Role of the EGFR Pathway in Lung Remodeling and Disease
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University of Cincinnati / OhioLINK
2009
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ndltd-OhioLink-oai-etd.ohiolink.edu-ucin12502068902021-08-03T06:13:37Z Role of the EGFR Pathway in Lung Remodeling and Disease Kramer, Elizabeth L. Biology EGFR TGF-alpha Egr-1 lung remodeling house dust mite airway smooth muscle remodeling Lung remodeling occurs in many chronic lung diseases, including pulmonary fibrosis, bronchopulmonary dysplasia (BPD), and asthma. The signaling pathways that mediate lung remodeling are largely unclear; however, clinical studies in patients have reported increases in the epidermal growth factor receptor (EGFR) and its ligands, including epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α). Our studies examined the role of the EGFR pathway in several models of lung disease. Previous work has shown that increases in TGF-α expression in neonates disrupts both airway and vascular morphogenesis and causes remodeling. Induction of TGF-α and EGFR in adult mice causes progressive pulmonary fibrosis that is largely reversible once TGF-α overexpression is discontinued. Here, we show that increased expression of TGF-α during the saccular phase of lung morphogenesis caused a severe and lethal lung disease with pathologic characteristics similar to those seen in patients with BPD. Since this prenatal TGF-α induced disease was different from the diseases seen after neonatal and adult induction, the timing of EGFR activation plays a vital role in determining the disease outcome. Microarray analysis of mRNA from the lungs of TGF-α transgenic mice identified a transcription factor, early growth response-1 (Egr-1), as highly upregulated downstream of EGFR signaling. When TGF-α transgenic mice were crossed to Egr-1 knockout mice, adults developed more severe lung remodeling, including extensive airway smooth muscle (ASM) thickening and more severe pulmonary fibrosis. This phenotype developed in the absence of inflammation, and lung mechanics studies showed that loss of Egr-1 also caused severe airway hyperresponsiveness (AHR) to methacholine. Since airway remodeling and AHR are key characteristics of asthma, we investigated the role of EGFR in a mouse model of asthma induced by chronic house dust mite (HDM) inhalation. Blockade of the EGFR in HDM treated mice, using either the chemical inhibitor erlotinib or mice expressing a dominant negative mutant EGFR in the lung epithelium, attenuated HDM induced AHR without affecting inflammation. To examine the role of the PI3K-mTOR pathway downstream of EGFR, we treated HDM exposed mice with the mTOR inhibitor rapamycin. mTOR inhibition prevented HDM induced inflammation and AHR. Since inflammation was blocked by rapamycin, it is unclear whether reductions in AHR were due to direct effects of rapamycin or its effects on inflammation. Hence, we repeated the study using TGF-α transgenic Egr-1 null mice, which develop AHR and ASM thickening in the absence of inflammation. In these mice, rapamycin treatment reduced AHR, ASM thickening, and fibrosis. Hence, mTOR inhibition prevented EGFR-mediated lung remodeling and AHR independent of inflammation. Overall, this work reveals a critical role for the EGFR pathway in lung remodeling and airway dysfunction downstream of allergen induced inflammation. This suggests that inhibition of EGFR or its downstream pathways may be a therapeutic target in human lung diseases in which this pathway is activated. 2009 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1250206890 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1250206890 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
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NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Biology EGFR TGF-alpha Egr-1 lung remodeling house dust mite airway smooth muscle remodeling |
| spellingShingle |
Biology EGFR TGF-alpha Egr-1 lung remodeling house dust mite airway smooth muscle remodeling Kramer, Elizabeth L. Role of the EGFR Pathway in Lung Remodeling and Disease |
| author |
Kramer, Elizabeth L. |
| author_facet |
Kramer, Elizabeth L. |
| author_sort |
Kramer, Elizabeth L. |
| title |
Role of the EGFR Pathway in Lung Remodeling and Disease |
| title_short |
Role of the EGFR Pathway in Lung Remodeling and Disease |
| title_full |
Role of the EGFR Pathway in Lung Remodeling and Disease |
| title_fullStr |
Role of the EGFR Pathway in Lung Remodeling and Disease |
| title_full_unstemmed |
Role of the EGFR Pathway in Lung Remodeling and Disease |
| title_sort |
role of the egfr pathway in lung remodeling and disease |
| publisher |
University of Cincinnati / OhioLINK |
| publishDate |
2009 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1250206890 |
| work_keys_str_mv |
AT kramerelizabethl roleoftheegfrpathwayinlungremodelinganddisease |
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