced LF mouse model and (3) differences between the fully restored lung function and the partially reduced fibrotic burden compared to healthy and untreated mice. The presented analysis pipeline underlines the importance of a combined functional and anatomical readout to reliably measure treatment response and could easily be adapted to other preclinical lung disease models.

Topics: Animals; Bleomycin; Disease Models, Animal; Fibrosis; Idiopathic Pulmonary Fibrosis; Lung; Mice; Pulmonary Fibrosis; X-Rays

Since triple angiokinase inhibitor could not fully explain the anti-pulmonary fibrosis activity of nintedanib (NDNB), the chemoproteomic strategy was performed to identify TANK-binding kinase 1 (TBK1) as the key target of NDNB in human pulmonary fibroblasts (HPFs). Functionally, NDNB exerts anti-fibrosis activity through impairing the p-TBK1-mediated Yes-associated protein (YAP)/transcriptional cofactor with PDZ-binding motif (TAZ) nuclear translocation.

Topics: Dose-Response Relationship, Drug; Humans; Indoles; Molecular Structure; Phosphorylation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pulmonary Fibrosis; Structure-Activity Relationship

Aberrant extracellular matrix (ECM) deposition and remodelling is important in the disease pathogenesis of pulmonary fibrosis (PF). We characterised neoepitope biomarkers released by ECM turnover in lung tissue from bleomycin-treated rats and patients with PF and analysed the effects of two antifibrotic drugs: nintedanib and pirfenidone.. Precision-cut lung slices (PCLS) were prepared from bleomycin-treated rats or patients with PF. PCLS were incubated with nintedanib or pirfenidone for 48 h, and levels of neoepitope biomarkers of type I, III and VI collagen formation or degradation (PRO-C1, PRO-C3, PRO-C6 and C3M) as well as fibronectin (FBN-C) were assessed in the culture supernatants.. In rat PCLS, incubation with nintedanib led to a reduction in C3M, reflecting type III collagen degradation. In patient PCLS, incubation with nintedanib reduced the levels of PRO-C3 and C3M, thus showing effects on both formation and degradation of type III collagen. Incubation with pirfenidone had a marginal effect on PRO-C3. There were no other notable effects of either nintedanib or pirfenidone on the other neoepitope biomarkers studied.. This study demonstrated that nintedanib modulates neoepitope biomarkers of type III collagen turnover and indicated that C3M is a promising translational neoepitope biomarker of PF in terms of therapy assessment.

Topics: Animals; Biomarkers; Bleomycin; Collagen Type III; Complement C3; Idiopathic Pulmonary Fibrosis; Indoles; Lung; Pulmonary Fibrosis; Rats

Nintedanib is an effective treatment for pulmonary fibrosis (PF), but the exact mechanism by which this agent works to delay the progression of PF remains unclear. In this study, we explored whether nintedanib alleviates PF at least partially by inhibiting the focal adhesion kinase (FAK)/ERK/S100A4 signalling pathway. Bleomycin (BLM) was used to induce PF in a mouse model, and human fetal lung fibroblast 1 (HFL-1) cells were exposed to transforming growth factor-β 1 (TGF-β1) to create an in vitro model of PF. In both models, nintedanib was administered either alone or in conjunction with a FAK vector. In mouse lung tissues, histopathology, inflammatory factor levels, and collagen content were assessed; in HFL-1 cells, HFL-1 activity was assessed, along with collagen I, collagen III, and α-SMA levels. Both mouse tissue and HFL-1 cells were examined for levels of indices associated with extracellular matrix and the FAK/ERK/S100A4 signalling pathway. In mice exposed to BLM, lung inflammation and extracellular matrix deposition were significantly increased. These factors were alleviated by nintedanib treatment but were aggravated by overexpression of FAK. In HFL-1 cells, nintedanib inhibited HFL-1 activity and collagen I, collagen III, and α-SMA levels, whereas overexpression of FAK produced the opposite effect. In both tissues and cells, the FAK/ERK/S100A4 signalling pathway was activated, but nintedanib was able to suppress this pathway. These results suggest that nintedanib alleviates PF by inhibiting the FAK/ERK/S100A4 signalling pathway both in vivo and in vitro.

Topics: Animals; Bleomycin; Collagen Type I; Focal Adhesion Protein-Tyrosine Kinases; Humans; Indoles; MAP Kinase Signaling System; Mice; Pulmonary Fibrosis; S100 Calcium-Binding Protein A4

Systemic sclerosis (SSc) is an autoimmune disease characterized by an excessive production and accumulation of collagen in the skin and internal organs often associated with interstitial lung disease (ILD). Its pathogenetic mechanisms are unknown and the lack of animal models mimicking the features of the human disease is creating a gap between the selection of anti-fibrotic drug candidates and effective therapies. In this work, we intended to pharmacologically validate a SSc-ILD model based on 1 week infusion of bleomycin (BLM) by osmotic minipumps in C57/BL6 mice, since it will serve as a tool for secondary drug screening. Nintedanib (NINT) has been used as a reference compound to investigate antifibrotic activity either for lung or skin fibrosis. Longitudinal Micro-CT analysis highlighted a significant slowdown in lung fibrosis progression after NINT treatment, which was confirmed by histology. However, no significant effect was observed on lung hydroxyproline content, inflammatory infiltrate and skin lipoatrophy. The modest pharmacological effect reported here could reflect the clinical outcome, highlighting the reliability of this model to better profile potential clinical drug candidates. The integrative approach presented herein, which combines longitudinal assessments with endpoint analyses, could be harnessed in drug discovery to generate more reliable, reproducible and robust readouts.

Topics: Animals; Bleomycin; Disease Models, Animal; Drug Delivery Systems; Indoles; Lung; Lung Diseases, Interstitial; Mice; Protein Kinase Inhibitors; Pulmonary Fibrosis; Scleroderma, Systemic

Augmented glycolysis due to metabolic reprogramming in lung myofibroblasts is critical to their profibrotic phenotype. The primary glycolysis byproduct, lactate, is also secreted into the extracellular milieu, together with which myofibroblasts and macrophages form a spatially restricted site usually described as fibrotic niche. Therefore, we hypothesized that myofibroblast glycolysis might have a non-cell autonomous effect through lactate regulating the pathogenic phenotype of alveolar macrophages. Here, we demonstrated that there was a markedly increased lactate in the conditioned media of TGF-β1 (transforming growth factor-β1)-induced lung myofibroblasts and in the BAL fluids (BALFs) from mice with TGF-β1- or bleomycin-induced lung fibrosis. Importantly, the media and BALFs promoted profibrotic mediator expression in macrophages. Mechanistically, lactate induced histone lactylation in the promoters of the profibrotic genes in macrophages, consistent with the upregulation of this epigenetic modification in these cells in the fibrotic lungs. The lactate inductions of the histone lactylation and profibrotic gene expression were mediated by p300, as evidenced by their diminished concentrations in p300-knockdown macrophages. Collectively, our study establishes that in addition to protein, lipid, and nucleic acid molecules, a metabolite can also mediate intercellular regulations in the setting of lung fibrosis. Our findings shed new light on the mechanism underlying the key contribution of myofibroblast glycolysis to the pathogenesis of lung fibrosis.

Topics: Animals; Cells, Cultured; Histones; Humans; Indoles; Lactates; Lung; Macrophages, Alveolar; Male; Mice; Mice, Inbred C57BL; Myofibroblasts; Pulmonary Fibrosis; Pyridones

Topics: Acetylcysteine; Convalescence; COVID-19; COVID-19 Drug Treatment; Early Medical Intervention; Glucocorticoids; Humans; Indoles; Pulmonary Fibrosis; Pyridones; SARS-CoV-2

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Connective Tissue Diseases; Disease Progression; Humans; Indoles; Interleukin-6; Lung Diseases, Interstitial; Methotrexate; Prevalence; Protein Kinase Inhibitors; Pulmonary Fibrosis; Randomized Controlled Trials as Topic; Scleroderma, Systemic; Vital Capacity

Topics: Antibodies, Monoclonal, Humanized; Humans; Indoles; Protein Kinase Inhibitors; Pulmonary Fibrosis; Scleroderma, Systemic

One of the most significant features of poor prognosis in COVID-19 is pulmonary fibrosis. Nintedanib is a new antifibrotic agent that interferes with processes of pulmonary fibrosis. This study aimed to investigate the efficacy and safety of nintedanib in COVID-19.. This was an interventional study in which adult patients with COVID-19 requiring mechanical ventilation were consecutively enrolled. The primary endpoint was 28-day mortality after the initiation of mechanical ventilation. The secondary endpoints were length of mechanical ventilation, volume of lung injury, and the incidence of gastrointestinal adverse events and acute liver failure.. Thirty patients with COVID-19 underwent nintedanib therapy. We included 30 patients not receiving nintedanib as the historical control group. There were no significant differences in 28-day mortality between the groups (23.3% vs 20%, P = 0.834). Lengths of mechanical ventilation were significantly shorter in the nintedanib group (P = 0.046). Computed tomography volumetry showed that the percentages of high-attenuation areas were significantly lower in the nintedanib group at liberation from mechanical ventilation (38.7% vs 25.7%, P = 0.027). There were no significant differences in the adverse events.. The administration of nintedanib may offer potential benefits for minimizing lung injury in COVID-19.

Topics: Adult; COVID-19; Humans; Indoles; Pulmonary Fibrosis; Respiration, Artificial; SARS-CoV-2

To date, more than 100 million people worldwide have recovered from COVID-19. Unfortunately, although the virus is eradicated in such patients, fibrotic irreversible interstitial lung disease (pulmonary fibrosis, PF) is clinically evident. Given the vast numbers of individuals affected, it is urgent to design a strategy to prevent a second wave of late mortality associated with COVID-19 PF as a long-term consequence of such a devastating pandemic. Available antifibrotic therapies, namely nintedanib and pirfenidone, might have a role in attenuating profibrotic pathways in SARS-CoV-2 infection but are not economically sustainable by national health systems and have critical adverse effects. It is our opinion that the mesenchymal stem cell secretome could offer a new therapeutic approach in treating COVID-19 fibrotic lungs through its anti-inflammatory and antifibrotic factors.

Topics: Biological Factors; COVID-19; COVID-19 Drug Treatment; Humans; Indoles; Lung; Mesenchymal Stem Cells; Pulmonary Fibrosis; Pyridones; SARS-CoV-2

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a fatal event that can occur during the clinical course of idiopathic pulmonary fibrosis (IPF). Although data from clinical trials suggest that the antifibrotic agents pirfenidone and nintedanib might reduce the risk of AE-IPF, the incidence of AE-IPF in patients receiving antifibrotic agents in clinical settings is unclear.. To determine the incidence of AE-IPF in patients receiving antifibrotic agents and compare AE-IPF frequency in patients receiving pirfenidone and nintedanib.. We retrospectively reviewed the clinical records of 199 patients with IPF who were started on pirfenidone or nintedanib at our institution during the period from 2009 through 2018. Baseline characteristics, incidence of AE-IPF, and outcome after AE-IPF onset were analyzed.. During the observation period, the 1-, 2-, and 3-year cumulative incidences of AE-IPF were 9.3 %, 22.1 %, and 25.0 %, respectively. The 1-, 2-, and 3-year cumulative incidence rates for AE-IPF in the pirfenidone group and nintedanib group were 5.1 % vs. 18.6 %, 20.4 % vs. 25.2 %, and 22.6 % vs. 29.6 %, respectively. AE-IPF incidence was significantly lower in patients treated with pirfenidone than in those treated with nintedanib (log rank test, P = 0.035). The 3-month survival rate after AE-IPF onset was 61.1 % in the pirfenidone group and 61.5 % in the nintedanib group; thus, outcomes after AE-IPF onset were similar in the 2 groups.. The reduction in AE-IPF risk might be greater for pirfenidone than for nintedanib.

Topics: Aged; Aged, 80 and over; Antifibrotic Agents; Disease Progression; Female; Humans; Incidence; Indoles; Male; Pulmonary Fibrosis; Pyridones; Time Factors; Treatment Outcome

Idiopathic pulmonary fibrosis, characterized by excess accumulation of extracellular matrix, involved in many chronic diseases or injuries, threatens human health greatly. We have reported a series of compounds bearing coumarin scaffold which potently inhibited TGF-β-induced total collagen accumulation in NRK-49F cell line and migration of macrophages. Compound 9d also suppressed the TGF-β-induced protein expression of COL1A1, α-SMA, and p-Smad3 in vitro. Meanwhile, 9d at a dose of 100 mg/kg/day through oral administrations for 4 weeks effectively alleviated infiltration of inflammatory cells in lung tissue and fibrotic degree in bleomycin-induced pulmonary fibrosis model, which may related to its inhibition of TGF-β/Smad3 pathway and anti-inflammation efficacy. In addition, 9d demonstrated decent bioavailability (F = 39.88%) and suitable eliminated half-life time (T

Topics: Animals; Bleomycin; Cell Movement; Cell Survival; Cells, Cultured; Coumarins; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Pulmonary Fibrosis; RAW 264.7 Cells; Structure-Activity Relationship

Topics: Humans; Indoles; Lung Diseases, Interstitial; Pulmonary Fibrosis

Topics: Humans; Indoles; Lung Diseases, Interstitial; Pulmonary Fibrosis

Topics: Humans; Indoles; Lung Diseases, Interstitial; Pulmonary Fibrosis

Topics: Humans; Indoles; Lung Diseases, Interstitial; Pulmonary Fibrosis

Topics: Double-Blind Method; Humans; Indoles; Lung Diseases, Interstitial; Pulmonary Fibrosis

Topics: Humans; Indoles; Lung Diseases, Interstitial; Pulmonary Fibrosis; Treatment Outcome

Neutrophils are involved in the alveolitis of idiopathic pulmonary fibrosis (IPF). However, their pathogenic mechanisms are still poorly understood. Nintedanib has antifibrotic and anti-inflammatory activity in IPF. This study aimed to investigate the regulatory mechanism of nintedanib on neutrophil chemotaxis in bleomycin (BLM)-induced pulmonary fibrosis. Nintedanib was administered via oral gavage to male C57BL/6 mice 24 h after a bleomycin intratracheal injection (1.5 U/kg). Lung histopathological findings, the expression of cytokines, and the regulatory signaling pathways of neutrophil chemotaxis were analyzed. The effect of nintedanib was also investigated in a mouse model with adoptive neutrophil transfer in vivo. Nintedanib significantly decreased the histopathological changes and neutrophil recruitment in BLM-induced pulmonary fibrosis. Nintedanib mediated a downregulation of chemokine (C-X-C motif) receptor 2 (CXCR2) and very late antigen 4 (VLA-4) expression, as well as an upregulation of G protein-coupled receptor kinase 2 (GRK2) activity in peripheral blood neutrophils in BLM-induced pulmonary fibrosis. Nintedanib also decreased the activation of endothelial cells by the decreased expression of vascular cell adhesion molecule 1 (VCAM-1). The effect of nintedanib on regulating neutrophil chemotaxis was also confirmed by a mouse model with adoptive neutrophil transfer in vivo. In conclusion, nintedanib reduces neutrophil chemotaxis and endothelial cell activation to regulate the severity of BLM-induced pulmonary fibrosis. These effects are associated with an enhancement of GRK2 activity and a reduction in CXCR2 and VLA-4 expression on neutrophils and a decrease in VCAM-1 expression on endothelial cells.

Topics: Animals; Bleomycin; Chemotaxis; Chemotaxis, Leukocyte; Endothelial Cells; G-Protein-Coupled Receptor Kinase 2; Idiopathic Pulmonary Fibrosis; Indoles; Lung; Male; Mice; Mice, Inbred C57BL; Neutrophils; Pulmonary Fibrosis; Signal Transduction

In this review, the authors describe therapeutic strategies for a disease group called progressive fibrosing interstitial lung disease (PF-ILD) and highlight the importance of the definition of progression, prognosis, and treatment response.. Although it is a relatively new concept, the term PF-ILD has been increasingly applied in clinical research and practice. Three domains commonly used to detect the disease progression include clinical symptoms, rate of forced vital capacity (FVC) decline and the extent of fibrosis on imaging. Although details of the pathogenesis of PF-ILD are still unclear, it has become apparent that genetic predisposition and an abnormal tissue microenvironment and host response are involved in the nature of the disease. Antifibrotic agents recently showed their efficacy on the treatment of PF-ILD. Both nintedanib and pirfenidone can slow the disease progression, as defined by a decline of FVC from baseline, of PF-ILD whenever compared with placebo, similar to the results in idiopathic pulmonary fibrosis (IPF) trials. This effect seems consistent irrespective of the underlying ILD diagnosis.. Recent evidence supports the use of antifibrotic therapy in the management of the phenotype progressive non-IPF ILD. Ongoing studies exploring genetic and other molecular biomarkers could identify at-risk individuals or predict treatment response and prognosis (endotypes). This would support the concept of 'treatable traits' in the field of ILD.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Disease Progression; Humans; Indoles; Lung Diseases, Interstitial; Phenotype; Prognosis; Protein Kinase Inhibitors; Pulmonary Fibrosis; Pyridones; Treatment Outcome; Vital Capacity

Immunotherapy-related adverse events (irAEs) are common immunotherapy-associated diseases. Severe pulmonary fibrosis with hypercytokinaemia has not been reported with programmed cell death 1 (PD-1) inhibitors. We describe a case of sintilimab-induced pulmonary fibrosis with cytokine storm induced in a 50-year-old patient with colon cancer refractory to second-line systemic chemotherapy.. Our patient developed hypercytokinaemia with elevated levels of interleukin (IL)-6 and IL-10 and pulmonary fibrosis, which differed from other irAEs. The patient benefited from a back-titrated regimen of methylprednisolone with the initial dosage of 2 mg/kg and anti-fibrotic effect of nintedanib and was successfully weaned from the ventilator.. This is the first report that a PD-1 inhibitor may have caused pulmonary fibrosis and a cytokine storm. This case indicates that the addition of nintedanib and glucocorticoid might possibly have potentially therapeutic effects of PD-1 induced pulmonary fibrosis and hypercytokinaemia.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Colonic Neoplasms; Cytokine Release Syndrome; Glucocorticoids; Humans; Immunotherapy; Indoles; Male; Methylprednisolone; Middle Aged; Pulmonary Fibrosis

The present study compared the effects of antifibrotic medications, pirfenidone, and nintedanib, with transplantation of human umbilical mesenchymal stem cells (HUMSCs) in restoring rat pulmonary fibrosis (PF).. Pulmonary function examination revealed that BLM rats exhibited a significant decrease in blood oxygen saturation and an increase in respiratory rates. While no significant improvements were found in BLM rats receiving nintedanib or pirfenidone, those who transplanted with HUMSCs showed a statistical amelioration in blood oxygen saturation and significant alleviation in respiratory rates. Quantification results revealed that a significant reduction in alveolar space and marked increases in substantial cell infiltration and collagen deposition in the left lungs of BLM rats. No significant alteration was observed in BLM rats administered nintedanib or pirfenidone. However, BLM rats transplanted with HUMSCs had a significant recovery in alveolar space and noticeable decreases in cell infiltration and collagen deposition. The inflammatory cell numbers in the bronchoalveolar lavage was increased in the BLM group. While the rats treated with nintedanib or pirfenidone had a lower cell number than the BLM group, a higher cell number was found as compared with the Normal group. In rats transplanted with HUMSCs, the cell number did not differ from the Normal group.. Transplantation of HUMSCs could effectively treat PF as opposed to the administration of anti-fibrotic drugs with nintedanib or pirfenidone with a significant better result in lung volume, pathological changes, lung function, and blood oxygen saturation.

Topics: Animals; Bleomycin; Humans; Indoles; Lung; Mesenchymal Stem Cells; Pulmonary Fibrosis; Pyridones; Rats; Wharton Jelly

Fibrosing, non-idiopathic pulmonary fibrosis (non-IPF) interstitial lung diseases (fILDs) are a heterogeneous group of diseases characterized by a different amount of inflammation and fibrosis. Therapy is currently based on corticosteroids and/or immunomodulators. However, response to these therapies is highly variable, sometimes without meaningful improvement, especially in more fibrosing forms. Pirfenidone and nintedanib have recently demonstrated to reduce functional decline in patients with IPF. However, their antifibrotic mechanism makes these two drugs an interesting approach for treatment of fibrosing ILDs other than IPF.. We here report our experience with antifibrotic drugs in fibrosing non-IPF ILDs patients having a progressive phenotype during immunosuppressive therapy.. Patients with a multidisciplinary team diagnosis of fibrosing non-IPF ILDs experiencing a progressive phenotype during treatment with corticosteroids and/or immunomodulators between October-2014 and January-2018 at our tertiary referral Center for ILDs were retrospectively analyzed. Antifibrotic therapy was administered after application with the respective health insurance company and after consent by the patient. Pulmonary-function-tests and follow-up visits were performed every 6 ± 1 months.. Eleven patients were treated with antifibrotic drugs (8 males, mean age 62 ± 12.8 years, mean FVC% 62.8 ± 22.3, mean DLCO% 35.5 ± 10.7, median follow-up under antifibrotic treatment 11.1 months). Patients had a diagnosis of unclassifiable ILD in 6 cases, pleuroparenchymal fibroelastosis in 2 cases, idiopathic-NSIP in 1 case, asbestos-related ILD in 1 case and Hermansky-Pudlak syndrome in 1 case. Treatment before antifibrotics consisted of corticosteroids in all patients: 5 combined with Azathioprin, 1 with either methotrexate or cyclophosphamide (i.v.). Ten patients were treated with pirfenidone (2403 mg/die) and 1 with nintedanib (300 mg/die). Median FVC was 56, 56, 50%, at time points - 24, - 12, - 6 before initiation, 44% at time of initiation and 46.5% at 6 months after initiation of antifibrotic treatment. Antifibrotic treatment was generally well tolerated with a need of dose reduction in 2 cases (rash and nausea) and early termination in 3 cases.. Antifibrotic treatment may be a valuable treatment option in patients with progressive fibrosing non-IPF ILD if currently no other treatment options exist. However, prospective, randomized clinical trials are urgently needed to assess the real impact of antifibrotic therapy in these patients.

Topics: Aged; Disease Progression; Female; Humans; Indoles; Lung; Lung Diseases, Interstitial; Male; Middle Aged; Phenotype; Pulmonary Fibrosis; Pyridones; Retrospective Studies; Risk Factors; Tertiary Care Centers; Tomography, X-Ray Computed

Topics: Adult; Allografts; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Indoles; Lymphoma, T-Cell, Peripheral; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pulmonary Fibrosis

Fibrosis is a severe health problem characterized by progressive stiffening of tissues which causes organ malfunction and failure. A major bottleneck in developing new anti-fibrosis therapies is the lack of in vitro models that recapitulate dynamic changes in tissue mechanics during fibrogenesis. Here we create membranous human lung microtissues to model key biomechanical events occurred during lung fibrogenesis including progressive stiffening and contraction of alveolar tissue, decline in alveolar tissue compliance and traction force-induced bronchial dilation. With these capabilities, we provide proof of principle for using this fibrotic tissue array for multi-parameter, phenotypic analysis of the therapeutic efficacy of two anti-fibrosis drugs recently approved by the FDA. Preventative treatments with Pirfenidone and Nintedanib reduce tissue contractility and prevent tissue stiffening and decline in tissue compliance. In a therapeutic treatment regimen, both drugs restore tissue compliance. These results highlight the pathophysiologically relevant modeling capability of our novel fibrotic microtissue system.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Drug Evaluation, Preclinical; Fibroblasts; Fibrosis; Humans; Indoles; Lung; Lung Compliance; Primary Cell Culture; Pulmonary Fibrosis; Pyridones; Tissue Culture Techniques; Tissue Scaffolds; Treatment Outcome

Nintedanib (NDN), a tyrosine kinase inhibitor, has been shown to have anti-tumor, anti-inflammatory, and anti-fibrotic effects in several reports. We investigated the protective effects of NDN against polyhexamethylene guanidine phosphate (PHMG)-induced lung fibrosis in mice. The following three experimental groups were evaluated: (1) vehicle control; (2) PHMG (1.1 mg/kg); and (3) PHMG & NDN (60 mg/kg). PHMG induced pulmonary inflammation and fibrosis by intratracheal instillation in mice. In contrast, NDN treatment effectively alleviated the PHMG induced lung injury, and attenuated the number of total cells and inflammatory cells in the bronchoalveolar lavage fluid, including the fibrotic histopathological changes, and also reduced the hydroxyproline content. NDN also significantly decreased the expression of inflammatory cytokines and fibrotic factors, and the activation of the NLRP3 inflammasome in lung tissues. These results suggest that NDN may mitigate the inflammatory response and development of pulmonary fibrosis in the lungs of mice treated with PHMG.

Topics: Animals; Body Weight; Bronchoalveolar Lavage Fluid; Cell Count; Cytokines; Guanidines; Hydroxyproline; Indoles; Inflammasomes; Inflammation Mediators; Lung; Male; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Organ Size; Protective Agents; Pulmonary Fibrosis

Topics: Anti-Inflammatory Agents, Non-Steroidal; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Pulmonary Fibrosis; Pyridones

A 70-year-old patient with known hereditary haemorrhagictelangiectasia (HHT) was seen regularly in our outpatient clinic. He underwent multiple therapeutical interventions, including both surgical and medical, for the treatment of recurrent epistaxis without sustained success. Due to a concurrent diagnosis of idiopathic pulmonary fibrosis, treatment with the tyrosine kinase inhibitor nintedanib was initiated, after which point the patient reported a dramatic and unanticipated improvement in his epistaxis and skin telangiectasia. On the basis of this case report, we propose that nintedanib may be a potential treatment option for refractory epistaxis in HHT.

Topics: Aged; Enzyme Inhibitors; Epistaxis; Humans; Indoles; Male; Protein-Tyrosine Kinases; Pulmonary Fibrosis; Skin Diseases; Telangiectasia, Hereditary Hemorrhagic

Topics: Animals; Collagen; Humans; Indoles; Pulmonary Fibrosis; Pyridones

Nintedanib has anti-fibrotic and anti-inflammatory activity and is approved for the treatment of idiopathic pulmonary fibrosis. The aim of this study was to noninvasively assess the efficacy of nintedanib in a mouse model of partial lung irradiation to prevent radiation-induced lung damage (RILD).. 266 C57BL/6 adult male mice were irradiated with a single radiation dose (0, 4, 8, 12, 16 or 20Gy) using parallel-opposed fields targeting the upper right lung using a precision image-guided small animal irradiator sparing heart and spine based on micro-CT images. One week post irradiation, mice were randomized across nintedanib daily oral gavage treatment (0, 30 or 60mg/kg). CT density analysis of the lungs was performed on monthly acquired micro-CT images. After 39weeks, lungs were processed to evaluate the fibrotic phenotype.. Although the CT density increase correlated with the radiation dose, nintedanib did not influence this relationship. Immunohistochemical analysis confirmed the ability of nintedanib to reduce the microscopic fibrotic phenotype, in particular interstitial edema, interstitial and perivascular fibrosis and inflammation, and vasculitis.. Nintedanib reduces radiation-induced lung fibrosis after partial lung irradiation without adverse effects, however, noninvasive CT imaging measuring electron density cannot be applied for monitoring its effects.

Topics: Animals; Disease Models, Animal; Indoles; Lung; Male; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Radiation Injuries; Radiotherapy, Image-Guided; Tomography, X-Ray Computed

Nintedanib, a tyrosine kinase inhibitor that is specific for platelet-derived growth factor receptors (PDGFR), fibroblast growth factor receptors (FGFR), and vascular endothelial growth factor receptors (VEGFR), has recently been approved for idiopathic pulmonary fibrosis. Fibrocytes are bone marrow-derived progenitor cells that produce growth factors and contribute to fibrogenesis in the lungs. However, the effects of nintedanib on the functions of fibrocytes remain unclear.. Human monocytes were isolated from the peripheral blood of healthy volunteers. The expression of growth factors and their receptors in fibrocytes was analyzed using ELISA and Western blotting. The effects of nintedanib on the ability of fibrocytes to stimulate lung fibroblasts were examined in terms of their proliferation. The direct effects of nintedanib on the differentiation and migration of fibrocytes were also assessed. We investigated whether nintedanib affected the accumulation of fibrocytes in mouse lungs treated with bleomycin.. Human fibrocytes produced PDGF, FGF2, and VEGF-A. Nintedanib and specific inhibitors for each growth factor receptor significantly inhibited the proliferation of lung fibroblasts stimulated by the supernatant of fibrocytes. Nintedanib inhibited the migration and differentiation of fibrocytes induced by growth factors in vitro. The number of fibrocytes in the bleomycin-induced lung fibrosis model was reduced by the administration of nintedanib, and this was associated with anti-fibrotic effects.. These results support the role of fibrocytes as producers of and responders to growth factors, and suggest that the anti-fibrotic effects of nintedanib are at least partly mediated by suppression of fibrocyte function.

Topics: Animals; Cell Movement; Cells, Cultured; Dose-Response Relationship, Drug; Fibroblasts; Humans; Indoles; Male; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Treatment Outcome; Vascular Endothelial Growth Factor A

Topics: Acetylcysteine; Azathioprine; Clinical Trials as Topic; Forecasting; Glucocorticoids; Humans; Indoles; Multicenter Studies as Topic; Prognosis; Pulmonary Fibrosis; Pyridones

Topics: Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Clinical Trials as Topic; Congresses as Topic; Drug Approval; Enzyme Inhibitors; Humans; Indoles; Patient Selection; Pulmonary Fibrosis; Pyridones; Rare Diseases

Topics: Disease Progression; Enzyme Inhibitors; Humans; Indoles; Long-Term Care; Protein-Tyrosine Kinases; Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating disease for which two medications, pirfenidone and nintedanib, have only recently been approved for treatment. The cytokine TGF-β has been shown to be a central mediator in the disease process. We investigated the role of a novel kinase, MAP3K19, upregulated in IPF tissue, in TGF-β-induced signal transduction and in bleomycin-induced pulmonary fibrosis. MAP3K19 has a very limited tissue expression, restricted primarily to the lungs and trachea. In pulmonary tissue, expression was predominantly localized to alveolar and interstitial macrophages, bronchial epithelial cells and type II pneumocytes of the epithelium. MAP3K19 was also found to be overexpressed in bronchoalveolar lavage macrophages from IPF patients compared to normal patients. Treatment of A549 or THP-1 cells with either MAP3K19 siRNA or a highly potent and specific inhibitor reduced phospho-Smad2 & 3 nuclear translocation following TGF-β stimulation. TGF-β-induced gene transcription was also strongly inhibited by both the MAP3K19 inhibitor and nintedanib, whereas pirfenidone had a much less pronounced effect. In combination, the MAP3K19 inhibitor appeared to act synergistically with either pirfenidone or nintedanib, at the level of target gene transcription or protein production. Finally, in an animal model of IPF, inhibition of MAP3K19 strongly attenuated bleomycin-induced pulmonary fibrosis when administered either prophylactically ortherapeutically. In summary, these results strongly suggest that inhibition of MAP3K19 may have a beneficial therapeutic effect in the treatment of IPF and represents a novel strategy to target this disease.

Topics: A549 Cells; Animals; Bleomycin; Bronchoalveolar Lavage; Cell Line, Tumor; Disease Models, Animal; Epithelial Cells; Female; HeLa Cells; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Lung; Lung Injury; MAP Kinase Kinase Kinases; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Pyridones; Signal Transduction; Transforming Growth Factor beta; Up-Regulation