Kastratovic Nikolina, Markovic Vladimir, Arsenijevic Aleksandar, Volarevic Ana, Zdravkovic Natasa, Zdravkovic Marija, Brankovic Marija, Gmizic Tijana, Harrell Carl Randall, Jakovljevic Vladimir, Djonov Valentin, Volarevic Vladislav
Center for Research on Harmful Effects of Biological and Chemical Hazards, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.
Nicotine Tob Res. 2025 Feb 24;27(3):542-552. doi: 10.1093/ntr/ntae193.
The effects of combustible cigarettes (CCs) and electronic nicotine delivery systems (ENDS) on immune cell-driven colon inflammation and intestinal healing of patients with ulcerative colitis (UC) are still unknown and, therefore, were examined in this study.
Intracellular staining and flow cytometry analysis of immune cells isolated from UC patients who used ENDS (UCENDS), CCs (UCCC) and who were nonsmokers (UCAIR) were performed to elucidate cellular mechanisms which were responsible for CCs and ENDS-dependent modulation of immune response during UC progression. Additionally, dextran sulfate sodium (DSS)-colitis was induced in ENDS/CC/air-exposed mice (DSSENDS/ DSSCC/DSSAIR groups) to support clinical findings.
Significantly increased number of immunosuppressive, IL-10, TGF-β, and IL-35-producing, FoxP3-expressing CD3 + CD4 + T regulatory cells (Tregs) was observed in the blood of UCENDS patients while the reduced presence of inflammatory, TNF-α and IFN-γ-producing, Tbx21-expressing CD3 + CD4 + Th1, IL-4-producing Gata3-expresing Th2 and IL-17, IL-22-producing, RORγT, IL-23R-expressing Th17 cells were noticed in the blood of UCCC patients. Exposure to either CCs or ENDS was associated with enhanced mucosal healing, ameliorated spontaneous recovery, and improved survival of DSS-treated mice. An expansion of immunosuppressive cells (IL-10-producing tolerogenic CD11c + dendritic cells, alternatively activated CD206, Arginase 1-expressing, IL-10-producing F4/80 + macrophages, IL-10-producing FoxP3-expressing Tregs) was noticed in the colons of DSSENDS-treated mice, while reduced number of inflammatory, IL-17- and IL-4-producing T lymphocytes was observed in the colons of DSSCC-compared to DSSAIR-treated mice.
Despite different mechanisms of action, both ENDS and CCs attenuated ongoing colon inflammation, enhanced healing, and ameliorated recovery of injured intestines of DSS-treated mice and UC patients.
This is the first study that compared the effects of CCs and ENDS on immune cells of patients suffering from UC, providing new information about molecular and cellular mechanisms which were responsible for ENDS and CCs-dependent modulation of immune cell-driven colon injury and inflammation. Obtained results showed that both ENDS and CCs had the capacity to attenuate detrimental immune response, enhance healing, and ameliorate recovery of injured intestines.
可燃香烟（CCs）和电子尼古丁传送系统（ENDS）对免疫细胞驱动的溃疡性结肠炎（UC）患者结肠炎症和肠道愈合的影响尚不清楚，因此本研究对其进行了检测。
对使用ENDS（UCENDS组）、CCs（UCCC组）的UC患者及不吸烟者（UCAIR组）分离出的免疫细胞进行细胞内染色和流式细胞术分析，以阐明在UC进展过程中导致CCs和ENDS依赖的免疫反应调节的细胞机制。此外，在暴露于ENDS/CC/空气的小鼠中诱导葡聚糖硫酸钠（DSS）结肠炎（DSSENDS/DSSCC/DSSAIR组）以支持临床研究结果。
在UCENDS患者血液中观察到免疫抑制性、产生IL-10、TGF-β和IL-35、表达FoxP3的CD3 + CD4 + 调节性T细胞（Tregs）数量显著增加，而在UCCC患者血液中观察到炎症性、产生TNF-α和IFN-γ、表达Tbx21的CD3 + CD4 + Th1细胞、产生IL-4、表达Gata3的Th2细胞以及产生IL-17、IL-22、表达RORγT和IL-23R的Th17细胞数量减少。暴露于CCs或ENDS均与DSS处理小鼠的黏膜愈合增强、自发恢复改善和生存率提高相关。在DSSENDS处理小鼠的结肠中观察到免疫抑制细胞（产生IL-10的耐受性CD11c + 树突状细胞、交替活化的CD206、表达精氨酸酶1、产生IL-10的F4/80 + 巨噬细胞、产生IL-10、表达FoxP3的Tregs）数量增加，而与DSSAIR处理小鼠相比，DSSCC处理小鼠结肠中炎症性、产生IL-17和IL-4的T淋巴细胞数量减少。
尽管作用机制不同，但ENDS和CCs均减轻了DSS处理小鼠和UC患者持续的结肠炎症，促进了愈合，并改善了受损肠道的恢复。
这是第一项比较CCs和ENDS对UC患者免疫细胞影响的研究，提供了有关导致ENDS和CCs依赖的免疫细胞驱动的结肠损伤和炎症调节的分子和细胞机制的新信息。获得的结果表明，ENDS和CCs均有能力减轻有害的免疫反应，促进愈合，并改善受损肠道的恢复。
