Pulmonary fibrosis is a progressive and often fatal disease complicating many types of human lung diseases. The epidermal growth factor receptor (EGFR) mediates signals induced by a family of growth factors including transforming growth factor-( (TGF-(). Studies from this laboratory and others have shown increased EGFR ligands in several human fibrotic diseases including idiopathic pulmonary fibrosis (IFF). Expression of TGF-( in the epithelium of transgenic mice caused progressive and extensive pulmonary fibrosis with histological features very similar to those seen in human disease. Fibrosis in TGF-( transgenic mice is prevented or reversed using genetic or pharmacological approaches signifying that EGFR-mediated fibrosis is a feasible therapeutic target. Phosphorylation of the EGFR can induce several downstream signaling pathways, including the phosphatidylinositol 3'-kinase (PI3K)-Akt pathway. Activation of EGFR in TGF-( transgenic mice phosphorylates Akt in the epithelium and TGF-( added to respiratory epithelial cells stimulates profibrotic gene expression that can be prevented by blocking PI3K signaling. The long term goal of this application is to develop novel and effective therapeutic intervention strategies for the treatment of pulmonary fibrosis in humans. The objective of this application is to utilize data from cultured lung cells and transgenic models of fibrosis to determine signaling mechanisms mediating EGFR-induced pulmonary fibrosis and determine if these pathways are increased in fibrotic human lung disease. The central hypothesis is that that increased EGFR signaling via PI3K induces pulmonary fibrosis. To test this hypothesis, in Aim 1, we will use model human cell lines to determine EGFR-induced intracellular signaling pathways leading to synthesis of collagen and proliferation of cells.
In Aim 2, we will determine EGFR-induced signaling molecules expressed in vivo in the transgenic model of EGFR-induced lung fibrosis and use well-characterized archival tissue of IPF patients to assess whether EGFR and similar kinases are activated. Preliminary data in the transgenic mice in vivo show that Type II cells produce modulators that regulate fibrosis.
In Aim 3, we will use co-cultures to determine mechanisms whereby TGF-( expressing Type II cells regulate pulmonary fibroblasts. Completion of the proposed studies will determine a role of EGFR in lung fibrosis and suggest therapeutic targets to alter the course of human lung fibrosis.
|Madala, Satish K; Schmidt, Stephanie; Davidson, Cynthia et al. (2012) MEK-ERK pathway modulation ameliorates pulmonary fibrosis associated with epidermal growth factor receptor activation. Am J Respir Cell Mol Biol 46:380-8|
|Madala, Satish K; Edukulla, Ramakrishna; Davis, Katy R et al. (2012) Resistin-like molecule ?1 (Fizz1) recruits lung dendritic cells without causing pulmonary fibrosis. Respir Res 13:51|
|Le Cras, Timothy D; Acciani, Thomas H; Mushaben, Elizabeth M et al. (2011) Epithelial EGF receptor signaling mediates airway hyperreactivity and remodeling in a mouse model of chronic asthma. Am J Physiol Lung Cell Mol Physiol 300:L414-21|
|Kramer, Elizabeth L; Hardie, William D; Mushaben, Elizabeth M et al. (2011) Rapamycin decreases airway remodeling and hyperreactivity in a transgenic model of noninflammatory lung disease. J Appl Physiol 111:1760-7|
|Hardie, William D; Hagood, James S; Dave, Vrushank et al. (2010) Signaling pathways in the epithelial origins of pulmonary fibrosis. Cell Cycle 9:2769-76|
|Le Cras, Timothy D; Korfhagen, Thomas R; Davidson, Cynthia et al. (2010) Inhibition of PI3K by PX-866 prevents transforming growth factor-alpha-induced pulmonary fibrosis. Am J Pathol 176:679-86|
|Deshmukh, Hitesh S; McLachlan, Anne; Atkinson, Jeffrey J et al. (2009) Matrix metalloproteinase-14 mediates a phenotypic shift in the airways to increase mucin production. Am J Respir Crit Care Med 180:834-45|
|Kramer, Elizabeth L; Mushaben, Elizabeth M; Pastura, Patricia A et al. (2009) Early growth response-1 suppresses epidermal growth factor receptor-mediated airway hyperresponsiveness and lung remodeling in mice. Am J Respir Cell Mol Biol 41:415-25|
|Hardie, William D; Glasser, Stephan W; Hagood, James S (2009) Emerging concepts in the pathogenesis of lung fibrosis. Am J Pathol 175:3-16|
|Korfhagen, Thomas R; Le Cras, Timothy D; Davidson, Cynthia R et al. (2009) Rapamycin prevents transforming growth factor-alpha-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 41:562-72|
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