The Emerging Role of NOTCH3 Receptor Signaling 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 subdivides rapidly ending in capillaries adjacent to alveolar structures to enable gas exchange. The NOTCH signaling pathway plays an important role in lung development, differentiation and regeneration post-injury. Signaling 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 signaling plays an important role in the development and pathogenesis of chronic obstructive pulmonary disease (COPD), lung cancer, asthma, idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). Herein, we provide a comprehensive summary of the role of NOTCH3 signaling in regulating repair/regeneration of the adult lung, its association with development of lung disease and potential therapeutic strategies to target it's signaling activity.