Small Airways Remodeling in COPD Patients with Smoking and Diabetes

Abstract

Background: Diabetes mellitus (DM) could reinforce the injury of lung function in chronic obstructive pulmonary disease (COPD) patients. Epithelial-mesenchymal transition (EMT) is closely related to small airway remodeling, and was activated in both COPD and DM airway epithelial. The expression of TGF-β could increase EMT through TGF-β/Smad pathway, although the function of it in DM caused COPD patients' lung injury is unclear. Methods: In a retrospective study design, 347 COPD patients gathered from hospital records databases were divided into four subgroups normal group, smoking group, diabetes group, smoking with diabetes group. We calculated the mean or median of each indicator by different groups. With the injection of SB431542, lung function was detected in type 2 diabetes model and COPD rat. The mechanism of EMT through TGF-β/Smad pathway was studied using molecular biology and biochemical methods. Findings: Here we found that patients who had smoking or diabetes history had a worse airflow limitation and small airway disorder than normal COPD patients, and the combination of the two were even worse. Lung function test of rats supported the idea. EMT and TGFβ/Smad pathway were activated in COPD and DM rats' epithelial, while the combination of COPD and DM reinforced the effect, indicated by immunohistochemical staining results of down-regulation of Zo1, and up-regulation of vimentin, TGF-β and Smad4. 25mM glycose and/or 1% cigarette smoke extract (CSE) treated for 24 hours could up-regulate vimentin, TGF-β, Smad2/3/4, the phosphorylation of Smad2/3, and down-regulate Zo1 in airway epithelial cells (AEC). TGF-β/Smad pathway could modulate EMT, suppression of TGFβ/Smad pathway could block the EMT caused by cigarette smoking and/or hyperglycemia, and activation could reinforce it. Interpretation: Cigarette smoking and hyperglycemia could activate the small airway remodeling, as they could activate the EMT of AEC through TGF-β/Smad pathway. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (81570336，81300030). Declaration of Interests: The authors have declared that no conflict of interest exists. Ethical Approval Statement: Clinical study was approved by Medical Ethics Committe of Shandong Provincial Hospital affiliated to Shandong University (Ethical Review of Medical Research on Human Being No.2019-001). The animal research used the protocol that has been approved by the Medical Experimental Animal Care Commission of Shandong Provincial Hospital affiliated to Shandong University (Ethical Review of Medical Research on Animals No. 2019-019).