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

Blog Article

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 6.5 x 18.5 soccer goal 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 spacecase lemonhead 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.