Acute lung injury (ALI) is a devastating syndrome marked by alveolar edema, severe hypoxemia and unacceptably high mortality. Decreased pulmonary epithelial cell barrier function is central to the pathophysiology of acute lung injury, but our current understanding of the mechanisms leading to increased epithelial permeability is limited. Recently, activation of the human epidermal growth factor receptor 2 (HER2) by ADAM17-mediated shedding of the ligand neuregulin-1 (NRG-1) was demonstrated to increase pulmonary epithelial permeability and participate in ALI pathogenesis. The purpose of the current application is to determine the mechanisms of ADAM17 activation and define a requirement for ADAM17-mediated NRG-1 shedding and HER2 activation in ALI. Using a combination of in vitro and in vivo studies, we propose to test the overall hypothesis that IL-1? induces a signaling cascade resulting in ADAM17 activation and NRG-1 shedding leading to HER2 activation, increased para-cellular epithelial permeability and ALI.
The specific aims are: Hypothesis 1: Tyrosine phosphorylation of ADAM17 is required for ADAM17 activation and NRG-1 shedding in pulmonary epithelium.
Specific Aim 1 : Determine the role of tyrosine phosphorylation in ADAM17 activation and NRG-1 shedding in pulmonary epithelial cells. 1.1: Define the role of ADAM17 tyrosine phosphorylation in ADAM17-mediated NRG-1 shedding. 1.2: Define the role of Src family kinases in ADAM17 tyrosine phosphorylation and NRG-1 shedding. Hypothesis 2: ADAM17-mediated shedding of NRG-1 from pulmonary epithelium results in HER2 activation and is required for ALI in vivo.
Specific Aim 2 : Define ADAM17-mediated NRG-1 shedding and HER2 activation from pulmonary epithelial cells as a requirement for ALI in vivo. 2.1: Determine the effect of ADAM17 down-regulation on ALI in vivo. 2.2: Determine the effect of NRG-1 down-regulation on ALI in vivo. 2.3: Determine the role of HER2 blockade on ALI in vivo.

Public Health Relevance

Acute lung injury (ALI) is a devastating illness marked by increases in permeability of the lung resulting in flooding of the lung with edema fluid. While there have been some recent advances, treatment is largely supportive and unsuccessful. The purpose of this application is to study how ADAM17 sheds the protein neuregulin-1 from the surface of lung cells, leading to neuregulin-1 binding to the receptor HER2 and subsequent increases in permeability of the lung and ALI.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Harabin, Andrea L
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National Jewish Health
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Finigan, James H; Vasu, Vihas T; Thaikoottathil, Jyoti V et al. (2015) HER2 activation results in β-catenin-dependent changes in pulmonary epithelial permeability. Am J Physiol Lung Cell Mol Physiol 308:L199-207
Brune, Kieran; Frank, James; Schwingshackl, Andreas et al. (2015) Pulmonary epithelial barrier function: some new players and mechanisms. Am J Physiol Lung Cell Mol Physiol 308:L731-45
Kim, Jihye; Vasu, Vihas T; Mishra, Rangnath et al. (2014) Bioinformatics-driven discovery of rational combination for overcoming EGFR-mutant lung cancer resistance to EGFR therapy. Bioinformatics 30:2393-8
Ito, Yoko; Correll, Kelly; Schiel, John A et al. (2014) Lung fibroblasts accelerate wound closure in human alveolar epithelial cells through hepatocyte growth factor/c-Met signaling. Am J Physiol Lung Cell Mol Physiol 307:L94-105
Berman, Reena; Huang, Chunjian; Jiang, Di et al. (2014) MUC18 Differentially Regulates Pro-Inflammatory and Anti-Viral Responses in Human Airway Epithelial Cells. J Clin Cell Immunol 5:
Finigan, James H; Kern, Jeffrey A (2013) Lung cancer screening: past, present and future. Clin Chest Med 34:365-71
Finigan, James H; Mishra, Rangnath; Vasu, Vihas T et al. (2013) Bronchoalveolar lavage neuregulin-1 is elevated in acute lung injury and correlates with inflammation. Eur Respir J 41:396-401
Finigan, James H; Kern, Jeffrey A (2012) Lung cancer: new therapeutic targets, new definitions. Am J Respir Crit Care Med 186:7-8
Finigan, James H; Downey, Gregory P; Kern, Jeffrey A (2012) Human epidermal growth factor receptor signaling in acute lung injury. Am J Respir Cell Mol Biol 47:395-404