Role of Novel Cytokine-like Molecule Secretoglobin (SCGB) 3A2 in Lung

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

We previously demonstrated that SCGB3A2 inhibits acrolein-induced apoptosis through decreased P53 phosphorylation. Acrolein is abundant in cigarette smoke, and is thought to be the most important component of smoke condensate leading to chronic obstructive pulmonary disease (COPD), a multifactorial disease with both airway and emphysematous lesions. We further demonstrated that SCGB3A2 may be required for maintaining homeostasis and immune activity in the lungs during aging, and SCGB3A2 deficiency might increase the risk of emphysema of the lung. Based on these results, we hypothesized that SCGB3A2 may play a role in the development of cigarette smoke (CS)-induced COPD. Accordingly, Scgb3a2-KO, Scgb3a2-lung-specific overexpressing (TG), and WT mice were subjected to the COPD mouse model by exposing them to cigarette smoke (CS) for 6 months. At the end of 6 months, their lungs were analyzed. As compared with WT mouse lungs, the KO mice showed loss of lung structure under control condition, and CS exposure resulted in more expansion of airspace and destruction of alveolar structure. In contrast, TG mouse lungs showed no significant changes after CS exposure. SCGB3A2 increased the expression and phosphorylation of STAT1 and STAT3, and the expression of alpha1-antitrypsin (A1AT) in mouse lung fibroblast-derived MLg cells and mouse lung epithelial-derived MLE-15 cells. A1AT is a serine proteinase inhibitor and its deficiency is known to cause emphysema. In MLg cells, A1AT expression was decreased in Stat3-knockdown cells, and increased upon Stat3 overexpression. STAT3 formed a homodimer when cells were stimulated with SCGB3A2. Chromatin immunoprecipitation and reporter assays demonstrated that STAT3 binds to specific binding sites on the Serpina1a gene encoding A1AT and upregulates its transcription in lung tissues of mice. Furthermore, nuclear localization of phosphorylated STAT3 was detected upon SCGB3A2 stimulation by immunocytochemistry. These findings demonstrate that SCGB3A2 protects the lungs from developing CS-induced emphysema by regulating A1AT expression through STAT3 signaling. This anti-emphysematous activity adds to the expanding list of biological functions of SCGB3A2 and as a potential therapeutic to treat lung diseases.