Chronic obstructive pulmonary disease (COPD), a small airway disease, is regarded as a metabolic disorder. To further uncover the metabolic profile of COPD patients, it is necessary to identify metabolism-related differential genes in small airway epithelium (SAE) of COPD. Metabolism-related differential genes in SAE between COPD patients and nonsmokers were screened from GSE128708 and GSE20257 datasets. KEGG, GO, and PPI analyses were performed to evaluate the pathway enrichment, term enrichment, and protein interaction of candidate metabolism-related differential genes, respectively. RT-PCR was used to verify the mRNA expression of the top ten differential genes. Western blotting was used to evaluate the protein expression of TXNRD1. TXNRD1 inhibitor auranofin (AUR) was used to assess the impact of TXNRD1 on oxidative stress and inflammation induced by cigarette smoke extraction (CSE). Twenty-four metabolism-related differential genes were selected. ALDH3A1, AKR1C3, CYP1A1, AKC1C1, CPY1B1, and TXNRD1 in the top ten genes were significantly upregulated after CSE simulation for 24 h in human bronchial epithelial (16HBE) cells. Among them, CYP1A1 and TXNRD1 also have a significant upregulation in primary SAE after simulation of CSE for 24 h. The overexpression of protein TXNRD1 has also been detected in 16HBE cells, primary SAE stimulated with CSE, and mouse lung exposed to cigarette smoke (CS). Additionally, inhibition of TXNRD1 with 0.1 μM AUR alleviated the expression of IL-6 and reactive oxygen species (ROS) induced by CSE by activating the Nrf2/HO-1 pathway in 16HBE cells. This study identified twenty-four metabolism-related differential genes associated with COPD. TXNRD1 might participate in the oxidative stress and inflammation induced by CS by regulating the activation of the Nrf2/HO-1 pathway.

Background: Chronic obstructive pulmonary disease (COPD)is a small airway chronic inflammatory disease with impaired lung function primarily induced by cigarette smoke (CS). Reduced Dach1 expression has a vicious role in numerous disorders. but its role in COPD is rarely known. This study aims to elucidate the role and underlying mechanism of Dach1 in airway inflammation of COPD. Methods:Dach1 expression in lung tissues of COPD patients has been calculated. Small airway epithelium-specific Dach1 knockdown mice and AAV-transfected Dach1 overexpressed mice were used to explore its role and potential for therapeutic targeting in experimental COPD induced by CS. Furtherly, we uncovered the promising mechanism of Dach1 in inflammation induced by cigarette smoke extract simulation (CSE) in vitro. Results:The expression of Dach1 decreased in COPD patients compared to non-smokers and smoker without COPD, especially in small airway epithelium. Small airway epithelium-specific Dach1 knockdown aggravated mice airway inflammation and lung function decline caused by CS, while Dach1 overexpression protected mice from airway inflammation and lung function decline. In 16 HBE cells, Dach1 knockdown and overexpression promoted and inhibited the secretion of IL-6 and IL-8 after simulation of CSE, respectively. Nuclear factor erythroid 2-related factor 2 (Nrf2) was identified as novel downstream target of Dach1, which directly binds to its promoter. Induction of Dach1 alleviated inflammation by activating Nrf2 signaling. Conclusions: Dach1 is decreased in COPD patients. Dach1 has protective effects against inflammation induced by CS by activating Nrf2 signaling pathway. Targeting Dach1 is a potential therapeutic strategy for COPD.