Abstract
Chronic obstructive pulmonary disease (COPD) is a debilitating disease caused by chronic exposure to cigarette smoke (CS). Celastrol is a pentacyclic triterpenoid compound exhibits potent antioxidant and anti-inflammatory activities. Also it is presently known to protect against liver damage induced by type II diabetes. However, its role in COPD is unclear. In this study, we investigated the effects of Celastrol on cellular inflammation in mice exposed to CS and Beas-2B cells treated with CS extract (CSE). C57BL/6 mice and Beas-2B cells were randomly divided into three groups: control group, COPD or CSE group, and Celastrol treatment group. The COPD mice models were subjected to smoke exposure and cell models were treated with CSE. Bioinformatics analysis was performed to identify differentially expressed genes following treatment with Celastrol in COPD, the molecular networks was mapped by Cytoscape. The levels of inflammatory cytokinesinterleukin-8, tumor necrosis factor α, monocyte chemoattractant protein-1, and oxidative stress factors superoxide dismutase and catalase were measured by enzyme-linked immunosorbent assay. Hematoxylin and eosin staining to detect the injury of mouse lung tissue. mRNA and protein levels of Ednrb and Kng1 in the tissues and cells were measured by quantitative polymerase chain reaction (PCR) and western blotting, respectively. Apoptosis was measured by flow cytometry and TUNEL staining. Compared to mice in the COPD group, mice treated with Celastrol had significantly reduced levels of inflammatory cytokines interleukin-8, tumor necrosis factor α and monocyte chemoattractant protein-1 in the serum and bronchoalveolar lavage fluid, and significantly increased levels of oxidative stress factors superoxide dismutase and catalase. The same results were obtained at the cellular level using Beas-2B cells. Compared to the model groups, Celastrol reduced lung injury in mice and significantly reduced cellular apoptosis. Bioinformatics analysis showed that Ednrb is a target gene of Celastrol and differentially expressed in COPD. Quantitative PCR analysis showed that Ednrb expression in patients with COPD was significantly increased compared to that in healthy controls. Additionally, Celastrol effectively reduced Ednrb/Kng1 expression in both cell and animal models. Celastrol has a therapeutic effect on COPD and may alleviate COPD by inhibiting inflammation development by suppressing the Ednrb/Kng1 signaling pathway.
Highlights
IntroductionCOPD, is a destructive pulmonary disease characterized by incompletely reversible airflow obstruction
Chronic obstructive pulmonary disease, or COPD, is a destructive pulmonary disease characterized by incompletely reversible airflow obstruction
IL-8, TNF-a, and monocyte chemoattractant protein (MCP)-1 and oxidative stress factors superoxide dismutase (SOD) and CAT in the mouse serum and Bronchoalveolar Lavage Fluid (BALF) as well as the supernatant of human bronchial epithelial cells were detected by Enzyme-linked immunosorbent assay (ELISA) (Figure 2)
Summary
COPD, is a destructive pulmonary disease characterized by incompletely reversible airflow obstruction. It is the third leading cause of death and fifth leading cause of chronic disability worldwide (Taivassalo and Hussain, 2016). The molecular mechanisms of COPD pathogenesis include alveolar epithelial or endothelial cell senescence, apoptosis, and chronic inflammation induced by oxidative stress (Fallica et al, 2014). Epigallocatechin gallate has been shown to inhibit chronic airway inflammation and abnormal airway mucus production by inhibiting the epidermal growth factor receptor signaling pathway (Liang et al, 2017). Silymarin has been shown to inhibit autophagy and the extracellular receptor kinase mitogen-activated protein kinase signaling pathway to reduce inflammatory responses (Li et al, 2016a)
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