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

Jaymin J Kathiriya,Vijay Vaghasiya,Jenna Nixon,Niyati Nakra,Puja S Patel,Diane Allen-Gipson,Vrushank Davé,Ahmed Alhassani,Zhi Tian

doi:10.1038/cddiscovery.2017.10

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.

Highlights

Idiopathic pulmonary fibrosis (IPF), a disease of unknown etiology, causes over 80 000 deaths per year in the United States and Europe combined.[1]
Proteomics analysis of normoxic and hypoxic epithelial cells cell death, cellular movement, cellular growth and proliferation, and cellular assembly and organization (Figure 2e). As these processes are initiated during cytoskeletal remodeling in aberrantly activated lung epithelial cells of IPF patients,[4] we sought to identified 1476 significantly deregulated proteins (Figures 2a–c). identify molecules causing epithelial abnormalities
Data are shown as mean ± S.E. (n = 3 independent experiments). (e) Loss of FAK1 abrogated hypoxia-mediated induction of profibrotic mediators TGF-β, TNF-α, and PAI-1 compared with normal H441 cells as determined by qRT-PCR. *Po 0.05 (Student’s t-test)

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF), a disease of unknown etiology, causes over 80 000 deaths per year in the United States and Europe combined.[1]. While persistent accumulation of extracellular matrix (ECM) proteins and differentiation of lung fibroblasts to collagensecreting myofibroblasts is a hallmark of IPF, the role of dysfunctional lung epithelium in IPF has only recently emerged.[2,3] Chronic repetitive injuries to the lung epithelium leads to aberrant epithelial repair associated with pathogenic cellular reprograming, causing IPF.[4] Chronic hypoxia of the lung is one such injury and a significant clinical feature of patients with IPF.[2] This is true in the aged with a history of lung infections and other interstitial lung diseases (ILDs). Chronic ILDs cause progressive decline in lung function associated with reduced elastic recoil, chest wall compliance, and loss of intercostal muscle mass, leading to restrictive ventilatory response and hypoxemia.[5,6,7] worsening levels of hypoxemia, which may occur because of impaired alveolar gas exchange, is a clinical feature of IPF patients undergoing acute exacerbations of IPF (AE-IPF).[2,3,7,8,9]

Methods

Results

Conclusion