Targeting 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 GPX-1 mRNA decay in COPD airway epithelial cells. Targeting the tyrosine kinase c-Src with siRNA inhibited GPX-1 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 GPX-1 mRNA stability. The chemical inhibitors for c-Src (saracatinib and dasanitib) restored GPX-1 mRNA levels and GPX-1 activity in COPD airway cells in vitro. Similarly, saracatinib prevented the loss of lung Gpx-1 expression in response to chronic smoke exposure in vivo. 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.

Posttranscriptional control of airway inflammation.

Acute inflammation in the lungs is a vital protective response, efficiently and swiftly eliminating inciters of tissue injury. However, in respiratory diseases characterized by chronic inflammation, such as chronic obstructive pulmonary disease and asthma, enhanced expression of inflammatory mediators leads to tissue damage and impaired lung function. Although transcription is an essential first step in the induction of proinflammatory genes, tight regulation of inflammation requires more rapid, flexible responses. Increasing evidence shows that such responses are achieved by posttranscriptional mechanisms directly affecting mRNA stability and translation initiation. RNA-binding proteins, microRNAs, and long noncoding RNAs interact with messenger RNA and each other to impact the stability and/or translation of mRNAs implicated in lung inflammation. Recent research has shown that these biological processes play a central role in the pathogenesis of several important pulmonary conditions. This review will highlight several posttranscriptional control mechanisms that influence lung inflammation and the known associations of derangements in these mechanisms with common respiratory diseases. WIREs RNA 2018, 9:e1455. doi: 10.1002/wrna.1455 This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Turnover and Surveillance > Regulation of RNA Stability.