CAAP48, a New Sepsis Biomarker, Induces Hepatic Dysfunction in an in vitro Liver-on-Chip Model
CAAP48, a New Sepsis Biomarker, Induces Hepatic Dysfunction in an in vitro Liver-on-Chip Model
复制标题
DOI：
10.3389/fimmu.2019.00273
复制
发表时间：
2019-02-25
影响因子：
7.3
通讯作者：
Kiehntopf, Michael
中科院分区：
文献类型：
--
作者：
Blaurock-Moeller, Nancy;Groeger, Marko;Kiehntopf, Michael
脓毒症是危重患者死亡的主要原因，其特征是由于宿主对感染反应的失调而导致危及生命的器官功能障碍。通过质谱分析，我们鉴定出α -1-抗胰蛋白酶的c端片段，命名为CAAP48，作为一种新的脓毒症生物标志物，积极参与脓毒症的病理生理。众所周知，肝功能障碍是脓毒症相关多器官衰竭的早期事件，因此我们在微流体支持的体外肝脏芯片模型中分析了CAAP48的病理生理功能。用合成的CAAP48和几种控制肽刺激肝细胞。caap48处理导致肝细胞特异性胞内酶天冬氨酸转氨酶和丙氨酸转氨酶的积累，并损害肝脏多药耐药相关蛋白2和细胞色素P450 3A4的活性。此外，CAAP48降低了肝脏多药耐药相关蛋白2的表达，破坏了内皮结构的完整性，VE-cadherin、F-actin的表达减少，紧密连接蛋白zonula occludens-1的改变，导致内皮屏障功能丧失。此外，CAAP48诱导粘附分子和促炎性和抗炎性细胞因子的释放。我们的研究结果表明，在模拟炎症病理生理条件的肝脏芯片模型中，CAAP48触发炎症相关的内皮屏障破坏以及肝细胞功能障碍。因此，除了作为新的脓毒症生物标志物的功能外，CAAP48可能在脓毒症中因宿主免疫炎症反应失调而导致肝功能障碍的发展中发挥重要作用。
Sepsis is a leading cause of mortality in the critically ill, characterized by life-threatening organ dysfunctions due to dysregulation of the host response to infection. Using mass spectrometry, we identified a C-terminal fragment of alpha-1-antitrypsin, designated CAAP48, as a new sepsis biomarker that actively participates in the pathophysiology of sepsis. It is well-known that liver dysfunction is an early event in sepsis-associated multi-organ failure, thus we analyzed the pathophysiological function of CAAP48 in a microfluidic-supported in vitro liver-on-chip model. Hepatocytes were stimulated with synthetic CAAP48 and several control peptides. CAAP48-treatment resulted in an accumulation of the hepatocyte-specific intracellular enzymes aspartate-and alanine-transaminase and impaired the activity of the hepatic multidrug resistant-associated protein 2 and cytochrome P450 3A4. Moreover, CAAP48 reduced hepatic expression of the multidrug resistant-associated protein 2 and disrupted the endothelial structural integrity as demonstrated by reduced expression of VE-cadherin, F-actin and alteration of the tight junction protein zonula occludens-1, which resulted in a loss of the endothelial barrier function. Furthermore, CAAP48 induced the release of adhesion molecules and pro-and anti-inflammatory cytokines. Our results show that CAAP48 triggers inflammation-related endothelial barrier disruption as well as hepatocellular dysfunction in a liver-on-chip model emulating the pathophysiological conditions of inflammation. Besides its function as new sepsis biomarker, CAAP48 thus might play an important role in the development of liver dysfunction as a consequence of the dysregulated host immune-inflammatory response in sepsis.