Universität zu Köln

Chung, Ha-Yeun, Hupe, Daniel C., Otto, Gordon P., Sprenger, Marcel, Bunck, Alexander C., Dorer, Michael J., Bockmeyer, Clemens L., Deigner, Hans-Peter, Graeler, Markus H. and Claus, Ralf A. (2016). Acid Sphingomyelinase Promotes Endothelial Stress Response in Systemic Inflammation and Sepsis. Mol. Med., 22. S. 412 - 424. NEW YORK: SPRINGER. ISSN 1528-3658

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Abstract

The pathophysiology of sepsis involves activation of acid sphingomyelinase (SMPD1) with subsequent generation of the bioactive mediator ceramide. We herein evaluate the hypothesis that the enzyme exerts biological effects in endothelial stress response. Plasma-secreted sphingomyelinase activity, ceramide generation and lipid raft formation were measured in human microcirculatory endothelial cells (HMEC-1) stimulated with serum obtained from sepsis patients. Clustering of receptors relevant for signal transduction was studied by immunostaining. The role of SMPD1 for macrodomain formation was tested by pharmacological inhibition. To confirm the involvement of the stress enzyme, direct inhibitors (amino bisphosphonates) and specific downregulation of the gene was tested with respect to ADAMTS13 expression and cytotoxicity. Plasma activity and amount of SMPD1 were increased in septic patients dependent on clinical severity. Increased breakdown of sphingomyelin to ceramide in HMECs was observed following stimulation with serum from sepsis patients in vitro. Hydrolysis of sphingomyelin, clustering of receptor complexes, such as the CD95L/Fas-receptor, as well as formation of ceramide enriched macrodomains were abrogated using functional inhibitors (desipramine and NB6). Strikingly, the stimulation of HMECs with serum obtained from sepsis patients or mixture of proinflammatory cytokines resulted in cytotoxicity and ADAMTS13 downregulation which was abrogated using desipramine, amino bisphosphonates and genetic inhibitors. SMPD1 is involved in the dysregulation of ceramide metabolism in endothelial cells leading to macrodomain formation, cytotoxicity and downregulation of ADAMTS13 expression. Functional inhibitors, such as desipramine, are capable of improving endothelial stress response during sepsis and might be considered as a pharmacological treatment strategy to obtain a favorable outcome.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Chung, Ha-Yeun UNSPECIFIED UNSPECIFIED UNSPECIFIED Hupe, Daniel C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Otto, Gordon P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sprenger, Marcel UNSPECIFIED UNSPECIFIED UNSPECIFIED Bunck, Alexander C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dorer, Michael J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bockmeyer, Clemens L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Deigner, Hans-Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Graeler, Markus H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Claus, Ralf A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-288860
DOI:	10.2119/molmed.2016.00140
Journal or Publication Title:	Mol. Med.
Volume:	22
Page Range:	S. 412 - 424
Date:	2016
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1528-3658
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PLASMA-MEMBRANE; LIPID RAFTS; CELL-DEATH; CERAMIDE; MECHANISMS; INHIBITORS; FLUORESCENT; DYSFUNCTION; DESIPRAMINE; COAGULATION Multiple languages Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28886