Galectin-1 inhibition attenuates profibrotic signaling in hypoxia-induced pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by lung remodeling arising from epithelial injury, aberrant fibroblast growth, and excessive deposition of extracellular matrix. Repeated epithelial injury elicits abnormal wound repair and lung remodeling, often associated with alveolar collapse and edema, leading to focal hypoxia. Here, we demonstrate that hypoxia is a physiological insult that contributes to pulmonary fibrosis (PF) and define its molecular roles in profibrotic activation of lung epithelial cells. Hypoxia increased transcription of profibrotic genes and altered the proteomic signatures of lung epithelial cells. Network analysis of the hypoxic epithelial proteome revealed a crosstalk between transforming growth factor-β1 and FAK1 (focal adhesion kinase-1) signaling, which regulated transcription of galectin-1, a profibrotic molecule. Galectin-1 physically interacted with and activated FAK1 in lung epithelial cells. We developed a novel model of exacerbated PF wherein hypoxia, as a secondary insult, caused PF in mice injured with subclinical levels of bleomycin. Hypoxia elevated expression of phosphorylated FAK1, galectin-1, and α-smooth muscle actin and reduced caspase-3 activation, suggesting aberrant injury repair. Galectin-1 inhibition caused apoptosis in the lung parenchyma and reduced FAK1 activation, preventing the development of hypoxia-induced PF. Galectin-1 inhibition also attenuated fibrosis-associated lung function decline. Further, galectin-1 transcript levels were increased in the lungs of IPF patients. In summary, we have identified a profibrotic role of galectin-1 in hypoxia signaling driving PF.

Intranasal delivery of human umbilical cord Wharton's jelly mesenchymal stromal cells restores lung alveolarization and vascularization in experimental bronchopulmonary dysplasia

“…The final stage of healing focuses on remodeling the scar and regaining normal tissue function. These dynamic processes describes the tissue remodeling (Galectin‐1, Fibulin 3) seen in our study . The protein microarray of rat lung homogenates with BPD also demonstrated cell survival properties after MSC delivery.…”

“…These dynamic processes describes the tissue remodeling (Galectin-1, Fibulin 3) seen in our study. 74,75 The protein microarray of rat lung homogenates with BPD also demonstrated cell survival properties after MSC delivery. For example, osteoprotegerin and WISP-1 support cell survival in TNF-induced apoptotic events and while prolactin is known for its role in reproductive functions it is also contains anti-apoptotic properties.…”

Analysis of the Interaction Network of Hub miRNAs-Hub Genes, Being Involved in Idiopathic Pulmonary Fibers and Its Emerging Role in Non-small Cell Lung Cancer

“…were considered to be significantly related to IPF and NSCLC. Focal adhesion was considered as a key pathway shared by blue module and turquoise module, and many gens/proteins have been considered to be involved in the progression of IPF through disordering focal adhesion (Gimenez et al, 2017;Kathiriya et al, 2017;Molina-Molina et al, 2018). For example, it has been reported that decreased expression of collagen VI, an important kind of protein of ECM, would upregulate the focal adhesion (Knueppel et al, 2018).…”

Galectin‐1 promotes choroidal neovascularization and subretinal fibrosis mediatedviaepithelialmesenchymal transition

“…In addition to angiogenesis, galectin-1 has also been reported to be involved in mesenchymal activity via SMAD2 signaling in various cells, including gastric cancer cells, pancreatic stellate cells, and fibroblasts (19)(20)(21). Galectin-1 induced the phosphorylation of SMAD2 through its molecular interaction with SMAD2 in lung fibroblasts (19), thus promoting pulmonary fibrosis (19,22). As concerns the eye, however, there have been no data reported on the profibrotic role of galectin-1 in fibrogenic disorders such as neovascular AMD.…”