The Role of the Notch Signaling Pathway in Pathogenesis of Lung Diseases with Noninfectious Etiology

Abstract: This review presents current literature data on significance of the Notch signaling pathway in mechanisms of the development of respiratory system diseases: chronic obstructive pulmonary disease (COPD), bronchial asthma (BA) and lung cancer. Studies of lung tissue samples from patients with COPD and lung tissues of mice found that activation of the Notch signaling pathway promoted metaplasia and increased functional activity of goblet cells, protects epithelial cells from apoptosis and oxidative stress. Suppression of the Notch–Jagged1/Jagged2 pathway is associated with club to ciliated cell transdifferentiation. In BA patients, the Notch signaling pathway promotes the differentiation of Th2-lymphocytes. In the model of ovalbumin-induced asthma, the Notch cascade increases the imbalance of Th17/Treg lymphocyte populations and production of IL-4, IL-5, IL-13, IL-17, and allergen-specific IgE, as well as stimulating eosinophilic infiltration and goblet-cell metaplasia of the airway epithelium. A decrease in the concentration of IgE and Th2-type cytokines (IL-4, IL-5, and IL-13), as well as an increase in the number of Treg cells and the level of TGFβ in bronchoalveolar lavage in mice with asthma, mediated by the introduction of dendritic cells expressing DLL1 and Jagged1 ligands, indicates that the Notch signaling pathway plays a protective role. It was found on tumor tissue samples and a non-small-cell lung-cancer cell line that increased Notch-1 and Notch-3 mRNA expression is associated with enhanced proliferative activity, malignant cell transformation, a high risk of metastasis to the lymph nodes, and unfavorable prognosis of the disease. In tumor tissue samples of small-cell lung cancer, increased expression of the Notch signaling inhibitor gene, ligand DLK1, Ascl1 transcription factor gene, and lysine-specific histone demethylase 1 (LSD1) is recorded. Suppression of LSD1 activity is accompanied by reactivation of signaling through the Notch-1 receptor and subsequent inhibition of the transcription factor Ascl1, which induces the initial stages of tumor transformation. © 2023, Pleiades Publishing, Ltd.