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Ingram JL, Bonner JC. EGF and PDGF receptor tyrosine kinases as therapeutic targets for chronic lung diseases

Division of Pulmonary, Allergy and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina 27709, USA.
Current Molecular Medicine (Impact Factor: 3.61). 07/2006; 6(4):409-21. DOI: 10.2174/156652406777435426
Source: PubMed

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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    • "Recent reports demonstrated that mpBM-MSCs express receptors for EGF and that proliferation can be stimulated by EGF, which interacts with erbB4 and EGFR (Hofer et al. 2005; Kratchmarova et al. 2005). The receptors for EGF are prototypical tyrosine kinase receptors that are present on most adherent cells, including mpBM-MSCs (Ingram and Bonner 2006), and the binding of EGF and EGFR activates extracellular signal-regulated protein kinase, protein kinase B/akt, and phospho-lipase C-γ, which can promote cell proliferation. Some studies confirmed that the addition of 10 ng/ml EGF to promote cell proliferation was the best choice (Deasy et al. 2002; McCarty et al. 2009); this concentration was equivalent to 1.6 nM/L, which was higher than our low-dose EGF (1 nM/L) condition but much lower than our moderate-dose and high-dose EGF (10 and 100 nM/L) groups, so we speculated that there may be a narrow threshold before EGF was able to apace promote cell expansion . "
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    • "Communication between the airway epithelium and underlying fibroblasts and smooth muscle cells via paracrine signaling is referred to as the " epithelial mesenchymal cell trophic unit. " Epithelial–mesenchymal cell interactions also are postulated to play an important role in the pathogenesis of asthema (Ingram & Bonner, 2006). The epithelial– mesenchymal cell trophic unit is likely important to understanding the pathogenesis of asbestosis. "
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    • "The EGFR has been shown to be involved in the airway remodeling associated with asthma and pulmonary fibrosis (Boxall et al., 2006; Ingram and Bonner, 2006), which includes hyperplasia and hypertrophy of smooth muscle cells and fibroblasts, goblet cell metaplasia, excess epithelial repair , thickening of the lamina reticularis, and increased angiogenesis (Lazaar and Panettieri, 2003; Boxall et al., 2006); together, these changes contribute to the airway hyperresponsiveness and other aspects of the pathology of chronic airway diseases (Munakata, 2006). In addition, the EGFR is expressed, mutated, and/or abnormally activated in many epithelial tumors, leading to receptor overexpression and/or "
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