Asthma, chronic pulmonary obstructive disease (COPD), cystic fibrosis, and acute respiratory infections are severe respiratory conditions that significantly contribute to global morbidity and mortality. Airway mucus hypersecretion is an important common pathophysiological and clinical manifestation of these diseases and is closely associated with adverse clinical outcomes. At present, the management of airway mucus hypersecretion lacks a viable clinical intervention. However, the revelation that the EGFR signaling pathway acts as a convergent intracellular pathway for many inflammatory mediators indicates that it exhibits the greatest potential for inhibiting excessive mucus production. This review provides a comprehensive overview of the role of EGFR in airway mucus hypersecretion and the therapeutic progress of targeting it, intending to improve clinicians' understanding of the mechanism and offer insights and recommendations for developing novel pharmaceutical interventions to regulate mucus secretion.
| [1] |
S. T. Gohy, C. Hupin, C. Pilette, and M. Z. Ladjemi, “Chronic Inflammatory Airway Diseases: The Central Role of the Epithelium Revisited,” Clinical and Experimental Allergy 46, no. 4 (2016): 529–542.
|
| [2] |
B. K. Shah, B. Singh, Y. Wang, S. Xie, and C. Wang, “Mucus Hypersecretion in Chronic Obstructive Pulmonary Disease and Its Treatment,” Mediators of Inflammation (2023): 8840594.
|
| [3] |
I. Cerveri and V. Brusasco, “Revisited Role for Mucus Hypersecretion in the Pathogenesis of COPD,” European Respiratory Review 19, no. 116 (2010): 109–112.
|
| [4] |
L. Huang, J. Pu, F. He, et al., “Positive Feedback of the Amphiregulin-EGFR-ERK Pathway Mediates PM2.5 From Wood Smoke-Induced MUC5AC Expression in Epithelial Cells,” Scientific Reports 7, no. 1 (2017): 11084.
|
| [5] |
M. Seo, S. Park, W. Kim, et al., “Multi-Center Korean Cohort Study Based on RNA-Sequencing Data Targeting COPD Patients,” Scientific Data 11, no. 1 (2024): 593.
|
| [6] |
C. Yang, H.-H. Zeng, Y.-J. Du, J. Huang, Q.-Y. Zhang, and K. Lin, “Correlation of Luminal Mucus Score in Large Airways With Lung Function and Quality of Life in Severe Acute Exacerbation of COPD: A Cross-Sectional Study,” International Journal of Chronic Obstructive Pulmonary Disease 16 (2021): 1449–1459.
|
| [7] |
P.-W. Tian and F.-Q. Wen, “Clinical Significance of Airway Mucus Hypersecretion in Chronic Obstructive Pulmonary Disease,” Journal of Translational Internal Medicine 3, no. 3 (2015): 89–92.
|
| [8] |
O. Miyazaki, A. Igarashi, K. Sato, et al., “Rapidly Progressive Mucus Plugs in Allergic Bronchopulmonary Mycosis,” Journal of Asthma 61, no. 9 (2024): 1103–1108.
|
| [9] |
E. M. Dunican, D. C. Watchorn, and J. V. Fahy, “Autopsy and Imaging Studies of Mucus in Asthma. Lessons Learned About Disease Mechanisms and the Role of Mucus in Airflow Obstruction,” supplement, Annals of the American Thoracic Society 15, no. S3 (2018): S184–S191.
|
| [10] |
H. Y. Lai and D. F. Rogers, “Mucus Hypersecretion in Asthma: Intracellular Signalling Pathways as Targets for Pharmacotherapy,” Current Opinion in Allergy and Clinical Immunology 10, no. 1 (2010): 67–76.
|
| [11] |
X. M. Bustamante-Marin and L. E. Ostrowski, “Cilia and Mucociliary Clearance,” Cold Spring Harbor Perspectives in Biology 9, no. 4 (2017): a028241.
|
| [12] |
B. Button, L.-H. Cai, C. Ehre, et al., “A Periciliary Brush Promotes the Lung Health by Separating the Mucus Layer From Airway Epithelia,” Science 337, no. 6097 (2012): 937–941.
|
| [13] |
J. Ma, B. K. Rubin, and J. A. Voynow, “Mucins, Mucus, and Goblet Cells,” Chest 154, no. 1 (2018): 169–176.
|
| [14] |
S. M. Casalino-Matsuda, M. E. Monzón, and R. M. Forteza, “Epidermal Growth Factor Receptor Activation by Epidermal Growth Factor Mediates Oxidant-Induced Goblet Cell Metaplasia in Human Airway Epithelium,” American Journal of Respiratory Cell and Molecular Biology 34, no. 5 (2006): 581–591.
|
| [15] |
A. Ayati, S. Moghimi, S. Salarinejad, M. Safavi, B. Pouramiri, and A. Foroumadi, “A Review on Progression of Epidermal Growth Factor Receptor (EGFR) Inhibitors as an Efficient Approach in Cancer Targeted Therapy,” Bioorganic Chemistry 99 (2020): 103811.
|
| [16] |
D. A. Sabbah, R. Hajjo, and K. Sweidan, “Review on Epidermal Growth Factor Receptor (EGFR) Structure, Signaling Pathways, Interactions, and Recent Updates of EGFR Inhibitors,” Current Topics in Medicinal Chemistry 20, no. 10 (2020): 815–834.
|
| [17] |
L. C. Zanetti-Domingues, D. Korovesis, S. R. Needham, et al., “The Architecture of EGFR’s Basal Complexes Reveals Autoinhibition Mechanisms in Dimers and Oligomers,” Nature Communications 9, no. 1 (2018): 4325.
|
| [18] |
P.-R. Burgel and J. A. Nadel, “Roles of Epidermal Growth Factor Receptor Activation in Epithelial Cell Repair and Mucin Production in Airway Epithelium,” Thorax 59, no. 11 (2004): 992–996.
|
| [19] |
B. Singh, G. Carpenter, and R. J. Coffey, “EGF Receptor Ligands: Recent Advances,” F1000Research 5 (2016): 2270.
|
| [20] |
E. R. Purba, E.-I. Saita, and I. N. Maruyama, “Activation of the EGF Receptor by Ligand Binding and Oncogenic Mutations: The ‘Rotation Model’,” Cells 6, no. 2 (2017): 13.
|
| [21] |
Y. Li and X. X. Tang, “Abnormal Airway Mucus Secretion Induced by Virus Infection,” Frontiers in Immunology 12 (2021): 701443.
|
| [22] |
K. Takeyama, J. V. Fahy, and J. A. Nadel, “Relationship of Epidermal Growth Factor Receptors to Goblet Cell Production in Human Bronchi,” American Journal of Respiratory and Critical Care Medicine 163, no. 2 (2001): 511–516.
|
| [23] |
S. Kim and J. A. Nadel, “Role of Neutrophils in Mucus Hypersecretion in COPD and Implications for Therapy,” Treatments in Respiratory Medicine 3, no. 3 (2004): 147–159.
|
| [24] |
C. A. Hewson, M. R. Edbrooke, and S. L. Johnston, “PMA Induces the MUC5AC Respiratory Mucin in Human Bronchial Epithelial Cells, via PKC, EGF/TGF-Alpha, Ras/Raf, MEK, ERK and Sp1-Dependent Mechanisms,” Journal of Molecular Biology 344, no. 3 (2004): 683–695.
|
| [25] |
G. Zhen, S. W. Park, L. T. Nguyenvu, et al., “IL-13 and Epidermal Growth Factor Receptor Have Critical but Distinct Roles in Epithelial Cell Mucin Production,” American Journal of Respiratory Cell and Molecular Biology 36, no. 2 (2007): 244–253.
|
| [26] |
H. Chen, Z. Gao, and X. Cao, “Preparation of Anti EGFR SCFV: FTH1/FTH1 Nanoparticles for Asthma Treatment” [in Chinese], Chinese Journal of Biotechnology 37, no. 8 (2021): 2870–2877.
|
| [27] |
K. Takeyama, K. Dabbagh, H. M. Lee, et al., “Epidermal Growth Factor System Regulates Mucin Production in Airways,” Proceedings of the National Academy of Sciences of the United States of America 96, no. 6 (1999): 3081–3086.
|
| [28] |
C. A. Hewson, J. J. Haas, N. W. Bartlett, et al., “Rhinovirus Induces MUC5AC in a Human Infection Model and In Vitro via NF-Κb and EGFR Pathways,” European Respiratory Journal 36, no. 6 (2010): 1425–1435.
|
| [29] |
G. Y. Hur, S. Y. Lee, S. H. Lee, et al., “Potential Use of an Anticancer Drug Gefinitib, an EGFR Inhibitor, on Allergic Airway Inflammation,” Experimental & Molecular Medicine 39, no. 3 (2007): 367–375.
|
| [30] |
A.-Y. Guan, Z.-B. Xu, F.-Q. Wen, B.-D. Wang, and Y.-L. Feng, “Effect of Gefinitib on Airway Mucus Hypersecretion Induced by Acrolein in Rats” [in Chinese], Journal of Sichuan University Medical Science Edition 39, no. 2 (2008): 231–234.
|
| [31] |
M. L. Martin-Fernandez, “Fluorescence Imaging of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance in Non-Small Cell Lung Cancer,” Cancers 14, no. 3 (2022): 686.
|
| [32] |
C. J. Gan, W. F. Li, C. N. Li, L. L. Li, W. Y. Zhou, and X. M. Peng, “EGF Receptor Inhibitors Comprehensively Suppress Hepatitis B Virus by Downregulation of STAT3 Phosphorylation,” Biochemistry and Biophysics Reports 22 (2020): 100763.
|
| [33] |
M. G. Currier, S. Lee, C. C. Stobart, et al., “EGFR Interacts With the Fusion Protein of Respiratory Syncytial Virus Strain 2-20 and Mediates Infection and Mucin Expression,” PLoS Pathogens 12, no. 5 (2016): e1005622.
|
| [34] |
T. Sakai, J. Hara, K. Yamamura, et al., “Histopathological Type of Lung Cancer and Underlying Driver Mutations in Patients With Chronic Obstructive Pulmonary Disease (COPD) Versus Patients With Asthma and COPD Overlap: A Single-Center Retrospective Study,” Turkish Thoracic Journal 21, no. 2 (2020): 75–79.
|
| [35] |
E. V. S. Ha and D. F. Rogers, “Novel Therapies to Inhibit Mucus Synthesis and Secretion in Airway Hypersecretory Diseases,” Pharmacology 97, no. 1–2 (2016): 84–100.
|
| [36] |
A. Razzaq, C. Disoma, Y. Zhou, et al., “Targeting Epidermal Growth Factor Receptor Signalling Pathway: A Promising Therapeutic Option for COVID-19,” Reviews in Medical Virology 34, no. 1 (2024): e2500.
|
| [37] |
P. G. Woodruff, M. Wolff, J. M. Hohlfeld, et al., “Safety and Efficacy of an Inhaled Epidermal Growth Factor Receptor Inhibitor (BIBW 2948 BS) in Chronic Obstructive Pulmonary Disease,” American Journal of Respiratory and Critical Care Medicine 181, no. 5 (2010): 438–445.
|
| [38] |
P. Thomas, B. Vincent, C. George, J. M. Joshua, K. Pavithran, and M. Vijayan, “A Comparative Study on Erlotinib & Gefitinib Therapy in Non-Small Cell Lung Carcinoma Patients,” Indian Journal of Medical Research 150, no. 1 (2019): 67–72.
|
| [39] |
J. B. MacDonald, B. MacDonald, L. E. Golitz, P. LoRusso, and A. Sekulic, “Cutaneous Adverse Effects of Targeted Therapies Part I: Inhibitors of the Cellular Membrane,” Journal of the American Academy of Dermatology 72, no. 2 (2015): 203–218.
|
RIGHTS & PERMISSIONS
2025 The Author(s). Pediatric Discovery published by John Wiley & Sons Australia, Ltd on behalf of Children's Hospital of Chongqing Medical University.
PDF
(900KB)
