The emerging role of NOTCH3 receptor signalling in human lung diseases

Abstract

The mammalian respiratory system or lung is a tree-like branching structure, and the main site of gas exchange with the external environment. Structurally, the lung is broadly classified into the proximal (or conducting) airways and the distal alveolar region, where the gas exchange occurs. In parallel with the respiratory tree, the pulmonary vasculature starts with large pulmonary arteries that subdivide rapidly ending in capillaries adjacent to alveolar structures to enable gas exchange. The NOTCH signalling pathway plays an important role in lung development, differentiation and regeneration post-injury. Signalling via the NOTCH pathway is mediated through activation of four NOTCH receptors (NOTCH1-4), with each receptor capable of regulating unique biological processes. Dysregulation of the NOTCH pathway has been associated with development and pathophysiology of multiple adult acute and chronic lung diseases. This includes accumulating evidence that alteration of NOTCH3 signalling plays an important role in the development and pathogenesis of chronic obstructive pulmonary disease, lung cancer, asthma, idiopathic pulmonary fibrosis and pulmonary arterial hypertension. Herein, we provide a comprehensive summary of the role of NOTCH3 signalling in regulating repair/regeneration of the adult lung, its association with development of lung disease and potential therapeutic strategies to target its signalling activity.

OM85 ameliorates bleomycin-induced pulmonary fibrosis in mice by inhibiting Notch expression and modulating the Th1/Th2 balance

“…The receptors and ligands are single-pass transmembrane proteins that have extracellular, transmembrane, and intracellular domains. The receptor's extracellular domain consists of a series of 29-36 epidermal growth-factor-like (EGFR-like) repeats [27,28]. The EGFR-like domains interact with ligands and are the functional part of the Notch receptors.…”

Huaier suppresses cell viability, migration and invasion in human non-small cell lung cancer via lncRNA DLEU2/miR-212-5p/ELF3 axis

“…The Notch3 upregulation facilitates the autologous invasion and migration of lung adenocarcinoma cells 43 . The modulation of Notch3 signaling is a pivotal factor in the progression and pathogenesis of lung cancer 44 , 45 . In the current study, overexpression of ELF3 reversed the effects of DLEU2 silencing and Huaier treatment by promoting Notch3 expression, which subsequently upregulated the downstream proteins Vimentin, MMP9 and VEGF while downregulating E-cadherin.…”

Lung Fibroblasts from Chronic Obstructive Pulmonary Disease Subjects Have a Deficient Gene Expression Response to Cigarette Smoke Extract Compared to Healthy

“…24 NOTCH1 has had some controversial relationships with airway diseases. In general, an increase in NOTCH1 has been associated with increased mucus hypersecretion and goblet-cell metaplasia in COPD airway cells 25,26 but an overexpression of NOTCH1 can protect against CSE-induced apoptosis in healthy endothelial cells via the ERK-MAPK signaling pathway. 24,27 Interestingly the levels of NOTCH1 do not change in this Figure 5 Summary of the clusters derived from the Enrichr analysis of biological processes involved based on the genes that had significant differences in expression in fibroblasts from baseline to after CSE stimulation.…”