Kagi Tomohiro, Tan Maoko, Suzuki Wakana, Otani Kohei, Suzuki Sara, Hirata Yusuke, Noguchi Takuya, Matsuzawa Atsushi
Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University.
J Toxicol Sci. 2025;50(1):11-21. doi: 10.2131/jts.50.11.
A representative surfactant, benzalkonium chloride (BAC) is used as a disinfectant, but sometimes causes serious side effects, including lung disorders such as interstitial pneumonia. However, its pathogenic mechanisms remain unexplained. In this study, we identified a novel mechanism by which BAC initiates inflammatory responses that may be responsible for its side effects. We firstly investigated whether BAC initiates inflammation, and found that BAC promotes the secretion of the pro-inflammatory cytokine interleukin-1β (IL-1β) but not tumor necrosis factor-α (TNF-α) in macrophages. Interestingly, the IL-1β secretion triggered by the surfactants was completely blocked by the K-ATP channel blocker glibenclamide or the calcium chelating agent 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA)-AM. Moreover, genetic experiments revealed that BAC-dependent IL-1β secretion is mediated by the NLRP3 inflammasome. These results suggest that derangement of ion fluxes associated with the interfacial effects of BAC triggers NLRP3 inflammasome activation and subsequent inflammation. Thus, the NLRP3-dependent mechanisms triggered by BAC may explain the pathogenesis of surfactant-caused adverse effects.
一种具有代表性的表面活性剂苯扎氯铵（BAC）被用作消毒剂，但有时会引起严重的副作用，包括间质性肺炎等肺部疾病。然而，其致病机制仍不清楚。在本研究中，我们确定了一种新的机制，通过该机制BAC引发炎症反应，这可能是其副作用的原因。我们首先研究了BAC是否引发炎症，发现BAC促进巨噬细胞中促炎细胞因子白细胞介素-1β（IL-1β）的分泌，但不促进肿瘤坏死因子-α（TNF-α）的分泌。有趣的是，表面活性剂触发的IL-1β分泌被K-ATP通道阻滞剂格列本脲或钙螯合剂1,2-双（2-氨基苯氧基）乙烷-N,N,N',N'-四乙酸（BAPTA）-AM完全阻断。此外，基因实验表明，BAC依赖的IL-1β分泌由NLRP3炎性小体介导。这些结果表明，与BAC界面效应相关的离子通量紊乱触发了NLRP3炎性小体的激活和随后的炎症。因此，BAC触发的NLRP3依赖性机制可能解释了表面活性剂引起的不良反应的发病机制。
