Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA.
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA.
Toxicol Appl Pharmacol. 2024 Apr;485:116908. doi: 10.1016/j.taap.2024.116908. Epub 2024 Mar 19.
Nitrogen mustard (NM) is a toxic vesicant that causes acute injury to the respiratory tract. This is accompanied by an accumulation of activated macrophages in the lung and oxidative stress which have been implicated in tissue injury. In these studies, we analyzed the effects of N-acetylcysteine (NAC), an inhibitor of oxidative stress and inflammation on NM-induced lung injury, macrophage activation and bioenergetics. Treatment of rats with NAC (150 mg/kg, i.p., daily) beginning 30 min after administration of NM (0.125 mg/kg, i.t.) reduced histopathologic alterations in the lung including alveolar interstitial thickening, blood vessel hemorrhage, fibrin deposition, alveolar inflammation, and bronchiolization of alveolar walls within 3 d of exposure; damage to the alveolar-epithelial barrier, measured by bronchoalveolar lavage fluid protein and cells, was also reduced by NAC, along with oxidative stress as measured by heme oxygenase (HO)-1 and Ym-1 expression in the lung. Treatment of rats with NAC attenuated the accumulation of macrophages in the lung expressing proinflammatory genes including Ptgs2, Nos2, Il-6 and Il-12; macrophages expressing inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and tumor necrosis factor (TNF)α protein were also reduced in histologic sections. Conversely, NAC had no effect on macrophages expressing the anti-inflammatory proteins arginase-1 or mannose receptor, or on NM-induced increases in matrix metalloproteinase (MMP)-9 or proliferating cell nuclear antigen (PCNA), markers of tissue repair. Following NM exposure, lung macrophage basal and maximal glycolytic activity increased, while basal respiration decreased indicating greater reliance on glycolysis to generate ATP. NAC increased both glycolysis and oxidative phosphorylation. Additionally, in macrophages from both control and NM treated animals, NAC treatment resulted in increased S-nitrosylation of ATP synthase, protecting the enzyme from oxidative damage. Taken together, these data suggest that alterations in NM-induced macrophage activation and bioenergetics contribute to the efficacy of NAC in mitigating lung injury.
氮芥（NM）是一种有毒的糜烂剂，会导致呼吸道急性损伤。这伴随着肺部中活化的巨噬细胞的积累和氧化应激，这些都与组织损伤有关。在这些研究中，我们分析了 N-乙酰半胱氨酸（NAC），一种抗氧化应激和炎症抑制剂，对 NM 诱导的肺损伤、巨噬细胞激活和生物能量学的影响。在 NM（0.125mg/kg，i.t.）给药后 30 分钟开始，用 NAC（150mg/kg，i.p.，每天）治疗大鼠，可减少暴露 3 天内肺部的组织病理学改变，包括肺泡间质增厚、血管出血、纤维蛋白沉积、肺泡炎症和肺泡壁细支气管化；NAC 还减少了肺泡上皮屏障的损伤，这是通过支气管肺泡灌洗液蛋白和细胞来衡量的，同时还减少了氧化应激，这是通过肺部血红素加氧酶（HO）-1 和 Ym-1 的表达来衡量的。用 NAC 治疗大鼠可减轻肺中表达促炎基因的巨噬细胞的积累，包括 Ptgs2、Nos2、Il-6 和 Il-12；在组织切片中也减少了表达诱导型一氧化氮合酶（iNOS）、环氧化酶（COX）-2 和肿瘤坏死因子（TNF）α 的巨噬细胞。相反，NAC 对表达抗炎蛋白精氨酸酶-1 或甘露糖受体的巨噬细胞或 NM 诱导的基质金属蛋白酶（MMP）-9 或增殖细胞核抗原（PCNA）无影响，这些是组织修复的标志物。NM 暴露后，肺巨噬细胞基础和最大糖酵解活性增加，而基础呼吸减少，表明更多地依赖糖酵解产生 ATP。NAC 增加了糖酵解和氧化磷酸化。此外，在来自对照和 NM 处理动物的巨噬细胞中，NAC 处理导致 ATP 合酶的 S-亚硝基化增加，从而保护酶免受氧化损伤。总之，这些数据表明，NM 诱导的巨噬细胞激活和生物能量学的改变有助于 NAC 减轻肺损伤的疗效。
