Zhu Yin, Dutta Saugata, Han Yohan, Choi Dooyoung, Polverino Francesca, Owen Caroline A, Somanath Payaningal R, Wang Xiaoyun, Zhang Duo
Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA, 30912, USA.
Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, 30912, USA; Department of Microbiology, Wonkwang University School of Medicine, Iksan, 54538, Republic of Korea.
Redox Biol. 2025 Feb;79:103481. doi: 10.1016/j.redox.2024.103481. Epub 2024 Dec 21.
Emerging evidence suggests that lipid-laden macrophages (LLM) participate in lung damage in various clinical conditions. However, the mechanisms involved in LLM formation are not fully understood. In this study, we aimed to investigate the link between reactive oxygen species (ROS) and LLM formation. We found that ROS triggered by cigarette smoke extract (CSE) or HO significantly promoted LLM formation. Given the key role of ROS in LLM formation, we further demonstrated that LLM formation is induced by various ROS-producing stimuli, including bacteria, oxidized low-density lipoprotein (OxLDL), hyperoxia, and E-cigarette vapor extract (EVE). Meanwhile, cytochrome P450 family-1 subfamily B member 1 (CYP1B1) was highly upregulated in lung macrophages from chronic obstructive pulmonary disease (COPD) patients and CSE-treated macrophages. Functionally, CYP1B1 contributes to the CSE-induced lipid accumulation and LLM formation. CYP1B1 expression and LLM formation were effectively suppressed by antioxidant N-acetylcysteine (NAC) and carvedilol. The formation of LLM was also associated with classically activated M1 but not the M2 state. CSE-induced LLM showed time-dependent alterations in inflammatory response and phagocytic ability. In summary, our study highlights the role of oxidative stress in LLM formation. CYP1B1 contributes to ROS-induced LLM formation and may serve as a therapeutic target for reducing LLM-induced lung damage.
新出现的证据表明，脂质负载巨噬细胞（LLM）在各种临床情况下参与肺损伤。然而，LLM形成所涉及的机制尚未完全了解。在本研究中，我们旨在研究活性氧（ROS）与LLM形成之间的联系。我们发现，香烟烟雾提取物（CSE）或HO引发的ROS显著促进LLM形成。鉴于ROS在LLM形成中的关键作用，我们进一步证明，LLM形成是由各种产生ROS的刺激诱导的，包括细菌、氧化型低密度脂蛋白（OxLDL）、高氧和电子烟烟雾提取物（EVE）。同时，细胞色素P450家族-1亚家族B成员1（CYP1B1）在慢性阻塞性肺疾病（COPD）患者的肺巨噬细胞和CSE处理的巨噬细胞中高度上调。在功能上，CYP1B1有助于CSE诱导的脂质积累和LLM形成。抗氧化剂N-乙酰半胱氨酸（NAC）和卡维地洛有效抑制CYP1B1表达和LLM形成。LLM的形成也与经典激活的M1状态而非M2状态相关。CSE诱导的LLM在炎症反应和吞噬能力方面表现出时间依赖性变化。总之，我们的研究突出了氧化应激在LLM形成中的作用。CYP1B1有助于ROS诱导的LLM形成，并可能作为减少LLM诱导的肺损伤的治疗靶点。
