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.

Genome-Wide Fetalization of Enhancer Architecture in Heart Disease

“…Our study identified the genomic locations and activation states of this intriguing subset of diseaseassociated enhancers, offering an entry point for targeted experimental exploration for hundreds of genes with diseaseassociated activity changes. Reactivation of individual fetal pathways has also been observed in other, non-cardiac disease processes [15][16][17] . While limited to anecdotal examples, in conjunction with data from the present study, these reports raise the possibility that widespread reactivation of fetal enhancers is a more generalized disease-associated phenomenon.…”

“…These studies have con-sistently shown that heart failure is associated with the reactivation of a fetal gene program: a curated set of genes with well-established roles in fetal heart development that are normally repressed in non-failing adult heart 13,14 . Notably, a fetalization mechanism has also been suggested for similar pathways involved in lung disease 15,16 and tumorigenesis 17 . However, the full quantitative extent of fetal gene program reactivation in disease processes and the identity of the gene regulatory sequences correlated with these changes remain unknown.…”

Lung biopsy cells transcriptional landscape from COVID-19 patient stratified lung injury in SARS-CoV-2 infection through impaired pulmonary surfactant metabolism

“…GLI3, which exerts essential role in developing the lung, and regulating the innate immune cells [97], is downregulated in COVID-19 lungs ( Figure 6). LTBP3 can promote lung alveolarization [98] but can be modulated by SARS-CoV-2 protein NSP12 ( Figure 6). Aberration in NOTCH signaling contributes significantly in various lung diseases [99], and in SARS-CoV-2 infection NOTCH1, HES1 is found to be downregulated ( Figure 6).…”

Altered polarization of PAR-2 signaling during airway epithelial remodeling

“…To further examine effects of PAR-2 signaling alterations above, we examined secretion of TGF-b2, an important epithelial-derived cytokine in type 2 airway diseases, 50 In RPMI 2650 ALIs, TGF-b2 secretion was activated by basolateral 2FLI and inhibited ~50% by Gi inhibitor pertussis toxin (PTX; Fig 5A). In contrast, activation of the TNF-a receptor, which is not a GPCR, increased TGF-b2 that was not inhibited by PTX (Fig 5A).…”