Purpose

Inflammation is involved in many disease processes. However, accurate imaging tools permitting diagnosis and characterization of inflammation are still missing. As inflamed tissues exhibit a high rate of glycolysis, pyruvate metabolism may offer a unique approach to follow the inflammatory response and disease progression. Therefore, the aim of the study was to follow metabolic changes and recruitment of inflammatory cells after onset of inflammation in arthritic ankles using hyperpolarized 1-¹³C-pyruvate magnetic resonance spectroscopy (MRS) and ¹⁹F magnetic resonance imaging (MRI), respectively.

Procedure

Experimental rheumatoid arthritis (RA) was induced by intraperitoneal injection of glucose-6-phosphate-isomerase-specific antibodies (GPI) containing serum. To monitor pyruvate metabolism, the transformation of hyperpolarized 1-¹³C-pyruvate into hyperpolarized 1-¹³C-lactate was followed using MRS. To track phagocytic immune cell homing, we intravenously injected a perfluorocarbon emulsion 48 h before imaging. The animals were scanned at days 1, 3, or 6 after GPI-serum injection to examine the different stages of arthritic inflammation. Finally, to confirm the pyruvate metabolic activity and the link to inflammatory cell recruitment, we conducted hematoxylin-eosin histopathology and monocarboxylase transporter (MCT-1) immune histochemistry (IHC) of inflamed ankles.

Results

Hyperpolarized 1-¹³C-pyruvate MRS revealed a high rate of lactate production immediately at day 1 after GPI-serum transfer, which remained elevated during the progression of the disease, while ¹⁹F-MRI exhibited a gradual recruitment of phagocytic immune cells in arthritic ankles, which correlated well with the course of ankle swelling. Histopathology and IHC revealed that MCT-1 was expressed in regions with inflammatory cell recruitment, confirming the metabolic shift identified in arthritic ankles.

Conclusions

Our study demonstrated the presence of a very early metabolic shift in arthritic joints independent of phagocytic immune cell recruitment. Thus, hyperpolarized 1-¹³C-pyruvate represents a promising tracer to monitor acute arthritic joint inflammation, even with minor ankle swelling. Furthermore, translated to the clinics, these methods add a detailed characterization of disease status and could substantially support patient stratification and therapy monitoring.

中文翻译：

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关节炎踝关节中乳酸的产生先于炎症细胞的募集：一项影像学研究。

目的

炎症涉及许多疾病过程。然而，仍然缺乏能够诊断和表征炎症的准确成像工具。由于发炎组织表现出高糖酵解率，丙酮酸代谢可能提供一种独特的方法来跟踪炎症反应和疾病进展。因此，本研究的目的是分别使用超极化 1- ¹³ C-丙酮酸磁共振波谱（MRS）和¹⁹ F 磁共振成像（MRI）来跟踪关节炎踝关节炎症发作后的代谢变化和炎症细胞的募集。

程序

通过腹腔注射含有血清的葡萄糖-6-磷酸异构酶特异性抗体（GPI）来诱导实验性类风湿性关节炎（RA）。为了监测丙酮酸代谢，使用MRS跟踪超极化1- ¹³ C-丙酮酸向超极化1- ¹³ C-乳酸的转化。为了追踪吞噬免疫细胞的归巢，我们在成像前 48 小时静脉注射全氟化碳乳剂。注射 GPI 血清后第 1、3 或 6 天对动物进行扫描，以检查关节炎炎症的不同阶段。最后，为了确认丙酮酸代谢活性以及与炎症细胞募集的联系，我们对发炎的脚踝进行了苏木精-伊红组织病理学和单羧化酶转运蛋白（MCT-1）免疫组织化学（IHC）。

结果

超极化 1- ¹³ C-丙酮酸 MRS 显示在 GPI 血清转移后第一天立即产生高乳酸生成率，并且在疾病进展期间保持升高状态，而¹⁹ F-MRI 显示关节炎中吞噬细胞免疫细胞的逐渐募集脚踝，这与脚踝肿胀的过程密切相关。组织病理学和 IHC 显示 MCT-1 在炎症细胞募集的区域表达，证实了关节炎脚踝中发现的代谢变化。

结论

我们的研究表明，关节炎关节中存在非常早期的代谢转变，与吞噬免疫细胞的招募无关。因此，超极化的 1- ¹³ C-丙酮酸代表了一种有前途的示踪剂，可以监测急性关节炎关节炎症，甚至伴有轻微的踝关节肿胀。此外，转化为临床后，这些方法增加了疾病状态的详细特征，可以极大地支持患者分层和治疗监测。