腹主動脈瘤的病理形成特徵為慢性發炎與胞外間質的蛋白分解。凝血脢調節素是一種穿膜糖蛋白，它具有抗發炎活性比方像是干擾細胞激素的訊號傳遞及阻絕促發炎的高遷移率族蛋白B1以防止它接合能夠延續發炎與組織破壞的高糖化終產物接收器。我們的目標是探討含有胞外所有功能區的重組凝血脢調節素是否能夠抑制動脈瘤發展的假設。
對氯化鈣引起小鼠腹主動脈瘤模式做特性分析發現，高遷移率族蛋白B1與高糖化終產物接收器兩者大多由巨噬細胞所表現且於28天的主動脈瘤形成過程中的表現增加是持續的。在體外實驗中，重組凝血脢調節素與高遷移率族蛋白B1的反應防止高遷移率族蛋白B1與巨噬細胞結合，因此抑制了巨噬細胞中高遷移率族蛋白B1與高糖化終產物接收器的訊號。在活體實驗中，在誘發腹主動脈瘤時以重組凝血脢調節素作短期治療可壓制促發炎細胞激素、高遷移率族蛋白B1與高糖化終產物接收器的表現程度，減少巨噬細胞的數量，而且最終在沒有干擾血管鈣化程度的情況下減緩基質金屬蛋白脢的產生、胞外間質的破壞與主動脈瘤形成。同樣地，以重組凝血脢調節素作後治療也緩和血管發炎並延緩腹主動脈瘤變大。
這些結果顯示了重組凝血脢調節素提供對抗腹主動脈瘤發展的保護作用。其作用機轉和減少促發炎間質、阻斷巨噬細胞的增援以及壓制與動脈瘤形成相關的巨噬細胞中高遷移率族蛋白B1與高糖化終產物接收器的訊號及其下游巨噬細胞的活化有關。

The pathogenesis of abdominal aortic aneurysm (AAA) is characterized by chronic inflammation and proteolytic degradation of extracellular matrix (ECM). Thrombomodulin (TM), a transmembrane glycoprotein, exerts anti-inflammatory activities such as inhibition of cytokine production and sequestration of proinflammatory high-mobility group box 1 (HMGB1) to prevent it from engaging the receptor for advanced glycation end product (RAGE) that may sustain inflammation and tissue damage. We aimed to investigate the hypothesis that recombinant TM containing all the extracellular domains (rTMD123) might have therapeutic potential against aneurysm development.
Characterization of the CaCl2-induced AAA model in mice revealed that HMGB1 and RAGE, both localized mainly to macrophages, were persistently upregulated during a 28-day period of AAA development. In vitro, rTMD123-HMGB1 interaction prevented HMGB1 binding to macrophages, thereby prohibiting activation of HMGB1-RAGE signaling in macrophages. In vivo, short-term treatment with rTMD123 upon AAA induction suppressed the levels of proinflammatory cytokines, HMGB1 and RAGE in the aortic tissue, reduced the infiltrating macrophage number, and finally attenuated matrix metalloproteinase production, ECM destruction and AAA formation without disturbing vascular calcification. Consistently, post-treatment with rTMD123 alleviated vascular inflammation and retarded AAA progression.
These data suggest that rTMD123 confers protection against AAA development. The mechanism of action may be associated with reduction of proinflammatory mediators, blockade of macrophage recruitment, and suppression of HMGB1-RAGE signaling involved in aneurysm formation and downstream macrophage activation.

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