Doldron Megan S, Chakraborty Sourav, Anand Santosh, Faheem Mehwish, Reh Beh, Wang Xuegeng, Mallik Saurav, Jia Zhenquan, Bhandari Ramji Kumar
Department of Biology, University of North Carolina Greensboro, Greensboro, NC 27412, USA.
Division of Biological Sciences, University of Missouri, Columbia, MO 65211, USA.
Int J Mol Sci. 2025 May 29;26(11):5212. doi: 10.3390/ijms26115212.
Delta-9-tetrahydrocannabinol (Δ-9-THC or THC), the primary psychoactive constituent of cannabis, can lead to adverse health conditions, including mental health issues, brain impairment, and cardiac and respiratory problems. The amount of THC in cannabis has steadily climbed over the past few decades, with today's cannabis having three times the concentration of THC compared to 25 years ago. Inhalation is a major route of exposure, allowing substances to enter the body via the respiratory tract. THC exposure causes cell death in the airway epithelium; however, the molecular underpinning of THC exposure-induced bronchial epithelial cell death is not clearly understood. To address the mechanisms involved in this process, the present study examined the cell viability, oxidative stress, lipid peroxidation, and transcriptional alterations caused by various concentrations of Δ-9-THC (0, 800, 1000, 1200, and 1500 ng/mL) in a human bronchial epithelial cell line (BEAS-2B) in vitro. Δ-9-THC exposure caused a significant dose-dependent decrease in cell viability after 24 h exposure. Transcriptome analysis showed a distinct dose-dependent response. HIF-1 signaling, ferroptosis, AMPK signaling, and immunogenic pathways were activated by Δ-9-THC-upregulated genes. Glutathione and fatty acid metabolic pathways were significantly altered by Δ-9-THC-dependent downregulated genes. Ingenuity Pathway Analysis (IPA) revealed several top canonical pathways altered by Δ-9-THC exposure, including ferroptosis, NRF-2-mediated oxidative stress response, caveolar-mediated endocytosis (loss of cell adhesion to the substrate), tumor microenvironment, HIF1alpha signaling, and the unfolded protein response pathway. Δ-9-THC-induced cell death was ameliorated by inhibiting the ferroptosis pathway, whereas treatments with ferroptosis agonist exacerbated the cell death process, suggesting that Δ-9-THC-induced bronchial epithelial cell death potentially involves the ferroptosis pathway.
Δ-9-四氢大麻酚（Δ-9-THC或THC）是大麻的主要精神活性成分，可导致不良健康状况，包括心理健康问题、脑损伤以及心脏和呼吸问题。在过去几十年中，大麻中THC的含量稳步攀升，如今大麻中THC的浓度是25年前的三倍。吸入是主要的接触途径，使物质通过呼吸道进入人体。THC暴露会导致气道上皮细胞死亡；然而，THC暴露诱导支气管上皮细胞死亡的分子机制尚不清楚。为了阐明这一过程涉及的机制，本研究在体外检测了不同浓度的Δ-9-THC（0、800、1000、1200和1500 ng/mL）对人支气管上皮细胞系（BEAS-2B）的细胞活力、氧化应激、脂质过氧化和转录变化的影响。暴露24小时后，Δ-9-THC暴露导致细胞活力显著呈剂量依赖性下降。转录组分析显示出明显的剂量依赖性反应。HIF-1信号通路、铁死亡、AMPK信号通路和免疫原性通路被Δ-9-THC上调的基因激活。谷胱甘肽和脂肪酸代谢途径被Δ-9-THC依赖性下调的基因显著改变。 Ingenuity Pathway Analysis（IPA）揭示了几种因Δ-9-THC暴露而改变的顶级经典通路，包括铁死亡、NRF-2介导的氧化应激反应、小窝介导的内吞作用（细胞与底物的粘附丧失）、肿瘤微环境、HIF1alpha信号通路和未折叠蛋白反应通路。抑制铁死亡途径可改善Δ-9-THC诱导的细胞死亡，而用铁死亡激动剂处理则会加剧细胞死亡过程，这表明Δ-9-THC诱导的支气管上皮细胞死亡可能涉及铁死亡途径。
