Epidermal growth factor receptor inhibition with Gefitinib does not alter lung responses to mechanical ventilation in fetal, preterm lambs.

Abstract

BACKGROUND:

Epidermal growth factor receptor (EGFR) is important for airway branching and lung maturation. Mechanical ventilation of preterm lambs causes increases in EGFR and EGFR ligand mRNA in the lung. Abnormal EGFR signaling may contribute to the development of bronchopulmonary dysplasia.

HYPOTHESIS:

Inhibition of EGFR signaling will decrease airway epithelial cell proliferation and lung inflammation caused by mechanical ventilation in preterm, fetal sheep.

METHODS:

Following exposure of the fetal head and chest at 123±1 day gestational age and with placental circulation intact, fetal lambs (n = 4-6/group) were randomized to either: 1) Gefitinib 15 mg IV and 1 mg intra-tracheal or 2) saline IV and IT. Lambs were further assigned to 15 minutes of either: a) Injurious mechanical ventilation (MV) or b) Continuous positive airway pressure (CPAP) 5 cmH2O. After the 15 minute intervention, the animals were returned to the uterus and delivered after i) 6 or ii) 24 hours in utero.

RESULTS:

MV caused lung injury and inflammation, increased lung mRNA for cytokines and EGFR ligands, caused airway epithelial cell proliferation, and decreased airway epithelial phosphorylated ERK1/2. Responses to MV were unchanged by Gefitinib. Gefitinib altered expression of EGFR mRNA in the lung and liver of both CPAP and MV animals. Gefitinib decreased the liver SAA3 mRNA response to MV at 6 hours. There were no differences in markers of lung injury or inflammation between CPAP animals receiving Gefitinib or saline.

CONCLUSION:

Inhibition of the EGFR pathway did not alter acute lung inflammation or injury from mechanical ventilation in preterm sheep.

• Authors: T Brett Kothe, Emily Royse, Matthew W Kemp, Haruo Usuda, Masatoshi Saito, Gabrielle C Musk, Alan H Jobe, Noah H Hillman
• Journal: PloS one (PLoS One) Vol. 13 Issue 7 Pg. e0200713 ( 2018) ISSN: 1932-6203 [Electronic] United States
• PMID: 30005089 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• EGF Family of Proteins
• Protein Kinase Inhibitors
• ErbB Receptors
• Gefitinib

Topics

• Animals
• Bronchopulmonary Dysplasia (pathology)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• EGF Family of Proteins (metabolism)
• Epithelial Cells (drug effects, pathology)
• ErbB Receptors (antagonists & inhibitors, physiology)
• Female
• Fetal Development (drug effects)
• Gefitinib (pharmacology, therapeutic use)
• Humans
• Lung (cytology, growth & development, pathology)
• Pregnancy
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Respiration, Artificial (adverse effects)
• Sheep, Domestic
• Treatment Outcome