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EGFR and Its Ligands in Idiopathic Pulmonary Fibrosis: Predicting Clinical Outcomes and Molecular Endotyping Through
Jong-Uk Lee1,2, Seung-Lee Park1, Min Kyung Kim1
1Department of Interdisciplinary Program in Biomedical Science Major, Soonchunhyang University, Asan, Korea.
Background:
The dysregulation of alveolar epithelial cells has been proposed as the cause of idiopathic pulmonary fibrosis (IPF) due to abnormal activation of epidermal growth factor receptor (EGFR). However, the ways of interaction with EGFR ligands including amphiregulin (AREG), epidermal growth factor (EGF), transforming growth factor (TGF)-α and heparin-binding EGF have not been revealed. The aim of the present study was to investigate the diagnostic and prognostic significance of EGFR and its ligands in IPF.
Methods:
EGFR and its ligands were quantified by enzyme-linked immunosorbent assay in bronchoalveolar lavage (BAL) fluids and serum from 131 patients with IPF and 52 normal controls (NCs). Mortality risk was evaluated using Cox proportional hazards models. Cluster analysis based on EGFR and its ligands was conducted using both hierarchical and K-means clustering methods.
Results:
The patients exhibited significantly higher levels of EGFR, AREG, EGF, and TGF-α compared to NCs. The threshold values for AREG, EGF and TGF-α were determined to be 12.2 pg/mL, 6.3 pg/mL and 5.2 pg/mL, respectively, for the two groups. The sensitivities were 79.83%, 88.24%, and 56.30%, and the specificities were 81.82%, 31.82%, and 63.64% to diagnose IPF, respectively. The mortality rate was significantly higher in IPF patients with low levels compared to those with high levels of EGFR and EGF on Cox analysis. Four distinct clusters were identified based on the levels of EGFR and its ligands in BAL fluids. C3 group (n = 7), which exhibited the highest levels of TGF-α, AREG and EGFR, showed the highest risk of mortality, whereas the C2 group (n = 40), with the highest level of EGF and the intermediate levels of AREG, EGFR, and TGF-α, had the lowest risk.
Conclusion:
The diverse effects of EGFR on mortality may depend on balance of TGF-α and EGF. Therefore, a comprehensive analysis of EGFR and its ligands could help predict molecular endotypes and clinical outcomes for IPF patients.
