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HER2 Signaling Implicated in Regulating Alveolar Epithelial Permeability with Cyclic Stretch
Nadir Yehya1,2, Min Jae Song3, Gladys G Lawrence4
1Department of Bioengineering, University of Pennsylvania, 40 Skirkanich Hall, 210 South 33rd Street, Philadelphia, PA 19104, USA. yehyan@email.chop.edu.
International Journal of Molecular Sciences
|March 1, 2019
Summary
Mechanical ventilation causes lung injury. Neuregulin-1 (NRG1) activates HER2, contributing to this injury. Inhibiting HER2 or NRG1 reduced lung permeability and ventilator-induced lung injury (VILI) in rats.
Area of Science:
- Cell Biology
- Molecular Biology
- Pulmonary Medicine
Background:
- Mechanical ventilation, while life-saving, can induce or worsen lung injury (VILI).
- The human epidermal growth factor receptor (HER) ligand neuregulin-1 (NRG1) and its role in inflammatory injuries are recognized.
- HER2 activation has been implicated in cellular damage, prompting investigation into its role in VILI.
Purpose of the Study:
- To investigate the hypothesis that HER2 activation contributes to ventilator-induced lung injury (VILI).
- To explore the role of neuregulin-1 (NRG1) and its downstream signaling in VILI.
- To assess the therapeutic potential of targeting the HER2 pathway in VILI.
Main Methods:
- Differential gene expression analysis of cyclically stretched rat alveolar epithelial cells (RAEC) for HER ligands.
- In vitro testing of NRG1 and HER2 inhibition on RAEC permeability and protein expression.
- In vivo assessment of a HER2 inhibitor (AG825) in a rat model of VILI.
Main Results:
- Cyclic stretch upregulated NRG1 and amphiregulin (AREG) in RAEC, with increased NRG1 protein.
- Inhibition of NRG1 cleavage, binding, or direct HER2 phosphorylation reduced stretch-induced RAEC permeability.
- MicroRNA miR-15b targeting NRG1 and in vivo HER2 inhibition with AG825 attenuated VILI in rats.
Conclusions:
- Cyclic stretch activates HER2 through the HER3 ligand NRG1, increasing lung epithelial cell permeability.
- Downregulating NRG1, preventing NRG1 binding, or directly inhibiting HER2 mitigates VILI.
- Ligand-dependent HER2 activation represents a potential therapeutic target for reducing VILI.
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