Original Research ARTICLE
CAAP48, a new sepsis biomarker, induces hepatic dysfunction in an in vitro liver-on-chip model.
- 1Institut für Klinische Chemie und Laboratoriumsdiagnostik, Universitätsklinikum Jena, Universitätsklinikum Jena, Germany
- 2Center for Sepsis Control and Care, Jena University Hospital, Germany
- 3Institut für Klinische Chemie und Laboratoriumsdiagnostik, Universitätsklinikum Jena, Germany
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.
Keywords: Alpha-1antitrypsin, serpin A1, systemic inflammation, Sepsis, Liver dysfunction
Received: 21 Sep 2018;
Accepted: 31 Jan 2019.
Edited by:Christoph Thiemermann, Queen Mary University of London, United Kingdom
Reviewed by:Lukas Martin, Uniklinik RWTH Aachen, Germany
Christine N. Metz, Feinstein Institute for Medical Research, United States
Marcin F. Osuchowski, AUVA Research Centre, Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Austria
Copyright: © 2019 Blaurock, Gröger, Siwczak, Dinger, Schmerler, Mosig and Kiehntopf. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. Michael Kiehntopf, Institut für Klinische Chemie und Laboratoriumsdiagnostik, Universitätsklinikum Jena, Jena, 07747, Thuringia, Germany, Michael.Kiehntopf@med.uni-jena.de