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: 3.62).
07/2006; 6(4):409-21. DOI: 10.2174/156652406777435426
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.
Available from: PubMed Central
- "Transforming growth factor-α (TGF-α) is a member of the epidermal growth factor family that binds to and activates EGF receptor (EGFR). The TGF-α/EGFR signaling pathway plays a central role in lung development . TGF-α has been suggested as the key stimulus for the stabilizing myofibroblasts polarity, which is critical to secondary septation and may contribute to arrested alveolar development in BPD . "
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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.
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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.
Available from: Kenichi Tamama
- "Besides HBEGF, AREG, PDGFA, and PDGFB, our published and unpublished data also showed that EGR1 regulates gene expression of connective tissue growth factor (CTGF) and transforming growth factor-beta 1 (TGFB1) in MSCs . Although HBEGF, AREG, PDGFA, PDGFB, and CTGF could promote angiogenesis and mitogenesis, these factors could enhance fibrogenesis in the presence of TGFB1 [46, 47], and thus, this group of molecules can be categorized as fibrogenic as well [48–51]. This is in agreement with a recent study showing that EGR1 was also identified as a key factor of fibrogenesis in dermal fibroblasts of patients with scleroderma and systemic sclerosis . "
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ABSTRACT: MSCs provide a promising method for cell therapy through their wound healing and tissue regenerative properties. Originally, MSCs' role in wound healing was thought to be tied to their multipotency, but it is now accepted that MSCs mediate the healing process through their strong paracrine capability. EGF was shown to facilitate in vitro expansion of MSCs without altering multipotency. Our previous data suggest that the molecular machinery underlying MSCs' strong paracrine capability lies downstream of EGFR signaling, and we focus on transcription factors EGR1 and EGR2. Evidence suggests that EGR1 regulates angiogenic and fibrogenic factor production in MSCs, and an EGFR-EGR1-EGFR ligands autocrine loop is one of the underlying mechanisms supporting their strong paracrine machinery through EGR1. EGR2 appears to regulate the expression of immunomodulatory molecules. Chronic nonhealing wounds are ischemic, inflammatory, and often fibrotic, and the hypoxic micro-environment of these wounds may compromise MSCs' wound healing properties in vivo by upregulating the EGR1's fibrogenic effects and downregulating the EGR2's immuno-modulatory effects. Thus, these transcription factors can be potential targets in the optimization of cell-based therapies. Further study in vitro is required to understand MSCs' paracrine machinery and to optimize it as a tool for effective cell-based therapies.
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