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IP₃ R attenuates oxidative stress and inflammation damage in smoking-induced COPD by promoting autophagy.

ABSTRACT: Tobacco smoking is one of the most important risk factors for chronic obstructive pulmonary disease (COPD). However, the most critical genes and proteins remain poorly understood. Therefore, we aimed to investigate these hub genes and proteins in tobacco smoke-induced COPD, together with the potential mechanism(s). Differentially expressed genes (DEGs) were analysed between smokers and patients with COPD. mRNA expression and protein expression of IP₃ R were confirmed in patients with COPD and extracted smoke solution (ESS)-treated human bronchial epithelial (HBE) cells. Moreover, expression of oxidative stress, inflammatory cytokines and/or autophagy-related protein was tested when IP₃ R was silenced or overexpressed in ESS-treated and/or 3-MA-treated cells. A total of 30 DEGs were obtained between patients with COPD and smoker samples. IP₃ R was identified as one of the key targets in tobacco smoke-induced COPD. In addition, IP₃ R was significantly decreased in patients with COPD and ESS-treated cells. Loss of IP₃ R statistically increased expression of oxidative stress and inflammatory cytokines in ESS-treated HBE cells, and overexpression of IP₃ R reversed the above functions. Furthermore, the autophagy-related proteins (Atg5, LC3 and Beclin1) were statistically decreased, and p62 was increased by silencing of IP₃ R cells, while overexpression of IP₃ R showed contrary results. Additionally, we detected that administration of 3-MA significantly reversed the protective effects of IP₃ R overexpression on ESS-induced oxidative stress and inflammatory injury. Our results suggest that IP₃ R might exert a protective role against ESS-induced oxidative stress and inflammation damage in HBE cells. These protective effects might be associated with promoting autophagy.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC8256356 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Smoking is a major risk factor for a variety of diseases, including cancer and immune-mediated inflammatory diseases. Tobacco smoke contains a mixture of chemicals, including a host of reactive oxygen- and nitrogen species (ROS and RNS), among others, that can damage cellular and sub-cellular targets, such as lipids, proteins, and nucleic acids. A growing body of evidence supports a key role for smoking-induced ROS and the resulting oxidative stress in inflammation and carcinogenesis. This comprehensive and up-to-date review covers four interrelated topics, including 'smoking', 'oxidative stress', 'inflammation', and 'cancer'. The review discusses each of the four topics, while exploring the intersections among the topics by highlighting the macromolecular damage attributable to ROS. Specifically, oxidative damage to macromolecular targets, such as lipid peroxidation, post-translational modification of proteins, and DNA adduction, as well as enzymatic and non-enzymatic antioxidant defense mechanisms, and the multi-faceted repair pathways of oxidized lesions are described. Also discussed are the biological consequences of oxidative damage to macromolecules if they evade the defense mechanisms and/or are not repaired properly or in time. Emphasis is placed on the genetic- and epigenetic alterations that may lead to transcriptional deregulation of functionally-important genes and disruption of regulatory elements. Smoking-associated oxidative stress also activates the inflammatory response pathway, which triggers a cascade of events of which ROS production is an initial yet indispensable step. The release of ROS at the site of damage and inflammation helps combat foreign pathogens and restores the injured tissue, while simultaneously increasing the burden of oxidative stress. This creates a vicious cycle in which smoking-related oxidative stress causes inflammation, which in turn, results in further generation of ROS, and potentially increased oxidative damage to macromolecular targets that may lead to cancer initiation and/or progression.

Project description:BackgroundOxidative stress in hepatocytes was important pathogenesis of nonalcoholic steatohepatitis (NASH). Autophagy was a cellular process that can remove damaged organelles under oxidative stress, and thus presented a potential therapeutic target against NASH. This work aimed to investigate whether autophagy was participated in the protective effects of dihydromyricetin (DHM) on palmitic acid (PA)-induced oxidative stress in hepatocytes and the underlying mechanism.MethodsHepG2 and HHL-5 cell lines were pretreated with DHM (20 μM) for 2 h, followed by PA (0.2 mM) treatment for 16 h. The oxidative stress was assessed by the quantification of intracellular reactive oxygen species (ROS), mitochondrial ROS (mtROS), mitochondrial membrane potential (MMP) and mitochondrial ultrastructural analyses. The protein expressions of SIRT3, LC3I/II, P62 and ATG4B, as well as the acetylation of AGT4B were determined by western blotting using HepG2 and HepG2/ATG4B± cells with heterozygous knockout of ATG4B.ResultsExposure to PA resulted in increased intracellular ROS and mtROS, decreased MMP and aggravated mitochondrial injury in HepG2 cells, which were notably attenuated by DHM treatment. DHM-induced inhibition of oxidative stress was associated with the induction of autophagy, characterized by upregulated ATG4B and LC3 II as well as downregulated P62 levels. Furthermore, the inhibitory effects of DHM on PA-induced autophagy arrest and oxidative stress were eliminated when pretreated with a SIRT3 inhibitor 3-TYP or conducted in HepG2/ATG4B± cells, suggesting that SIRT3 and ATG4B were involved in DHM-induced benefits. Moreover, DHM treatment increased the protein expression of SIRT3 and SIRT3-dependent deacetylation of ATG4B in HepG2 cells.ConclusionOur results demonstrated that DHM attenuated PA-induced oxidative stress in hepatocytes through induction of autophagy, which was mediated through the increased expression of SIRT3 and SIRT3-mediated ATG4B deacetylation following DHM treatment.

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IP₃ R attenuates oxidative stress and inflammation damage in smoking-induced COPD by promoting autophagy.

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IP₃ R attenuates oxidative stress and inflammation damage in smoking-induced COPD by promoting autophagy.