Abstract
Idiopathic Pulmonary Fibrosis (IPF) is a progressive, irreversible lung disease with complex pathophysiology. Evidence of endoplasmic reticulum (ER) stress has been reported in alveolar epithelial cells (AEC) in IPF patients. Secreted mediators from bone marrow stem cells (BMSC-cm) have regenerative properties. In this study we investigate the beneficial effects of BMSC-cm on ER stress response in primary AEC and ER stressed A549 cells. We hypothesize that BMSC-cm reduces ER stress. Primary AEC isolated from IPF patients were treated with BMSC-cm. To induce ER stress A549 cells were incubated with Tunicamycin or Thapsigargin and treated with BMSC-cm, or control media. Primary IPF-AEC had high Grp78 and CHOP gene expression, which was lowered after BMSC-cm treatment. Similar results were observed in ER stressed A549 cells. Alveolar epithelial repair increased in presence of BMSC-cm in ER stressed A549 cells. Hepatocyte growth factor (HGF) was detected in biologically relevant levels in BMSC-cm. Neutralization of HGF in BMSC-cm attenuated the beneficial effects of BMSC-cm including synthesis of surfactant protein C (SP-C) in primary AEC, indicating a crucial role of HGF in ER homeostasis and alveolar epithelial repair. Our data suggest that BMSC-cm may be a potential therapeutic option for treating pulmonary fibrosis.
Highlights
Repeated micro-injuries to the alveolar epithelium contribute to pathogenesis of idiopathic pulmonary fibrosis (IPF), resulting in cellular dysfunction aggravating disease progression[1]
In this study we show that alveolar epithelial cells (AEC) from Idiopathic Pulmonary Fibrosis (IPF) patients are under Endoplasmic reticulum (ER) stress
bone marrow-derived stromal cells (BMSC)-cm treatment reduced ER stress, increased cell proliferation and improved wound healing in alveolar epithelial cells. We demonstrate that these effects are partially mediated by hepatocyte growth factor (HGF) present in BMSC-cm; and suggest BMSC-cm as a potential novel therapeutic option for repair and regeneration in fibrotic lungs
Summary
Repeated micro-injuries to the alveolar epithelium contribute to pathogenesis of idiopathic pulmonary fibrosis (IPF), resulting in cellular dysfunction aggravating disease progression[1]. ER stress is defined as an accumulation of misfolded or unfolded proteins in the ER lumen, and is induced by three signaling receptors: ATF6 (activating transcription factor-6), PERK (PRK-like ER kinase) and IREIα(inositol-requiring enzyme1α). In physiological conditions, these receptors are bound in an inactive form to the ER chaperone GRP78. ER stress plays an important role in epithelial-to-mesenchymal transition (EMT)[14] and in alveolar epithelial cells (AEC) cell death[15] Together, these data indicate that ER stress is a key regulator involved in the pathogenesis of acute and chronic lung injuries. The effect of these secreted mediators on alveolar epithelium of fibrotic lungs and on endoplasmic reticulum balance has not been studied. We found BSMC-cm mediated improvement in wound healing in ER-stressed A549 in vitro
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