Dysregulation of IL-17A is closely associated with airway inflammation and remodeling in severe asthma. However, the molecular mechanisms by which IL-17A is regulated remain unclear. Here we identify epithelial sirtuin 6 (SIRT6) as an epigenetic regulator that governs IL-17A pathogenicity in severe asthma. Mice with airway epithelial cell-specific deletion of Sirt6 are protected against allergen-induced airway inflammation and remodeling via inhibiting IL-17A-mediated inflammatory chemokines and mesenchymal reprogramming. Mechanistically, SIRT6 directly interacts with RORγt and mediates RORγt deacetylation at lysine 192 via its PPXY motifs. SIRT6 promotes RORγt recruitment to the IL-17A gene promoter and enhances its transcription. In severe asthma patients, high expression of SIRT6 positively correlates with airway remodeling and disease severity. SIRT6 inhibitor (OSS_128167) treatment significantly attenuates airway inflammation and remodeling in mice. Collectively, these results uncover a function for SIRT6 in regulating IL-17A pathogenicity in severe asthma, implicating SIRT6 as a potential therapeutic target for severe asthma.

Background We have reported that heparin-binding epidermal growth factor (HB-EGF) is increased in patients with chronic obstructive pulmonary disease (COPD) and associated with collagen deposition, but the mechanisms remain unclear. In the present study, we aimed to investigated the inflammatory cytokines secreted by bronchial epithelial cells following exposure to HB-EGF that promoted proliferation and migration of human lung fibroblast. Methods HB-EGF-induced inflammatory cytokines were assayed in two airway epithelial cells (primary human bronchial epithelial cells [HBECs] and BEAS-2B cells). Moreover, the culture supernatants derived from HB-EGF-treated HBECs and BEAS-2B cells were added to human primary lung fibroblasts. The effect of culture supernatants on proliferation and migration of fibroblasts was assessed. Results IL-8 expression was significantly increased in bronchial epithelial cells treated with HB-EGF, which was at least partially dependent on NF-kB pathways activation. HB-EGF-induced IL-8 was found to further promote lung fibroblasts proliferation and migration, and the effects were attenuated after neutralizing IL-8. Conclusions These findings suggest that HB-EGF may be involved in the pathology of airway fibrosis by induction of IL-8 from airway epithelium, subsequently causing lung fibroblasts proliferation and migration. Thus, inhibition of HBEGF and/or IL-8 production could prevent the development of airway fibrosis by modulating fibroblast activation.

Purpose:Particulate matter (PM) has been implicated as a risk factor for airway injury. However, the molecular mechanisms remain largely unclear. The goal of this study was to determine whether sirtuin1 (SIRT1), an anti-inflammatory and antiaging protein, protects against PM-induced airway inflammation.Methods:The effect of SIRT1 on PM-induced airway inflammation was assessed by using in vivo models of airway inflammation induced by PM and in vitro culture of human bronchial epithelial (HBE) cells exposed to PM, resveratrol (SIRT1 activator), or both.Results:PM-stimulated HBE cells showed a significant decrease in SIRT1 but a notable increase in inflammatory cytokines. SIRT1 gene silencing further enhanced PM-induced expression of inflammatory cytokines. In contrast, resveratrol, a SIRT1 activator, reduced the expression of these cytokines compared with the control cells. In vivo, SIRT1 expression was significantly decreased in lung tissues of PM-exposed mice. Interestingly, resveratrol treatment reversed the enhanced total cells, neutrophils and inflammatory cytokines in PM-induced mice. Moreover, SIRT1 mediated PM-induced inflammatory cytokines expression at least partly through MAPK pathways.Conclusion:These findings suggest that SIRT1 is involved in the pathogenesis of PM-induced airway inflammation and activation of SIRT1 could prevent airway disorders or disease exacerbations induced by airborne particulate pollution.

*These authors contributed equally to this work Purpose: Particulate matter (PM) has been implicated as a risk factor for airway injury. However, the molecular mechanisms remain largely unclear. The goal of this study was to determine whether sirtuin1 (SIRT1), an anti-inflammatory and antiaging protein, protects against PM-induced airway inflammation. Methods: The effect of SIRT1 on PM-induced airway inflammation was assessed by using in vivo models of airway inflammation induced by PM and in vitro culture of human bronchial epithelial (HBE) cells exposed to PM, resveratrol (SIRT1 activator), or both. Results: PM-stimulated HBE cells showed a significant decrease in SIRT1 but a notable increase in inflammatory cytokines. SIRT1 gene silencing further enhanced PM-induced expression of inflammatory cytokines. In contrast, resveratrol, a SIRT1 activator, reduced the expression of these cytokines compared with the control cells. In vivo, SIRT1 expression was significantly decreased in lung tissues of PM-exposed mice. Interestingly, resveratrol treatment reversed the enhanced total cells, neutrophils and inflammatory cytokines in PMinduced mice. Moreover, SIRT1 mediated PM-induced inflammatory cytokines expression at least partly through MAPK pathways. Conclusion: These findings suggest that SIRT1 is involved in the pathogenesis of PMinduced airway inflammation and activation of SIRT1 could prevent airway disorders or disease exacerbations induced by airborne particulate pollution.

在现代社会,随着经济的快速发展和城市化进程加快,环境污染对人类健康的危害日益突出,其中空气污染已被证实是影响人类健康的有害因素之一,根据世界卫生组织报道,全世界由于空气污染造成死亡的大约有700万人[1]. 空气污染物由颗粒物质、气态污染物和挥发性有机化合物等组成[2]. 在这些空气污染物中,PM 2. 5不仅有大部分停留在肺部,还可以进一步穿过呼吸屏障并进入循环系统,从而扩散到全身[3]. 作为PM 2. 5 最先沉积的部位,肺部是受到PM 2. 5 毒性作用的主要目标之一,大量研究表明,PM 2. 5 可引起气道炎症,诱发和加重慢性支气管炎、支气管哮喘和慢性阻塞性肺疾病,导致肺功能下降,使肺部更易受到感染,呼吸道症状加重,如呼吸道高反应性和呼吸困难等.

Although airway fibrosis and epithelial-mesenchymal transition (EMT) contribute to airway remodeling in chronic obstructive pulmonary disease (COPD), the mechanisms underlying their development have not been fully elucidated. In the present study, we aimed to assess heparin-binding epidermal growth factor (HB-EGF) expression in the airways of patients with COPD and to elucidate the possible role of HB-EGF in the pathology of COPD. Sputum and lung tissue HB-EGF expression was evaluated in control subjects and patients with COPD. The relationships between HB-EGF expression, disease severity, collagen deposition (fibrosis), and EMT were investigated. In vitro, human bronchial epithelial (HBE) cells and lung fibroblast cells exposed to the recombinant HB-EGF, collagen deposition and EMT were assessed. We found that sputum HB-EGF expression was significantly increased in patients with COPD compared with non-smokers and smokers without COPD. There was a significant positive correlation between sputum HB-EGF and COPD assessment test (CAT) score. HB-EGF expression was significantly increased in the lung tissue samples of patients with COPD and associated with collagen deposition and N- and E-cadherin, and vimentin expression. In vitro, HB-EGF promoted collagen production in lung fibroblasts. Moreover, HB-EGF induced the EMT process through induction of N-and E-cadherin, and vimentin expression in HBE cells. Collectively, HB-EGF induces airway remodeling by modulating airway fibrosis and pulmonary EMT, and contributes to the COPD severity. The current data may provide insight into the underlying pathogenesis of COPD, in which HB-EGF has an important pathogenic role.

沉默信息调节因子2 (Sirt2) 是1986年Ivy等人在酵母菌中发现的和长寿相关的基因[1],后来发现在哺乳动物中也存在和 Sirt2同源蛋白,命名为SIRT1-SIRT7,其中SIRT1和酵母的 Sirt2同源性最高.SIRT1作为细胞内重要的调节因子,广泛分布于人类多种细胞的胞浆和胞核,参与调节炎症、细胞周期、衰老和凋亡、应激等重要生理过程.与多种肺部疾病的发生发展密切相关,例如慢性阻塞性肺疾病、支气管哮喘(简称哮喘)、肺纤维化、肺癌等.然而,目前SIRT1在哮喘中发病机制的研究报道较少.本文主要从SIRT1与哮喘关系进行综述.

Purpose Fibrosis in peripheral airways is responsible for airflow limitation in chronic obstructive pulmonary disease (COPD). Annexin A1 modulates several key biological events during inflammation. However, little is known about its role in airway fibrosis in COPD. We investigated whether levels of Annexin A1 were upregulated in patients with COPD, and whether it promoted airway fibrosis. Methods We quantified serum Annexin A1 levels in never-smokers (n=12), smokers without COPD (n=11), and smokers with COPD (n=22). Correlations between Annexin A1 expression and clinical indicators (eg, lung function) were assessed. In vitro, human bronchial epithelial (HBE) cells were exposed to cigarette smoke extract (CSE) and Annexin A1 expression was assessed. Primary human lung fibroblasts were isolated from patients with COPD and effects of Annexin A1 on fibrotic deposition of lung fibroblasts were evaluated. Results Serum Annexin A1 was significantly higher in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines stage III or IV than in those with GOLD stages I or II (12.8±0.8 ng/mL versus 9.8±0.7 ng/mL; p=0.016). Annexin A1 expression was negatively associated with airflow obstruction (forced expiratory volume in one second % predicted; r=−0.72, p<0.001). In vitro, Annexin A1 was significantly increased in CSE-exposed HBE cells in a time- and concentration-dependent manner. Annexin A1 promoted lung fibroblasts proliferation, migration, differentiation, and collagen deposition via the ERK1/2 and p38 mitogen-activated protein kinase pathways. Conclusion Annexin A1 expression is upregulated in patients with COPD and affects lung fibroblast function. However, more studies are needed to clarify the role of Annexin A1 in airway fibrosis of COPD.