Bhunyakarnjanarat Thansita, Udompornpitak Kanyarat, Saisorn Wilasinee, Chantraprapawat Bhumdhanin, Visitchanakun Peerapat, Dang Cong Phi, Issara-Amphorn Jiraphorn, Leelahavanichkul Asada
Medical Microbiology, Interdisciplinary and International Program, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand.
Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
Int J Mol Sci. 2021 Jan 29;22(3):1377. doi: 10.3390/ijms22031377.
A high dose of NSAIDs, a common analgesic, might induce lupus activity through several NSAIDs adverse effects including gastrointestinal permeability defect (gut leakage) and endotoxemia. Indomethacin (25 mg/day) was orally administered for 7 days in 24-wk-old Fc gamma receptor IIb deficient (FcgRIIb-/-) mice, an asymptomatic lupus model (increased anti-dsDNA without lupus nephritis), and age-matched wild-type (WT) mice. Severity of indomethacin-induced enteropathy in FcgRIIb-/- mice was higher than WT mice as demonstrated by survival analysis, intestinal injury (histology, immune-deposition, and intestinal cytokines), gut leakage (FITC-dextran assay and endotoxemia), serum cytokines, and lupus characteristics (anti-dsDNA, renal injury, and proteinuria). Prominent responses of FcgRIIb-/- macrophages toward lipopolysaccharide (LPS) compared to WT cells due to the expression of only activating-FcgRs without inhibitory- were demonstrated. Extracellular flux analysis indicated the greater mitochondria activity (increased respiratory capacity and respiratory reserve) in FcgRIIb-/- macrophages with a concordant decrease in glycolysis activity when compared to WT cells. In conclusion, gut leakage-induced endotoxemia is more severe in indomethacin-administered FcgRIIb-/- mice than WT, possibly due to the enhanced indomethacin toxicity from lupus-induced intestinal immune-deposition. Due to a lack of inhibitory- expression, mitochondrial function, and cytokine production of FcgRIIb-/- macrophages were more prominent than WT cells. Hence, lupus disease-activation from NSAIDs-enteropathy-induced gut leakage is possible.
高剂量的非甾体抗炎药（一种常见的镇痛药）可能通过多种非甾体抗炎药的不良反应诱导狼疮活动，这些不良反应包括胃肠道通透性缺陷（肠道渗漏）和内毒素血症。在24周龄的Fcγ受体IIb缺陷（FcgRIIb-/-）小鼠（一种无症状的狼疮模型，抗双链DNA增加但无狼疮性肾炎）和年龄匹配的野生型（WT）小鼠中，口服吲哚美辛（25毫克/天），持续7天。生存分析、肠道损伤（组织学、免疫沉积和肠道细胞因子）、肠道渗漏（异硫氰酸荧光素-葡聚糖测定和内毒素血症）、血清细胞因子以及狼疮特征（抗双链DNA、肾损伤和蛋白尿）表明，FcgRIIb-/-小鼠中吲哚美辛诱导的肠病严重程度高于WT小鼠。与WT细胞相比，FcgRIIb-/-巨噬细胞对脂多糖（LPS）有明显反应，这是由于仅表达激活型Fcγ受体而无抑制型Fcγ受体所致。细胞外流量分析表明，与WT细胞相比，FcgRIIb-/-巨噬细胞中的线粒体活性更高（呼吸能力和呼吸储备增加），同时糖酵解活性相应降低。总之，在给予吲哚美辛的FcgRIIb-/-小鼠中，肠道渗漏诱导的内毒素血症比WT小鼠更严重，这可能是由于狼疮诱导的肠道免疫沉积增强了吲哚美辛的毒性。由于缺乏抑制型Fcγ受体的表达，FcgRIIb-/-巨噬细胞的线粒体功能和细胞因子产生比WT细胞更突出。因此，非甾体抗炎药引起的肠病导致肠道渗漏进而激活狼疮疾病是有可能的。
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