nintedanib and Inflammation

Idiopathic pulmonary fibrosis (IPF) is a progressive, and ultimately fatal, chronic interstitial lung disease characterized by enhanced extracellular matrix deposition. Repetitive alveolar epithelial injury triggers the early development of fibrosis. These injuries, in combination with dysregulated wound repair and fibroblast dysfunction, lead to ongoing tissue remodelling and fibrosis seen in end-stage pulmonary fibrosis. Although the exact etiology in IPF is unknown and probably diverse, all stages of fibrosis are accompanied by innate and adaptive immune responses. The role of inflammation as an important component in IPF etiology is controversial and sometimes seen as an epiphenomenon of fibrosis. This view is partly the result of negative multicenter trials of anti-inflammatory drugs for IPF treatment. However, new insights on the role of macrophages, the loss of T-cell and B-cell tolerance leading auto-immune responses in IPF, and the interaction of immune cells with (myo)fibroblasts have led to a slow change of this opinion. Clearly, more insight is needed to integrate basic immune mechanisms into translational research and finally new IPF therapies. In this concise review, we will focus on the role of our innate and adaptive immune system in the initiation and perpetuation of IPF pathobiology. Next, we will discuss how immune responses are influenced by current anti-fibrotic treatments, such as pirfenidone and nintedanib and end with an overview of recent and upcoming therapeutic trials that target and modulate our immune system in patients with IPF.

Topics: Adaptive Immunity; Anti-Inflammatory Agents; Clinical Trials as Topic; Extracellular Matrix; Fibroblasts; Fibrosis; Humans; Idiopathic Pulmonary Fibrosis; Immunity, Innate; Indoles; Inflammation; Protein Kinase Inhibitors; Pyridones

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by vasculopathy, inflammation and fibrosis. These three main disease-determining pathways are the target of the currently available treatments used to possibly modify the progression of disease-related manifestations, although this synergy has not been fully applied on SSc joint, skin or lung involvement yet. Areas covered: we describe the current status of SSc treatment/therapy performing a literature search in MEDLINE/Pubmed and Thomson Reuter's Web of Science for articles published until March 2016. Moreover, ongoing registered clinical trials (RCTs) on SSc were searched through clinicaltrials.gov website. Expert commentary: presently, promising drugs are under evaluation to target the different pathogenic pathways of systemic sclerosis: Tocilizumab and Abatacept for skin and lung fibrosis; Riociguat and Selexipag are approved for pulmonary arterial hypertension but promising anti-fibrotic effects are now being studied. Finally, several anti-fibrotic molecules are currently involved in RCTs, such as Nintedanib, IVA-337, Terguride.

Topics: Abatacept; Acetamides; Antibodies, Monoclonal, Humanized; Biological Products; Clinical Trials as Topic; Fibrinolytic Agents; Fibrosis; Humans; Hypertension, Pulmonary; Indoles; Inflammation; Joints; Lisuride; Lung; PubMed; Pyrazines; Pyrazoles; Pyrimidines; Scleroderma, Systemic; Skin

Accurate. Since sCD30 levels and sCD26/sCD30 ratios may contribute to the activity of the disease, they may be used to assess ITP disease activity.. hBMSCs and hFOB1.19 cells modulate the phenotype of PC3 prostate cancer cells and the expression of CD59 by activating the RANK/RANKL/OPG signaling pathway.. Results showed that the EEG responses at lower levels of the independent variables were significantly high than at higher levels; except for oxygen content, the EEG responses at lower levels were considerably lower than at a higher level. It also showed that an upsurge in the physical demand increased lifting frequency and replication and caused decreasing in alpha power, theta/beta, alpha/beta, (theta + alpha)/beta, (theta + alpha)/(alpha + beta) and increasing in the theta power and the gamma power. Furthermore, several interactions among independent variables had significant effects on the EEG responses.. The EEG implementation for the investigation of neural responses to physical demands allows for the possibility of newer nontraditional and faster methods of human performance monitoring. These methods provide effective and reliable results as compared to other traditional methods. This study will safeguard the physical capabilities and possible health risks of industrial workers. And the applications of these tasks can occur in almost all working environments (factories, warehouses, airports, building sites, farms, hospitals, offices, etc.) that are at high altitudes. It can include lifting boxes at a packaging line, handling construction materials, handling patients in hospitals, and cleaning.

Topics: Action Potentials; Adolescent; Adult; Aged; Alanine Transaminase; Analgesics; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Apoptosis; Arrhythmias, Cardiac; Atrial Fibrillation; Biological Transport; Biomarkers; Blood Gas Analysis; Blood-Brain Barrier; Blotting, Western; Bone and Bones; Bone Marrow; Bone Neoplasms; Brain; Breast Neoplasms; Calcium; Carbon Tetrachloride; Cartilage, Articular; Case-Control Studies; CD59 Antigens; CDC2 Protein Kinase; Celastrus; Cell Cycle; Cell Division; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chemical Fractionation; Colitis, Ulcerative; Colon; Computer Simulation; Curcumin; Cyclin B1; Cymenes; Cytokines; Dextran Sulfate; Dipeptidyl Peptidase 4; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Ectodysplasins; Electroencephalography; Endothelial Cells; Epithelial Cells; Epithelial-Mesenchymal Transition; Exosomes; Female; Flavonoids; G2 Phase; Gene Expression Regulation; Glial Cell Line-Derived Neurotrophic Factor; Heart Atria; Heart Conduction System; Heart Ventricles; HeLa Cells; Hemodynamics; Humans; Image Interpretation, Computer-Assisted; Indoles; Inflammation; Interleukin-1beta; Interleukin-6; Iridoid Glycosides; Ki-1 Antigen; Lens, Crystalline; Lifting; Liver; Liver Cirrhosis; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Microelectrodes; Middle Aged; Models, Cardiovascular; Multiparametric Magnetic Resonance Imaging; Myeloid Differentiation Factor 88; NADPH Oxidase 1; Neoplasm Grading; NF-kappa B; Osteoarthritis; Osteoblasts; Osteoclasts; Oxidative Stress; Oxygen; Patch-Clamp Techniques; PC-3 Cells; Permeability; Peroxidase; Plant Extracts; Plant Leaves; Prostate; Prostatic Neoplasms; Protective Agents; Proto-Oncogene Proteins c-akt; Psychophysics; Purpura, Thrombocytopenic, Idiopathic; Rabbits; Rats; Rats, Sprague-Dawley; Recovery of Function; Retrospective Studies; RNA, Long Noncoding; ROC Curve; Safety; Shoes; Signal Transduction; Sodium; Sonication; Spinal Cord; Spinal Cord Injuries; Syringa; Tight Junctions; Tissue Inhibitor of Metalloproteinase-1; Toll-Like Receptor 2; Transforming Growth Factor beta2; Transient Receptor Potential Channels; Tumor Microenvironment; Tumor Necrosis Factor-alpha; Umbilical Cord; Up-Regulation; Ventricular Function; Young Adult

We aimed to determine the effectiveness of Nintedanib treatment, which has known antifibrotic effect, in preventing fibrosis after urethral trauma.. Twenty-three adult Sprague-Dawley rats were divided randomly into 3 different groups: Sham, Urethral injury group (UI) and Urethral injury+ Nintedanib (UI+N). The urethral injury model was made with a pediatric urethrotome knife. Nintedanib was administered at a dose of 50mg/kg by oral gavage for 14 days at the same time every day. After 14 days of treatment, all rats were performed penectomy under general anesthesia. Urethral tissue was evaluated histopathologically (congestion, inflammatory cell infiltration and spongiofibrosis) and immunohistochemically (transforming growth factor (TBF) Beta-1 and vascular endothelial growth factor receptor 2 (VEBFR2)).. Histopathological findings: Group UI had higher scores in all categories (congestion, inflammatory cell infiltration, and spongiofibrosis), followed by Group UI+N and Group Sham, respectively. A statistically significant difference was found between Group UI and Group UI+N in terms of the scores of histopathological parameters (p<0.05). Immunohistochemical findings: Group UI had higher scores in both categories, followed by Group UI+N and Group Sham, respectively. A statistically significant difference was found between Group UI and Group UI+N in TGF Beta-1 and VEGF scores (p<0.05).. We found that Nintedanib administration after urethral trauma reduced inflammation and fibrosis histologically and immunohistochemically. The positive effect of Nintedanib on inflammation and fibrosis after urethral trauma reported in this animal study is encouraging for a potential clinical human application.

Topics: Animals; Child; Fibrosis; Humans; Inflammation; Male; Rats; Rats, Sprague-Dawley; Vascular Endothelial Growth Factor A

Idiopathic pulmonary fibrosis (IPF) seriously threatens human life and health, and no curative therapy is available at present. Nintedanib is the first agent approved by the US Food and Drug Administration (FDA) in order to treat IPF; however, its mechanism of inhibition of IPF is still elusive. According to recent studies, nintedanib is a potent inhibitor. It can antagonize platelet-derived growth factor (PDGF), basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF), etc., to inhibit pulmonary fibrosis. Whether there are other signaling pathways involved in IPF remains unknown. This study focused on investigating the therapeutic efficacy of nintedanib in bleomycin-mediated pulmonary fibrosis (PF) mice through PI3K/Akt/mTOR pathway. Following the induction of pulmonary fibrosis in C57 mice through bleomycin (BLM) administration, the mice were randomized into five groups: (1) the normal control group, (2) the BLM model control group, (3) the low-dose Nintedanib administration model group, (4) the medium-dose nintedanib administration model group, and (5) the high-dose nintedanib administration model group. For lung tissues, morphological changes were found by HE staining and Masson staining, ELISA method was used to detect inflammatory factors, alkaline water method to estimate collagen content, and western blotting for protein levels. TUNEL staining and immunofluorescence methods were used to analyze the effect of nintedanib on lung tissue and the impacts and underlying mechanisms of bleomycin-induced pulmonary fibrosis. After 28 days, bleomycin-treated mice developed significant pulmonary fibrosis. Relative to bleomycin-treated mice, nintedanib-treated mice had markedly reduced degrees of PF. In addition, nintedanib showed lung-protective effects by up-regulating antioxidant levels, down-regulating inflammatory protein expression, and reducing collagen accumulation. We demonstrated that nintedanib ameliorated bleomycin-induced lung injury by inhibiting the P13K/Akt/mTOR pathway as well as apoptosis. In addition, significant improvement in pulmonary fibrosis was seen after nintedanib (30/60/120 mg/kg body weight/day) treatment through a dose-dependent way. Histopathological results further corroborated the effect of nintedanib treatment on remarkably attenuating bleomycin-mediated mouse lung injury. According to our findings, nintedanib restores the antioxidant system, suppresses pro-inflammatory factors, and inhibits apoptosis.

Topics: Animals; Antioxidants; Apoptosis; Bleomycin; Collagen; Humans; Idiopathic Pulmonary Fibrosis; Inflammation; Lung; Mice; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

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

Atherosclerosis (AS) is a life-threatening cardiovascular disease and it has been reported that endothelial dysfunction is the initial inducer of AS. Recent reports suggest that inflammation and oxidative stress-induced cell senescence are main inducers of endothelial dysfunction. Nintedanib is an effective inhibitor of multityrosine kinase receptors developed for the treatment of fibrosis, which was recently reported to exert inhibitory effects against inflammation and oxidative stress. The present study plans to study the effect and mechanism of Nintedanib on endothelial dysfunction. We found that in oxidized low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs), the increased production of total cholesterol (TC), free cholesterol (FC), and pro-inflammatory cytokines were observed, reversed by 10 μM and 25 μM Nintedanib. The elevated reactive oxygen species (ROS) and malondialdehyde (MDA) levels, as well as the declined activity of glutathione peroxidase (GSH-Px) in ox-LDL-treated HUVECs, were significantly abolished by 10 μM and 25 μM Nintedanib. Increased proportion of senescence-associated β-galactosidase (SA-β-gal) positive staining cells, activated p53/p21 pathway, and promoted cell fraction in the G0/G1 phase were observed in ox-LDL-treated HUVECs, all of which were dramatically reversed by 10 μM and 25 μM Nintedanib. Lastly, the increased expression level of Arginase-II (Arg-II) in HUVECs by ox-LDL was repressed by Nintedanib. The protective effects of Nintedanib on ox-LDL- induced cellular senescence were pronouncedly blocked by the overexpression of Arg-II. Collectively, our data suggest that Nintedanib mitigates ox-LDL-induced inflammation and cellular senescence in vascular endothelial cells by downregulating Arg-II.

Topics: Apoptosis; Atherosclerosis; Cellular Senescence; Human Umbilical Vein Endothelial Cells; Humans; Indoles; Inflammation; Lipoproteins, LDL; Oxidative Stress

Psoriasis is a common chronic skin disorder characterized by keratinocyte hyperproliferation with altered differentiation accompanied by increased inflammation and angiogenesis. Nintedanib is a tyrosine kinase inhibitor that has anti-inflammatory, anti-angiogenesis, and anti-fibrotic effects. In this study, we explored the potential effects and mechanisms of nintedanib on psoriasis in vivo and in vitro. In vivo experiments showed that nintedanib effectively alleviated imiquimod-induced psoriasis-like skin lesions and reduced psoriasis severity index scores. For the mechanism research, we mainly focused on the abnormal phenotype of keratinocyte in the pathogenesis of psoriasis. We used HaCaT cells in the in vitro experiments and the result revealed that nintedanib restored keratinocyte homeostasis by downregulated the expression of proinflammatory factors, inhibited hyperproliferation, promoted apoptosis, maintained normal differentiation via regulating the NF-κB pathway. In addition, nintedanib regulated angiogenesis by inhibiting VEGFR2 activity. In summary, our study indicated that nintedanib is a promising candidate medication for psoriatic treatment.

Topics: Animals; Apoptosis; Cell Proliferation; Cytokines; HaCaT Cells; Humans; Imiquimod; Indoles; Inflammation; Keratinocytes; Male; Mice; Mice, Inbred BALB C; Neovascularization, Physiologic; NF-kappa B; Psoriasis; Signal Transduction; Skin; Vascular Endothelial Growth Factor Receptor-2

Surfactant protein D (SPD) is a member of the collectin family that lines the airway epithelial cells with host defense. However, the role of SPD in the pathogenesis of aspirin-exacerbated respiratory disease (AERD) is still unclear.. The serum SPD level was measured in patients with AERD (n = 336), those with aspirin-tolerant asthma (ATA, n = 442), and healthy controls (HC, n = 104). Polymorphisms of SFTPD in the study subjects were analyzed. The effect of LTE4 on SPD production through eosinophil infiltration was investigated in BALB/c mice. The protective function of SPD against eosinophils inducing inflammation and remodeling was assessed in vitro/vivo. The potential efficacy of nintedanib against airway remodeling through the production of SPD was evaluated.. The decreased level of SPD in AERD was associated with airway inflammation/remodeling under the eosinophilic condition, suggesting that modulation of SPD may provide a potential benefit in AERD.

Topics: Adult; Airway Remodeling; Animals; Asthma, Aspirin-Induced; Eosinophils; Female; Humans; Indoles; Inflammation; Leukotriene E4; Male; Mice; Mice, Inbred BALB C; Middle Aged; Pulmonary Surfactant-Associated Protein D; Respiratory System

Prostate cancer is the most prevalent type of cancer in men around the world. Due to its high incidence, new therapies have been evaluated, including drugs capable of inhibiting the FGF/VEGF pathways, as Nintedanib. The aim herein was to evaluate the Nintedanib therapeutic effects on morphology and COX-2 and IL-17 levels in the prostate anterior lobe in different grades of the tumor progression in TRAMP mice. Animals were treated with Nintedanib at a dose of 10 mg/kg/day in initial and intermediate grades of tumor development. At the end of treatment, the prostate anterior lobe was collected and submitted to morphological, immunohistochemical and Western Blotting analyses. The results showed that Nintedanib delayed the prostate carcinogenesis progression, with over 20% of reduction in frequency of tissue injuries, particularly in the group treated from 12 to 16 weeks of age. Also, decreased COX-2 and IL-17 levels were observed in both groups treated with Nintedanib in the prostate anterior lobe. Thus, we concluded that Nintedanib was effective in delaying tumor progression and, despite not directly acting on inflammation, Nintedanib may adversely affect inflammatory pathways, favoring prostate cancer delay.

Topics: Animals; Carcinogenesis; Cyclooxygenase 2; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Indoles; Inflammation; Interleukin-17; Male; Mice; Pituitary Gland, Anterior; Prostate; Prostatic Neoplasms; Receptors, Tumor Necrosis Factor, Member 25

Hepatic fibrosis, a progressive chronic disease mainly caused by hepatitis viral infections, alcohol abuse or metabolic syndrome leading to liver dysfunction and is the growing cause of mortality worldwide. Tyrosine kinase inhibitor BIBF1120 (Nintedanib) has been evaluated in clinical trials for idiopathic pulmonary fibrosis and advanced Hepatocellular carcinoma, but has not been explored for liver fibrosis yet. In this study, we aimed to investigate the therapeutic effects and mechanism of BIBF1120 in liver fibrogenesis. The effects of BIBF1120 were evaluated in TGFβ-activated mouse 3T3 fibroblasts, LX2 cells, primary human hepatic stellate cells (HSCs) and CCl

Topics: 3T3 Cells; Animals; Carbon Tetrachloride; Disease Models, Animal; Humans; Indoles; Inflammation; Liver Cirrhosis; Mice; Neovascularization, Pathologic; Protein-Tyrosine Kinases; Signal Transduction; Transforming Growth Factor beta

In the present study, we tested whether serum amyloid A (SAA) protein, an established biomarker of inflammation, also plays a role in stimulating neovascularization. To evaluate this possibility, human carotid artery endothelial (HCtAE) cells were cultured and cellular migration and the proinflammatory and/or thrombotic activity of SAA (0, 1 or 10 μg/mL) on vascular endothelial cells was verified by determining gene regulation relative to control (in the absence of SAA). Exposure of HCtAE cells to SAA increased expression of the transcription factor nuclear factor-κB (NFKB), tumour necrosis factor (TNF) and pro-coagulative tissue factor (F3), and stimulated phosphorylation of the P65 subunit of the NFKB complex. Enhanced production of TNF and NFKB was paralleled by increased vascular endothelial growth factor (VEGF) mRNA and protein expression, as demonstrated by quantitative polymerase chain reaction, western blotting and ELISA. Administration of 10 μg/mL SAA enhanced endothelial cell migration (1.6-fold vs control), stimulated regrowth of HCtAE cells after mechanical injury (~1.2-fold vs control) and increased endothelial tube formation relative to control after 6 h. The SAA-mediated enhancement of endothelial cell migration, proliferation and tube formation were markedly inhibited by pretreatment of HCtAE cells with the multi-angiokinase receptor inhibitor BIBF1120 (100 nmol/L), although SAA-stimulated gene responses for F3 and NFKB were unaffected by 100 nmol/L BIBF1120 pretreatment. Overall, BIBF1120 inhibited the pro-angiogenic activity of SAA on vascular endothelial cells in this experimental model of inflammation.

Topics: Carotid Arteries; Carrier Proteins; Cell Movement; Cell Proliferation; Cells, Cultured; Endothelial Cells; Endothelium, Vascular; Gene Expression Regulation; Humans; Indoles; Inflammation; Intracellular Signaling Peptides and Proteins; Neoplasm Proteins; Neovascularization, Pathologic; NF-kappa B; Phosphorylation; Serum Amyloid A Protein; Thromboplastin; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A