cGAS/STING pathway modulation in polyhexamethyleneguanidine phosphate-induced immune dysregulation and pulmonary fibrosis using human monocytic cells (THP-1) and male C57BL/6 mice.

IF 2.3 4区 医学 Q3 ENVIRONMENTAL SCIENCES
Jin Kyung Seok, Jung In Jee, Minwoo Jeon, Donghyun Kim, Kyu Hyuck Chung, Ha Ryong Kim, Yong-Wook Baek, HanGoo Kang, Jungyun Lim, Ok-Nam Bae, Joo Young Lee
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Abstract

Polyhexamethyleneguanidine phosphate (PHMG), a widely used antimicrobial agent, has been implicated in humidifier disinfectant-associated lung injuries (HDLI). PHMG exposure suppressed interferon regulatory factor 3 (IRF3) activation and interferon-β (IFN-β) expression induced by a cGAS agonist or a STING agonist in human monocytic cells (THP-1), which are known to transition to alveolar macrophages during pulmonary fibrosis development. However, the mechanisms underlying PHMG-induced pulmonary toxicity in lung remain unclear. Thus, it was of interest to investigate the effects of PHMG on the innate immune system in male C57BL/6 mouse, focusing on the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway and potential role in pulmonary fibrosis. Intratracheal administration of PHMG (1 or 2 mg/kg) in mice resulted in lung fibrosis, as evidenced by H&E staining with Szapiel scoring, Masson's trichrome staining with Ashcroft scoring, and increased mRNA levels of TGF-β and collagen type I. Interestingly, lower dose of PHMG enhanced IFN-β production in the lungs, whereas higher dose decreased IFN-β levels, indicating a biphasic effect that initially promotes inflammation but ultimately impairs host defense mechanisms, leading to pulmonary fibrosis. Our findings demonstrate the critical role of the cGAS/STING pathway in PHMG-induced mouse lung injury and suggest that targeting this pathway might serve as a potential therapeutic strategy for treating pulmonary fibrosis.

使用人单核细胞(THP-1)和雄性 C57BL/6 小鼠研究 cGAS/STING 通路在聚六亚甲基胍磷酸盐诱导的免疫失调和肺纤维化中的调节作用。
聚六亚甲基胍磷酸盐(PHMG)是一种广泛使用的抗菌剂,与加湿器消毒剂相关肺损伤(HDLI)有关。人单核细胞(THP-1)会在cGAS激动剂或STING激动剂的诱导下活化干扰素调节因子3(IRF3)并表达干扰素-β(IFN-β),众所周知,THP-1会在肺纤维化发展过程中转变为肺泡巨噬细胞。然而,PHMG 诱导肺毒性的机制仍不清楚。因此,我们有兴趣研究 PHMG 对雄性 C57BL/6 小鼠先天性免疫系统的影响,重点是环 GMP-AMP 合成酶(cGAS)/干扰素基因刺激器(STING)通路以及在肺纤维化中的潜在作用。小鼠气管内注射 PHMG(1 或 2 毫克/千克)会导致肺纤维化,表现为 H&E 染色和 Szapiel 评分、Masson 三色染色和 Ashcroft 评分,以及 TGF-β 和 I 型胶原 mRNA 水平的升高。有趣的是,较低剂量的 PHMG 会增强肺中 IFN-β 的产生,而较高剂量的 PHMG 则会降低 IFN-β 的水平,这表明 PHMG 具有双相效应,最初会促进炎症,但最终会损害宿主防御机制,导致肺纤维化。我们的研究结果证明了cGAS/STING通路在PHMG诱导的小鼠肺损伤中的关键作用,并表明靶向该通路可能成为治疗肺纤维化的一种潜在治疗策略。
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来源期刊
CiteScore
5.20
自引率
19.20%
发文量
46
审稿时长
8-16 weeks
期刊介绍: The Journal of Toxicology and Environmental Health, Part A , Current Issues is an authoritative journal that features strictly refereed original research in the field of environmental sciences, public and occupational health, and toxicology.
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