Inhibition of plasmin attenuates murine acute graft-versus-host disease mortality by suppressing the matrix metalloproteinase-9-dependent inflammatory cytokine storm and effector cell trafficking
Inhibition of plasmin attenuates murine acute graft-versus-host disease mortality by suppressing the matrix metalloproteinase-9-dependent inflammatory cytokine storm and effector cell trafficking
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DOI：
10.1038/leu.2014.151
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发表时间：
2015-01-01
期刊：
影响因子：
11.4
通讯作者：
Hattori, K.
中科院分区：
文献类型：
--
作者：
Sato, A.;Nishida, C.;Hattori, K.
在急性移植物抗宿主病（aGVHD）期间观察到的全身性炎症反应由促炎细胞因子（“细胞因子风暴”）驱动。纤溶酶在调节炎症反应中的功能尚未完全了解，其在aGVHD发展中的作用仍未得到解决。在这里，我们表明，纤溶酶在小鼠aGVHD的早期阶段被激活，其激活与人类aGVHD的严重程度相关。药理学纤溶酶抑制在小鼠中保护免于aGVHD相关的致死性。从机制上讲，纤溶酶抑制损害了炎症细胞的浸润，直接或间接通过基质金属蛋白酶（MMP）和改变单核细胞趋化蛋白-1（MCP-1）信号传导的膜相关促炎细胞因子（包括肿瘤坏死因子-α（TNF-α）和Fas-配体）的释放。我们认为，纤溶酶和潜在的MMP-9抑制提供了一种新的治疗策略，以控制致命的细胞因子风暴与aGVHD患者，从而防止组织破坏。
The systemic inflammatory response observed during acute graft-versus-host disease (aGVHD) is driven by proinflammatory cytokines, a 'cytokine storm'. The function of plasmin in regulating the inflammatory response is not fully understood, and its role in the development of aGVHD remains unresolved. Here we show that plasmin is activated during the early phase of aGVHD in mice, and its activation correlated with aGVHD severity in humans. Pharmacological plasmin inhibition protected against aGVHD-associated lethality in mice. Mechanistically, plasmin inhibition impaired the infiltration of inflammatory cells, the release of membrane-associated proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) and Fas-ligand directly, or indirectly via matrix metalloproteinases (MMPs) and alters monocyte chemoattractant protein-1 (MCP-1) signaling. We propose that plasmin and potentially MMP-9 inhibition offers a novel therapeutic strategy to control the deadly cytokine storm in patients with aGVHD, thereby preventing tissue destruction.