The Role of the Notch Signaling Pathway in the Pathogenesis of Lung Diseases of Non-infectious Etiology

Abstract

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