Cigarette Smoke Induces Human Epidermal Receptor 2-Dependent Changes in Epithelial Permeability
Rangnath Mishra1, Daniel Foster1, Vihas T Vasu1
11 Division Oncology, National Jewish Health, Denver, Colorado.
American Journal of Respiratory Cell and Molecular Biology
|November 25, 2015
Summary
Cigarette smoke (CS) damages airway epithelial barrier function. This study reveals that CS activates human epidermal growth factor receptor 2 (HER2), a key mediator of this damage, highlighting HER2 as a therapeutic target for CS-related lung diseases.
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Toxicology
Background:
- The airway epithelium forms a critical barrier against inhaled pollutants like cigarette smoke (CS).
- Disruption of this barrier by CS contributes to lung diseases such as chronic obstructive pulmonary disease (COPD).
- Mechanisms underlying CS-induced epithelial barrier dysfunction are not fully understood.
Purpose of the Study:
- To investigate the role of human epidermal growth factor receptor 2 (HER2) in CS-induced airway epithelial barrier disruption.
- To determine if CS activates HER2 in airway epithelial cells and if this activation is dependent on known ligands.
- To elucidate the downstream signaling pathways and consequences of HER2 activation by CS.
Main Methods:
- Exposure of cultured bronchial epithelial cells and whole lung tissue to CS.
- Assessment of HER2 activation using Western blotting and immunohistochemistry.
- Gene silencing (knockdown) of HER2 to evaluate its necessity for CS effects.
- Measurement of epithelial permeability using transepithelial electrical resistance (TEER).
- Analysis of cytokine (IL-6) production and extracellular signal-regulated kinases (Erk) activation.
Main Results:
- CS exposure activated HER2 in both smokers' lung tissue and cultured bronchial epithelial cells.
- CS-induced HER2 activation was independent of neuregulin-1 but required epidermal growth factor receptor (EGFR) activation.
- HER2 was essential for CS-induced increases in epithelial permeability; HER2 knockdown prevented this effect.
- CS increased IL-6 production via HER2-mediated Erk activation.
- Blocking IL-6 attenuated CS-induced epithelial permeability.
Conclusions:
- CS activates pulmonary epithelial HER2 through an EGFR-dependent pathway.
- HER2 is a critical mediator of CS-induced airway epithelial barrier dysfunction.
- The HER2-IL-6-Erk signaling axis plays a significant role in CS-induced lung epithelial damage.
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