biostudies-literatureDabo AJNHLBI NIH HHS598-607https://www.ebi.ac.uk/biostudies/studies/S-EPMC7193784biostudies-literatureUnknown62(5)Enhanced expression of the cellular antioxidant glutathione peroxidase (GPX)-1 prevents cigarette smoke-induced lung inflammation and tissue destruction. Subjects with chronic obstructive pulmonary disease (COPD), however, have decreased airway GPX-1 levels, rendering them more susceptible to disease onset and progression. The mechanisms that downregulate GPX-1 in the airway epithelium in COPD remain unknown. To ascertain these factors, analyses were conducted using human airway epithelial cells isolated from healthy subjects and human subjects with COPD and lung tissue from control and cigarette smoke-exposed A/J mice. Tyrosine phosphorylation modifies GPX-1 expression and cigarette smoke activates the tyrosine kinase c-Src. Therefore, studies were conducted to evaluate the role of c-Src on GPX-1 levels in COPD. These studies identified accelerated <i>GPX-1</i> mRNA decay in COPD airway epithelial cells. Targeting the tyrosine kinase c-Src with siRNA inhibited <i>GPX-1</i> mRNA degradation and restored GPX-1 protein levels in human airway epithelial cells. In contrast, silencing the tyrosine kinase c-Abl, or the transcriptional activator Nrf2, had no effect on <i>GPX-1</i> mRNA stability. The chemical inhibitors for c-Src (saracatinib and dasanitib) restored <i>GPX-1</i> mRNA levels and GPX-1 activity in COPD airway cells <i>in vitro</i>. Similarly, saracatinib prevented the loss of lung Gpx-1 expression in response to chronic smoke exposure <i>in vivo</i>. Thus, this study establishes that the decreased GPX-1 expression that occurs in COPD lungs is at least partially due to accelerated mRNA decay. Furthermore, these findings show that targeting c-Src represents a potential therapeutic approach to augment GPX-1 responses and counter smoke-induced lung disease.American journal of respiratory cell and molecular biologyTargeting c-Src Reverses Accelerated GPX-1 mRNA Decay in Chronic Obstructive Pulmonary Disease Airway Epithelial Cells.PMC7193784R01 HL116597R01 HL136449Geraghty PForonjy RFLora AEzegbunam WMajka SMDabo AJWyman AEMoon JRailwah CfalseTargeting c-Src Reverses Accelerated GPX-1 mRNA Decay in Chronic Obstructive Pulmonary Disease Airway Epithelial Cells.Enhanced expression of the cellular antioxidant glutathione peroxidase (GPX)-1 prevents cigarette smoke-induced lung inflammation and tissue destruction. Subjects with chronic obstructive pulmonary disease (COPD), however, have decreased airway GPX-1 levels, rendering them more susceptible to disease onset and progression. The mechanisms that downregulate GPX-1 in the airway epithelium in COPD remain unknown. To ascertain these factors, analyses were conducted using human airway epithelial cells isolated from healthy subjects and human subjects with COPD and lung tissue from control and cigarette smoke-exposed A/J mice. Tyrosine phosphorylation modifies GPX-1 expression and cigarette smoke activates the tyrosine kinase c-Src. Therefore, studies were conducted to evaluate the role of c-Src on GPX-1 levels in COPD. These studies identified accelerated <i>GPX-1</i> mRNA decay in COPD airway epithelial cells. Targeting the tyrosine kinase c-Src with siRNA inhibited <i>GPX-1</i> mRNA degradation and restored GPX-1 protein levels in human airway epithelial cells. In contrast, silencing the tyrosine kinase c-Abl, or the transcriptional activator Nrf2, had no effect on <i>GPX-1</i> mRNA stability. The chemical inhibitors for c-Src (saracatinib and dasanitib) restored <i>GPX-1</i> mRNA levels and GPX-1 activity in COPD airway cells <i>in vitro</i>. Similarly, saracatinib prevented the loss of lung Gpx-1 expression in response to chronic smoke exposure <i>in vivo</i>. Thus, this study establishes that the decreased GPX-1 expression that occurs in COPD lungs is at least partially due to accelerated mRNA decay. Furthermore, these findings show that targeting c-Src represents a potential therapeutic approach to augment GPX-1 responses and counter smoke-induced lung disease.2020-01-01T00:00:00Z2020 May2022-02-09T18:06:17.895Z2022-02-09T18:06:17.895ZS-EPMC71937843180102310.1165/rcmb.2019-0177OC10.1165/rcmb.2019-0177oc