Department of Pediatrics, The Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland.
Faculty of Building Services, Hydro- and Environmental Engineering, Warsaw University of Technology, 00-653 Warsaw, Poland.
Int J Mol Sci. 2024 May 31;25(11):6051. doi: 10.3390/ijms25116051.
N-acetylcysteine (NAC) is a mucolytic agent with antioxidant and anti-inflammatory properties. The respiratory syncytial virus (RSV) is one of the most important etiological factors of lower respiratory tract infections, and exposure to air pollution appears to be additionally associated with higher RSV incidence and disease severity. We aimed to systematically review the existing literature to determine which molecular mechanisms mediate the effects of NAC in an RSV infection and air pollution, and to identify the knowledge gaps in this field. A search for original studies was carried out in three databases and a calibrated extraction grid was used to extract data on the NAC treatment (dose, timing), the air pollutant type, and the most significant mechanisms. We identified only 28 studies conducted in human cellular models ( = 18), animal models ( = 7), and mixed models ( = 3). NAC treatment improves the barrier function of the epithelium damaged by RSV and air pollution, and reduces the epithelial permeability, protecting against viral entry. NAC may also block RSV-activated phosphorylation of the epidermal growth factor receptor (EGFR), which promotes endocytosis and facilitates cell entry. EGFR also enhances the release of a mucin gene, MUC5AC, which increases mucus viscosity and causes goblet cell metaplasia; the effects are abrogated by NAC. NAC blocks virus release from the infected cells, attenuates the cigarette smoke-induced shift from necrosis to apoptosis, and reverses the block in IFN-γ-induced antiviral gene expression caused by the inhibited Stat1 phosphorylation. Increased synthesis of pro-inflammatory cytokines and chemokines is induced by both RSV and air pollutants and is mediated by the nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways that are activated in response to oxidative stress. MCP-1 (monocyte chemoattractant protein-1) and RANTES (regulated upon activation, expressed and secreted by normal T cells) partially mediate airway hyperresponsiveness (AHR), and therapeutic (but not preventive) NAC administration reduces the inflammatory response and has been shown to reduce ozone-induced AHR. Oxidative stress-induced DNA damage and cellular senescence, observed during RSV infection and exposure to air pollution, can be partially reversed by NAC administration, while data on the emphysema formation are disputed. The review identified potential common molecular mechanisms of interest that are affected by NAC and may alleviate both the RSV infection and the effects of air pollution. Data are limited and gaps in knowledge include the optimal timing or dosage of NAC administration, therefore future studies should clarify these uncertainties and verify its practical use.
N-乙酰半胱氨酸（NAC）是一种黏液溶解剂，具有抗氧化和抗炎特性。呼吸道合胞病毒（RSV）是下呼吸道感染的最重要病因之一，而暴露于空气污染似乎与 RSV 发病率和疾病严重程度的升高有关。我们旨在系统地回顾现有文献，以确定介导 NAC 在 RSV 感染和空气污染中的作用的分子机制，并确定该领域的知识空白。在三个数据库中进行了原始研究的搜索，并使用校准的提取网格提取了有关 NAC 治疗（剂量、时间）、空气污染物类型和最重要机制的数据。我们仅确定了在人类细胞模型（=18）、动物模型（=7）和混合模型（=3）中进行的 28 项研究。NAC 治疗可改善 RSV 和空气污染损伤的上皮屏障功能，并降低上皮通透性，从而防止病毒进入。NAC 还可能阻断 RSV 激活的表皮生长因子受体（EGFR）的磷酸化，该受体促进内吞作用并促进细胞进入。EGFR 还增强粘蛋白基因 MUC5AC 的释放，增加粘液粘度并导致杯状细胞化生；NAC 可阻断病毒从感染细胞中释放，减轻香烟烟雾诱导的从坏死向凋亡的转变，并逆转因 Stat1 磷酸化抑制而导致的 IFN-γ诱导的抗病毒基因表达受阻。RSV 和空气污染物均可诱导促炎细胞因子和趋化因子的合成增加，这是由核因子 kappa-B（NF-κB）和丝裂原活化蛋白激酶（MAPK）信号通路介导的，这些信号通路对氧化应激作出反应而被激活。MCP-1（单核细胞趋化蛋白-1）和 RANTES（正常 T 细胞激活、表达和分泌的调节物）部分介导气道高反应性（AHR），治疗（而非预防）性 NAC 给药可减轻炎症反应，并已显示可降低臭氧诱导的 AHR。RSV 感染和暴露于空气污染期间观察到的氧化应激诱导的 DNA 损伤和细胞衰老可部分被 NAC 给药逆转，而关于肺气肿形成的数据存在争议。该综述确定了潜在的共同分子机制，这些机制受 NAC 影响，可能减轻 RSV 感染和空气污染的影响。数据有限，知识空白包括 NAC 给药的最佳时间或剂量，因此未来的研究应澄清这些不确定性并验证其实际用途。
