Nintedanib ameliorates animal model of dermatitis

Abstract

nintedanib, a receptor tyrosine kinase (RtK) inhibitor has been developed as therapeutics for idiopathic pulmonary fibrosis and non-small lung cancer. We found that the expression levels of RTK, especially VEGFR1 is increased in skin biopsies of dermatitis patients from multiple independent datasets. Moreover, VEGFR1 is highly expressed by infiltrated cells in dermis from oxazolone (OXA) treated mice. Interestingly, nintedanib alleviates dermatitis symptom in OXA-induced animal model. Especially, levels of epidermis thickness, infiltrated immune cells including mast cells and eosinophils were decreased from mice cotreated with nintedanib and OXA compared with OXA treated mice. Moreover, serum IgE and Th2 cytokines including IL-4 and IL-13 were decreased by nintedanib treatment. These results suggest an evidence that nintedanib alleviates animal model of dermatitis. Receptor tyrosine kinases (RTKs) are membrane bound receptors for growth factors and hormones that modulate cellular process to have a crucial role in the development 1,2. Because RTKs also often overexpressed in cancers including breast and non-small lung cancers, many inhibitors against RTKs have been developed for anticancer treatments 3. On the other hands, tyrosine kinase mediates the signal from various immune related receptors including leukocyte antigen receptors, innate immune receptors, and cytokine receptors to activate immune cells and recruit to inflammation lesion 4. Autoimmune and inflammatory diseases are characterized by inflammatory microenvironment and tyrosine kinase serves essential role in immune-mediated disorders 5. Therefore, small molecules targeting tyrosine kinase have been developed for autoimmune and inflammatory diseases 6-8. Especially JAK is a one of primary tyrosine kinases for therapeutic target since JAK is responsible for numerous cytokines expression via type I/II cytokine receptor signaling 9-11. Many JAK inhibitors are FDA approved in clinic use for autoimmune and inflammatory diseases 12. Atopic dermatitis (AD) is one of the most common skin inflammatory diseases affecting 3-10% adults and 15-20% of children in USA 13-15. AD pathogenesis is a complex of skin barrier dysfunction, alteration of immune responses, IgE-mediated hypersensitivity 16,17. Treatments of atopic dermatitis are non-specific immunosuppressants and Th2 specific therapies including biologics 18-20. Because IL-4, which is a primary pathogenic in AD requires JAK1 and 3 with additional complex, JAK inhibitors including tofacitinib and baricitinib have been determined their efficacy on the AD 21-23. VEGFR1 is a receptor of VEGF, transduces a signal to induce angiogenesis and lymphangiogenesis 24,25. Dilated vessels and perivascular edema are frequently found in AD lesion with erythema 26,27. Moreover, increased levels of VEGF are found in plasma and AD lesion 28,29. Although VEGF-VEGFR signaling is highly activated in AD, use of VEGFR inhibitor for AD treatment remains unexplored. Interestingly, we found expression levels of RTKs are upregulated in...

Topical Administration of a Novel Acetylated Tetrapeptide Suppresses Vascular Permeability and Immune Responses and Alleviates Atopic Dermatitis in a Murine Model

“…Vascular endothelial growth factor (VEGF) is a cytokine that promotes the survival, migration, and proliferation of endothelial cells. High levels of VEGF and VEGFR are found in the plasma and AD lesions of AD patients [ 14 , 15 , 16 , 17 ]. Thus, highly activated VEGF–VEGFR signaling in AD can lead to vessel dilation, vascular hyperpermeability, and continuous extravasation of inflammatory cells and fluid into the inflamed tissue [ 16 ].…”

Exploration of the Potential Link, Hub Genes, and Potential Drugs for Coronavirus Disease 2019 and Lung Cancer Based on Bioinformatics Analysis

“…It has been reported that the binding of VEGFR can promote the growth of blood vessels in lung cancer [ 24 ], thereby affecting tumor proliferation. In addition, VEGFR was recently found to be highly expressed during inflammation [ 25 ]. KEGG pathways enrichment analysis showed the most enriched pathway was cell adhesion molecules (CAMs, hsa04514).…”

Perphenazine Attenuates the Pro-Inflammatory Responses in Mouse Models of Th2-Type Allergic Dermatitis

“…The oxazolone-induced animal model was prepared as previously described [26,37]. The mice were divided into four groups (n = 7).…”

“…Total IgE ELISA was performed as previously described [37]. Serum was collected from the aorta of mice.…”

“…Immunofluorescence was performed as previously described with slight modification [37]. Slides were incubated in blocking buffer (BLOXALL ® Endogenous Peroxidase and Alkaline Phosphatase Blocking Solution, Vector Laboratories, Inc., CA, USA) for 1 h at room temperature to remove non-specific binding.…”