背景:甲状腺风暴(TS),会损害多个器官的危及生命的疾病,治疗选择有限。高细胞因子血症是一个建议的背景,但病理情况尚不清楚,也没有合适的动物模型。我们的目的是通过给药三碘甲状腺原氨酸和脂多糖来建立TS小鼠模型,然后检查ghrelin对这个模型的影响。
方法:我们评估了血清IL-6水平作为TS患者高细胞因子血症的代表性标志物。建立小鼠模型,进行了初步实验以确定三碘甲状腺原氨酸和脂多糖单独给药时的非致死剂量。作为TS模型,C57BL/6小鼠给予三碘甲状腺原氨酸1.0mg/kg(皮下,每天一次,连续七天)和脂多糖0.5mg/kg(腹膜内,在第7天),以开发在第8天具有约30%存活率的致死模型。我们评估了生存率,小鼠败血症评分和血液生物标志物(IL-6,间肾上腺素,丙氨酸转氨酶),并评估了生长素释放肽300µg/kg对TS模型中这些参数的影响。
结果:与患有Graves病的患者相比,TS患者的血清IL-6升高(18.2vs.2.85pg/mL,P<.05,n=4)。小鼠TS模型的剂量为三碘甲状腺原氨酸1.0mg/kg和脂多糖0.5mg/kg。TS模型组小鼠脓毒症评分升高,血清IL-6、间肾上腺素和丙氨酸转氨酶。在这个模型中,ghrelin将生存率提高到66.7%(P<0.01,vs.0%[盐水治疗组])以及小鼠败血症评分,它降低了血清IL-6和间肾上腺素。
结论:我们建立了TS的动物模型,其表现出与人TS相似的病理生理状态,并通过施用T3和LPS诱导血清IL-6和其他生物标志物。结果表明ghrelin对人类TS的潜在有效性。
BACKGROUND: Thyroid storm (TS), a life-threatening condition that can damage multiple organs, has limited therapeutic options. Hypercytokinemia is a suggested background, but the pathological condition is unclear and there are no appropriate animal models. We aimed to develop a TS mouse model by administration of
triiodothyronine and lipopolysaccharide, and then to examine the effects of ghrelin on this model.
METHODS: We evaluated the use of serum IL-6 levels as a representative marker of hypercytokinemia in patients with TS. To establish the mouse model, preliminary experiments were conducted to determine the non-lethal doses of
triiodothyronine and lipopolysaccharide when administered individually. As a TS model, C57BL/6 mice were administered with
triiodothyronine 1.0 mg/kg (subcutaneously, once daily for seven consecutive days) and lipopolysaccharide 0.5 mg/kg (intraperitoneally, on day 7) to develop a lethal model with approximately 30% survival on day 8. We assessed the survival ratio, mouse sepsis scores and blood biomarkers (IL-6, metanephrine, alanine aminotransferase) and evaluated the effects of ghrelin 300 µg/kg on these parameters in TS model.
RESULTS: Serum IL-6 was increased in patients with TS compared with those with Graves\' disease as the diseased control (18.2 vs. 2.85 pg/mL, P < .05, n = 4 each). The dosage for the murine TS model was
triiodothyronine 1.0 mg/kg and lipopolysaccharide 0.5 mg/kg. The TS model group had increased mouse sepsis score, serum IL-6, metanephrine and alanine aminotransferase. In this model, the ghrelin improved the survival rate to 66.7% (P < .01, vs. 0% [saline-treated group]) as well as the mouse sepsis score, and it decreased the serum IL-6 and metanephrine.
CONCLUSIONS: We established an animal model of TS that exhibits pathophysiological states similar to human TS with induction of serum IL-6 and other biomarkers by administration of T3 and LPS. The results suggest the potential effectiveness of ghrelin for TS in humans.