TGF-β Signaling in Lung Health and Disease

Abstract

Transforming growth factor (TGF)-β is an evolutionarily conserved pleiotropic factor that regulates a myriad of biological processes including development, tissue regeneration, immune responses, and tumorigenesis. TGF-β is necessary for lung organogenesis and homeostasis as evidenced by genetically engineered mouse models. TGF-β is crucial for epithelial-mesenchymal interactions during lung branching morphogenesis and alveolarization. Expression and activation of the three TGF-β ligand isoforms in the lungs are temporally and spatially regulated by multiple mechanisms. The lungs are structurally exposed to extrinsic stimuli and pathogens, and are susceptible to inflammation, allergic reactions, and carcinogenesis. Upregulation of TGF-β ligands is observed in major pulmonary diseases, including pulmonary fibrosis, emphysema, bronchial asthma, and lung cancer. TGF-β regulates multiple cellular processes such as growth suppression of epithelial cells, alveolar epithelial cell differentiation, fibroblast activation, and extracellular matrix organization. These effects are closely associated with tissue remodeling in pulmonary fibrosis and emphysema. TGF-β is also central to T cell homeostasis and is deeply involved in asthmatic airway inflammation. TGF-β is the most potent inducer of epithelial-mesenchymal transition in non-small cell lung cancer cells and is pivotal to the development of tumor-promoting microenvironment in the lung cancer tissue. This review summarizes and integrates the current knowledge of TGF-β signaling relevant to lung health and disease.

Keywords: TGF-β; bronchial asthma; emphysema; lung cancer; pulmonary fibrosis.

Figure 1

Structure of the airway and alveolus. TGF-β regulates epithelial-mesenchymal interactions and is crucial for branching morphogenesis and alveologenesis during development.

Figure 2

Context-dependent action of TGF-β. (A) TGF-β promotes epithelial-mesenchymal transition (EMT) in alveolar epithelial cells to confer a mesenchymal phenotype, or in lung cancer cells to enhance migratory and invasive capacities. TGF-β induces EMT-related transcriptional repressors (SNAI1/SNAI2 and ZEB1/ZEB2) and inhibits the action of NKX2-1, a homeodomain transcription factor important for lung epithelial cell differentiation; (B) TGF-β promotes transdifferentiation of surfactant protein C (SPC)-positive type II alveolar epithelial cells to type I alveolar epithelial cells that express podoplanin (T1α); (C) TGF-β promotes transdifferentiation of lung fibroblasts to myofibroblasts positive for α-smooth muscle actin (α-SMA), and downregulates TBX4, a T-box family transcription factor unique to lung fibroblasts; (D) TGF-β suppresses induction of T helper type 1 (Th1) and type 2 (Th2) cells while positively regulating cell lineage specification from naïve CD⁴⁺ T cells to Th17 and regulatory T (Treg) cells. T-bet, GATA3, RORγt, and Foxp3 are master transcription factors for Th1, Th2, Th17, and Treg cells, respectively.

Figure 3

Upregulation of TGF-β ligands is observed in bronchial asthma, pulmonary fibrosis, emphysema, and lung cancer. Combined pulmonary fibrosis and emphysema (CPFE) and asthma-COPD overlap are increasingly recognized as distinct entities. Pulmonary fibrosis and emphysema are known as independent risk factors for lung cancer.