EGF and PDGF receptor tyrosine kinases as therapeutic targets for chronic lung diseases.
ABSTRACT Cell-surface receptor tyrosine kinases play pivotal roles in development, tissue repair, and normal cellular homeostasis. Aberrant expression or signaling patterns of these kinases has also been linked to the progression of a diversity of diseases, including cancer, atherosclerosis, asthma, and fibrosis. Two major families of receptor tyrosine kinases, the epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) families, have received a great deal of attention as potential therapeutic targets for pulmonary diseases, as these receptors have been shown to play key roles in chronic tissue remodeling in asthma, bronchitis, and pulmonary fibrosis. The EGFR system on epithelial cells and underlying mesenchymal cells (fibroblasts, myofibroblasts, and smooth muscle cells) drives numerous phenotypic changes during the progression of these pulmonary diseases, including epithelial cell mucous cell metaplasia and mesenchymal cell hyperplasia, differentiation, and extracellular matrix production. The PDGFR system, located primarily on mesenchymal cells, transduces signals for cell survival, growth and chemotaxis. The variety of EGFR and PDGFR ligands produced by the airway epithelium or adjacent mesenchymal cells allows for intimate epithelial-mesenchymal cell communication. A full understanding of the complex mechanisms involving these receptors and ligands should lead to therapeutic strategies for the treatment of a wide range of fibroproliferative lung diseases.
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ABSTRACT: Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification with decreased alveolar number and increased airspace. Previous studies suggested that transforming growth factor-α (TGF-α) may contribute to arrested alveolar development in BPD. Histone deacetylases (HDACs) control cellular signaling and gene expression. HDAC2 is crucial for suppression of inflammatory gene expression. Here we investigated whether HDAC2 was involved in the arrest of alveolarization, as well as the ability of HDAC2 to regulate TGF-α expression in a rat model of BPD induced by intra-amniotic injection of lipopolysaccharide (LPS). Results showed that LPS exposure led to a suppression of both HDAC1 and HDAC2 expression and activity, induced TGF-α expression, and disrupted alveolar morphology. Mechanistic studies showed that overexpression of HDAC2, but not HDAC1, suppressed LPS-induced TGF-α expression. Moreover, the HDAC inhibitor TSA or downregulation of HDAC2 by siRNA both significantly increased TGF-α expression in cultured myofibroblasts. Finally, preservation of HDAC activity by theophylline treatment improved alveolar development and attenuated TGF-α release. Together, these findings indicate that attenuation of TGF-α-mediated effects in the lung by enhancing HDAC2 may have a therapeutic effect on treating BPD.PLoS ONE 03/2014; 9(3):e91083. · 3.53 Impact Factor
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ABSTRACT: ABSTRACT Objective: The tyrosine kinase inhibitor nilotinib has potent inhibitory activity against the stem cell growth factor receptor c-Kit and platelet-derived growth factor receptor (PDGFR). The present study aimed to determine whether nilotinib suppresses airway remodeling and whether its effect is associated with the c-Kit and PDGFR pathways. We also aimed to compare the effect of nilotinib and imatinib on remodeling. Methods: We developed a mouse model of airway remodeling, which includes smooth muscle thickening, in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice a week for 3 months. Mice were treated with nilotinib or imatinib during the OVA challenge. Results: Compared with control mice, the mice chronically exposed to OVA developed sustained eosinophilic airway inflammation, airway hyperresponsiveness (AHR), and exhibited features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of nilotinib significantly inhibited eosinophilic inflammation, AHR, and remodeling in mice chronically exposed to OVA. Nilotinib showed a trend of more potent effect than imatinib on attenuating remodeling in hydroxyproline assay and smooth muscle staining. Nilotinib treatment significantly reduced the expression of phosphorylated (p)-c-Kit, p-PDGFRβ, and p-extracellular signal-regulated kinase 1/2. The expression levels of the genes encoding c-Kit and PDGFRβ were also reduced by nilotinib treatment. Treatment with nilotinib did not affect significantly the level of OVA-specific IgE and IgG1 in serum. In vitro, nilotinib significantly inhibited cell proliferation of fibroblast. Conclusions: These results suggest that nilotinib administration can prevent airway inflammation, AHR, and airway remodeling associated with chronic allergen challenge.Experimental Lung Research 05/2014; · 1.75 Impact Factor
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ABSTRACT: Epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), the AA and BB isoforms of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) are involved in the pathogenesis of airway inflammation in asthma. In the present study, the associations between asthmatic phenotypes and the expression levels of these mediators in induced sputum and serum were investigated. A total of 62 asthmatic patients were divided into eosinophilic or neutrophilic phenotypes by cytological classification of the induced sputum. In addition, patients were classified according to lung function (FEV1/FVC >70% or FEV1/FVC <70%) and asthma severity (mild, moderate or severe). The concentrations of EGF, bFGF, PDGF-AA, PDGF-BB and VEGF in the serum and induced sputum were measured using sandwich enzyme immunoassays. VEGF levels in the serum and induced sputum were higher in patients with an eosinophilic phenotype compared with those with a neutrophilic phenotype. In addition, VEGF expression was higher in patients with an FEV1/FVC value of <70% as compared with patients with an FEV1/FVC value of >70%. Furthermore, the levels of VEGF were higher in patients with severe asthma compared with the patients with mild and moderate asthma. There were no statistically significant differences observed with regard to EGF, bFGF, PDGF-AA and PDGF-BB levels among the various phenotypes. Therefore, the observations of the present study indicated that increased VEGF expression in the serum and induced sputum of patients may be associated with eosinophilic airway inflammation, severe airflow limitation and the severity of asthma.Experimental and therapeutic medicine 08/2014; 8(2):573-578. · 0.94 Impact Factor