5114 Establishment of Thyroid Storm Mouse Model and Therapeutic Effects of Ghrelin

Abstract

Abstract Disclosure: C. Kurimoto: None. Y. Furukawa: None. T. Akamizu: None. A. Doi: None. K. Takeshima: None. S. Morita: None. H. Iwakura: None. H. Ariyasu: None. H. Furuta: None. M. Nishi: None. T. Matsuoka: None. Context: Thyroid storm (TS), a life-threatening condition that can damage multiple organs, is caused by a combination of thyrotoxicosis and severe physical stresses. Infection is the most common triggering factor. Hypercytokinemia is a suggested background, but the pathological condition is unclear and there are no appropriate animal models. Further, TS has limited therapeutic options. Objectives: We aimed to confirm the hypercytokinemia in patients with TS, establish a TS model mouse by triiodothyronine and lipopolysaccharide administration, and explore the therapeutic effects of ghrelin on TS. Methods: We evaluated serum IL-6 levels as a representative marker of hypercytokinemia in patients with TS. As a TS model, C57BL/6 mice were titrated with triiodothyronine and lipopolysaccharide to develop a lethal model with approximately 30% survival at 24 hours. We assessed the survival ratio, mouse sepsis scores and blood biomarkers (IL-6, metanephrine, alanine aminotransferase) and evaluated the effects of ghrelin on these parameters. Results: Serum IL-6 was increased in patients with TS compared with those with Graves' disease without TS (55.7 ± 69.0 vs. 3.13 ± 1.41 pg/mL, P < .05, n=4 each). Next, we titrated the doses of T3 and LPS, aiming to achieve a survival rate of approximately 30% at 24 hours after administration. Two out of five mice in the T3 3.0 mg/kg group died, while none of the eight mice in the T3 1.0 mg/kg group died. Therefore, we determined that the appropriate T3 dose for the TS mouse model is 1.0 mg/kg, which is not lethal when administered alone. In the T3 1.0 mg/kg group (n=8), serum FT3 levels were approximately three times higher (15.3 ± 4.5 vs. 4.5 ± 0.7pg/ml) than those in the control group (n=8). Next, different doses of LPS was added to the T3 group. Survival at 24 hours post-dose was 60% in the T3 + LPS 0.2 mg/kg group (n=5) and 33% in the T3 + LPS 0.5 mg/kg group (n=5), while survival was 100% in the LPS 0.5 mg/kg alone group (n=5),. Based on these findings, the dosage for the murine TS model was determined to be “triiodothyronine 1.0 mg/kg and lipopolysaccharide 0.5 mg/kg”. This TS model group had increased mouse sepsis score, serum IL-6, metanephrine and alanine aminotransferase. In this model, the ghrelin at 300 µg/kg 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. Conclusion: We confirmed the hypercytokinemia in patients with TS. Next, we established a lethal model simulating TS by inducing “thyrotoxicosis” by exogenous administration of thyroid hormones, and by inducing “sepsis” by intraperitoneal administration of LPS. The model mice exhibited similar pathophysiological status to human TS associated with induction of serum IL-6 and other biomarkers, which were improved by ghrelin. Presentation: 6/1/2024