LncRNA MIR155HG contributes to smoke-related chronic obstructive pulmonary disease by targeting miR-128-5p/BRD4 axis

Abstract

Chronic obstructive pulmonary disease (COPD) is a common airway disease characterized by an exaggerated pulmonary inflammatory response. Long noncoding MIR155 host gene (lncRNA MIR155HG) has been identified to be related to the macrophage polarization in COPD. However, the detailed function of MIR155HG in cigarette smoke (CS)-mediated COPD remains largely unknown. The expression level of MIR155HG was elevated while miR-218-5p was decreased in lung tissues of smokers without or with COPD, especially in smokers with COPD, and cigarette smoke extract (CSE)-treated human pulmonary microvascular endothelial cell (HPMECs) in a dose-and time-dependent manner. Then, functional experiments showed that MIR155HG deletion could reverse CSE exposure-induced apoptosis and inflammation in HPMECs. MiR-218-5p was confirmed to be a target of MIR155HG and rescue assay showed miR-218-5p inhibitor attenuated the inhibitory action of MIR155HG knockdown on CSE-induced HPMECs. Subsequently, miR-218-5p was found to target bromodomain containing 4 (BRD4) directly, and miR-218-5p overexpression overturned CSE-induced injury of HPMECs via regulating BRD4. Additionally, co-expression analysis indicated MIR155HG indirectly regulated BRD4 expression in HP-MECs via miR-218-5p. Thus, we concluded that MIR155HG contributed to the apoptosis and inflammation of HPMECs in smoke-related COPD by regulating miR-128-5p/BRD4 axis, providing a novel insight on the pathogenesis of COPD and a therapeutic strategy on COPD treatments.According to the prediction of DIANA-LncBaseV2 prediction program, miR-218-5p might be a potential target of MIR155HG ( Figure 3A). To verify this prediction, luciferase reporter assay was performed and we found miR-218-5p mimic transfection reduced the luciferase activity of the MIR155HG-WT reporter vector but not MIR155HG-MUT reporter vector in HPMECs ( Figure 3B). However, miR-218-5p inhibitor transfection enhanced the luciferase activity

Circ-OSBPL2 Contributes to Smoke-Related Chronic Obstructive Pulmonary Disease by Targeting miR-193a-5p/BRD4 Axis

“… 33 BRD4-NFκB pathway plays important roles in airway remodeling and inflammation in COPD, and BRD4 inhibitors are potent anti-remodeling and anti-inflammatory agents. 6 , 34 In this study, we identified that circ-OSBPL2 acted as a sponge for miR-193a-5p to modulate BRD4 expression. Rescue assay analysis exhibited that up-regulation of BRD4 abolished the inhibitory action of miR-193a-5p on CSE-induced HBEC injury.…”

“… 3 , 4 The airway epithelium is the primary defense against inhaled harmful particles, the injury of endothelial cells can lead to acute oxidative injury, epithelial apoptosis, epithelial barrier formation reduction, disruption of cilia function, and chemokine production, ultimately causing the narrow of small airways, producing obstruction and reducing lung compliance. 5 , 6 Therefore, further investigations on the mechanisms underlying the CS-induced endothelial cell injury in the progression of COPD are necessary.…”

MiR-218 Inhibits CSE-Induced Apoptosis and Inflammation in BEAS-2B by Targeting BRD4

“… 26 , 27 In addition, Song et al found that BRD4 is implicated in inflammation in the development of COPD. 28 Meanwhile, miRNA might participate in COPD processes by regulating inflammatory cytokine expression through targeting BRD4, such as miR-29b. 29 Similarly, our data suggested that miR-218 inhibited CSE-induced apoptosis and inflammation in BEAS-2B by targeting BRD4.…”

The role of cigarette smoke-induced pulmonary vascular endothelial cell apoptosis in COPD

“…Bax and caspase-3 expression increased. Bcl-2 increased Bi et al [ 97 ] HPMECs + CSE HPMECs + PBS lncRNA MIR155H, miRNA-218-5p, BRD4 HPMECs E group showing cell apoptosis, lncRNA MIR155H and BRD4 expression increasedmiRNA-218-5p expression decreased Song et al [ 98 ] Exosomes RPMECs + CSE RPMECs + PBS Exosomes RPMECs Exosomes induced by 1% CSE significantly decreased the apoptosis rate of endothelial cells Zhao et al [ 105 ] …”

“…However, knockdown of lncRNA MEG3 showed the opposite effect, decreased cell apoptosis, decreased caspase activity, decreased Bax expression, and upregulated Bcl-2 expression. Also, Song et al [ 98 ] found that the expression of the lncRNA MIR155HG was increased, while miRNA-218-5p was decreased in CSE-induced HPMECs. Subsequently, it was found that miRNA-218-5p was a direct target of MIR155HG.…”