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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    ABSTRACT: Bone marrow-derived mesenchymal stem cells have become an attractive cell source for periodontal ligament regeneration treatment because of their potential to engraft to several tissue types after injury. Most researchers have focused on the transplantation process, but few have paid attention to cell safety concerns and rapid proliferation before transplantation. Using serum-free medium to culture stem cells may be an effective method to avoid problems associated with exogenous serum and the addition of growth factors to promote cell proliferation. Here, we randomly divided our serum-free cultures and treated them with different levels of epidermal growth factor (EGF). We then evaluated changes in rates of cell adhesion, proliferation, apoptosis, and cell cycle ratio as well as their differentiation potential. The data showed that all of these parameters were significantly different when comparing serum-free cultures with and without 10 nM/L EGF (p < 0.05/0.01); however, cells with 10 nM/L EGF did not respond differently than cells grown in standard serum-containing media without EGF (p > 0.05). In summary, our results demonstrate that 10 nM/L EGF was the optimal dose for serum-free culture, which can replace traditional standard serum medium for in vitro expansion of miniature pig bone marrow-derived mesenchymal stem cells.
    In Vitro Cellular & Developmental Biology - Animal 09/2013; 49(10). DOI:10.1007/s11626-013-9665-6 · 1.00 Impact Factor
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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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    ABSTRACT: Lung carcinomas and pulmonary fibrosis (asbestosis) occur in asbestos workers. Understanding the pathogenesis of these diseases is complicated because of potential confounding factors, such as smoking, which is not a risk factor in mesothelioma. The modes of action (MOA) of various types of asbestos in the development of lung cancers, asbestosis, and mesotheliomas appear to be different. Moreover, asbestos fibers may act differentially at various stages of these diseases, and have different potencies as compared to other naturally occurring and synthetic fibers. This literature review describes patterns of deposition and retention of various types of asbestos and other fibers after inhalation, methods of translocation within the lung, and dissolution of various fiber types in lung compartments and cells in vitro. Comprehensive dose-response studies at fiber concentrations inhaled by humans as well as bivariate size distributions (lengths and widths), types, and sources of fibers are rarely defined in published studies and are needed. Species-specific responses may occur. Mechanistic studies have some of these limitations, but have suggested that changes in gene expression (either fiber-catalyzed directly or by cell elaboration of oxidants), epigenetic changes, and receptor-mediated or other intracellular signaling cascades may play roles in various stages of the development of lung cancers or asbestosis.
    Journal of Toxicology and Environmental Health Part B 05/2011; 14(1-4):76-121. DOI:10.1080/10937404.2011.556047 · 5.15 Impact Factor
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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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    ABSTRACT: Lysophosphatidic acid (LPA) and epidermal growth factor (EGF) are important mediators of lung cell function and lung diseases. We showed previously that LPA decreases epidermal growth factor receptor (EGFR) binding rapidly in BEAS-2B airway epithelial cells, and this decrease is sustained to at least 18 h. The current studies investigate which LPA signaling pathways mediate the rapid versus sustained decreases in EGFR binding in BEAS-2B cells. The G(i/o) inhibitor pertussis toxin and the Rho kinase inhibitor Y-27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide] had no effect on the rapid or sustained decreases. However, the mitogen-activated protein kinase kinase (MEK) inhibitor U0126 [1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)-butadiene ethanolate] decreased extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, completely inhibited the rapid decrease in binding, and partially inhibited the sustained decrease. The direct Ca2+- and phospholipid-dependent protein kinase (PKC) activator phorbol-12-myristate-13-acetate stimulated ERK1/2 phosphorylation and decreased EGFR binding at both 15 min and 18 h. Furthermore, inhibitors of PKC partially inhibited ERK1/2 phosphorylation and the 15-min decrease but completely inhibited the 18-h decrease. Inhibitor time course studies showed that PKC induction of the 18-h decrease occurred during the first 3 h of treatment. We showed previously that LPA-stimulated EGFR transactivation contributes to the rapid decrease. Two transactivation inhibitors partially inhibited ERK1/2 phosphorylation, and U0126 partially inhibited EGFR transactivation, indicating that MEK may be involved both upstream and downstream of EGFR activation. Together, the data presented here indicate that LPA mediates the rapid decrease in EGFR binding via EGFR transactivation, MEK/ERK, and PKC, whereas the sustained decrease is regulated primarily by PKC.
    Journal of Pharmacology and Experimental Therapeutics 07/2008; 325(3):809-17. DOI:10.1124/jpet.107.133736 · 3.86 Impact Factor
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