Identifikation von prognostischen Markern bei Patienten mit Sepsis

Die Sepsis ist trotz der Fortschritte der modernen Medizin noch immer mit einer hohen Morbidität und Mortalität behaftet. Durch die Identifikation von protektiven Faktoren, die eine schwere Verlaufsform verhindern und kausale Therapieansätze, die nicht nur Pathogene eliminieren, sondern auch das na...

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1. Verfasser: Regner, Wiebke
Beteiligte: Bals, Robert (Prof. Dr. Dr.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Deutsch
Veröffentlicht: Philipps-Universität Marburg 2015
Innere Medizin
Ausgabe:http://dx.doi.org/10.17192/z2015.0457
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title_alt Identification of prognostic markers in patients with sepsis
format Dissertation
oai_set_str_mv doc-type:doctoralThesis
open_access
ddc:610
xMetaDissPlus
doi_str_mv http://dx.doi.org/10.17192/z2015.0457
edition http://dx.doi.org/10.17192/z2015.0457
language German
topic LL-37
sepsis
Medizin, Gesundheit
Cathelicidin
LL-37
Sepsis
Vitamin D
vitamin d
cathelicidin
spellingShingle LL-37
sepsis
Medizin, Gesundheit
Cathelicidin
LL-37
Sepsis
Vitamin D
vitamin d
cathelicidin
Regner, Wiebke
Despite many efforts in modern medicine, systemic inflammatory response syndrome (SIRS) and sepsis are still linked to high morbidity and mortality. Identification of protective factors that prevent a severe course of the disease and new therapeutic strategies that do not only eliminate pathogens but support the balance between pro-inflammatory and immunosuppressive phases could improve the outcome. Vitamin D has a great importance for the innate and adaptive immune system. Vitamin D deficiency is a widespread problem. 28% of the healthy population are affected. The aim of this study was to examine serum levels of vitamin D (25-Hydroxycholecalciferol), Cathelicidin-LL-37 (protein and mRNA-level) and alpha-1-antitrypsin during SIRS and to identify potential protective factors and prognostic mark-ers. For this purpose, blood samples were taken from SIRS patients and control patients from the intensive care unit as well as from healthy controls. Serum levels were measured and clinical data, particularly APACHE-II-Score, SOFA-Score and MODS-Score were collected to define the severity of sepsis. The main finding was that SIRS patients are vitamin D deficient and have significant lower vitamin D levels than controls from the intensive care unit and healthy controls. Even among the healthy controls, only 28% had sufficient vitamin D levels. Contrary to the hypothesis that Cathelicidin-LL-37 is decreased during SIRS, increased levels (12,39 ± 9,775 ng/ml) were measured compared to controls from the intensive care unit and healthy controls. This difference could not be detected on mRNA-level so that a physiological degranulation of neutrophils during the inflammatory process might be a reason for the increased Cathelicidin-LL-37-level. Because of the increased level of Cathelicidin-LL-37, a negative correlation was observed between the vitamin D and Cathelicidin-LL-37 levels. No measurable correlation between the severity of sepsis and the vitamin D level, re-spectively the Cathelicidin-LL-37 level was found. SIRS-patients had significant higher alpha-1-antitrypsin-levels. This study cannot answer questions about the mechanisms of the observations. Whether vitamin D levels and/or Cathelicidin-LL-37 levels could be used as prognostic markers has to be answered in further studies.
Identifikation von prognostischen Markern bei Patienten mit Sepsis
license_str http://archiv.ub.uni-marburg.de/adm/urhg.html
ref_str_mv references
first_indexed 2015-09-03T00:00:00Z
last_indexed 2015-09-03T23:59:59Z
publisher Philipps-Universität Marburg
description Die Sepsis ist trotz der Fortschritte der modernen Medizin noch immer mit einer hohen Morbidität und Mortalität behaftet. Durch die Identifikation von protektiven Faktoren, die eine schwere Verlaufsform verhindern und kausale Therapieansätze, die nicht nur Pathogene eliminieren, sondern auch das nachfolgende Immungeschehen beeinflussen, könnte das Outcome verbessert werden. Vitamin D hat eine große Bedeutung für das angeborene und erworbene Immunsystem. Mindestens 28 % der gesunden Bevölkerung sind von einem Vitamin-D-Mangel betroffen. Vitamin D reguliert unter anderem die Expression von antimikrobiellen Peptiden wie Cathelicidine, die ebenfalls eine Rolle bei der angeborenen Immunabwehr spielen. Ziel der vorliegenden Arbeit war es, die Serumkonzentration von 25-Hydroxycholecalciferol, Cathelicidin-LL-37 (zusätzlich auch Expressionsstudien auf mRNA-Ebene)- und von Alpha-1-Antitrypsin bei SIRS bzw. Sepsis zu untersuchen und so mögliche protektive Faktoren und prognostische Marker zu identifizieren. Dazu wurden Blutentnahmen bei SIRS-Patienten und Intensivpatienten ohne SIRS (Intensiv-Kontrolle) sowie bei gesunden Kontrollen durchgeführt und daraus die Parameter bestimmt. Weiterhin wurden bei den Intensivpatienten der APACHE-II-Score, SOFA-Score und MODS-Score erhoben, um die Schwere der Erkrankung einzuschät-zen. Die SIRS-Patienten zeigten eine ausgeprägte Vitamin-D-Defizienz und signifikant nied-rigere Spiegel (8,921 ± 6,812 ng/ml) als Patienten der Intensiv-Kontrolle und als ge-sunde Probanden. Auch unter den gesunden Kontrollen waren nur 28% suffizient mit Vitamin D versorgt. Entgegen der Annahme, dass SIRS-Patienten einen erniedrigten Cathelicin LL-37-Spiegel aufweisen, wurden verglichen mit den Patienten der Intensivkontrolle und mit gesunden Probanden signifikant erhöhte Werte (12,39 ± 9,775 ng/ml) gemessen. Auf mRNA-Ebene war dieser Unterschied nicht zu detektieren, daher ist eine im Rahmen von Entzündungsprozessen stattfindende Degranulierung von Neutrophilen eine mögliche Ursache für die Erhöhung der Cathelicidin-LL-37-Spiegel. Es bestand eine negative Korrelation zwischen den Vitamin-D- und Cathelicidin-LL-37-Spiegeln. Ein messbarer Zusammenhang zwischen der Schwere der Sepsis und dem Vitamin-D-Spiegel bzw. dem Cathelicidin-LL-37-Spiegel ließ sich nicht beobachten. Darüber hinaus zeigten die SIRS-Patienten signifikant erhöhte Alpha-1-Antitrypsin-Spiegel. Die vorliegenden Ergebnisse erlauben keine Aussagen zu den Mechanismen der beobachteten Veränderungen. Ob sich Vitamin-D- und/oder Cathelicidn LL-37 als prognostische Faktoren eignen, muss in weiterführenden Studien mit größerer Probandenzahl untersucht werden.
dewey-raw 610
dewey-search 610
genre Medical sciences, Medicine
genre_facet Medical sciences, Medicine
topic_facet Medizin, Gesundheit
institution Innere Medizin
author2 Bals, Robert (Prof. Dr. Dr.)
author2_role ths
url http://archiv.ub.uni-marburg.de/diss/z2015/0457/pdf/dwr.pdf
author Regner, Wiebke
publishDate 2015
era_facet 2015
contents Despite many efforts in modern medicine, systemic inflammatory response syndrome (SIRS) and sepsis are still linked to high morbidity and mortality. Identification of protective factors that prevent a severe course of the disease and new therapeutic strategies that do not only eliminate pathogens but support the balance between pro-inflammatory and immunosuppressive phases could improve the outcome. Vitamin D has a great importance for the innate and adaptive immune system. Vitamin D deficiency is a widespread problem. 28% of the healthy population are affected. The aim of this study was to examine serum levels of vitamin D (25-Hydroxycholecalciferol), Cathelicidin-LL-37 (protein and mRNA-level) and alpha-1-antitrypsin during SIRS and to identify potential protective factors and prognostic mark-ers. For this purpose, blood samples were taken from SIRS patients and control patients from the intensive care unit as well as from healthy controls. Serum levels were measured and clinical data, particularly APACHE-II-Score, SOFA-Score and MODS-Score were collected to define the severity of sepsis. The main finding was that SIRS patients are vitamin D deficient and have significant lower vitamin D levels than controls from the intensive care unit and healthy controls. Even among the healthy controls, only 28% had sufficient vitamin D levels. Contrary to the hypothesis that Cathelicidin-LL-37 is decreased during SIRS, increased levels (12,39 ± 9,775 ng/ml) were measured compared to controls from the intensive care unit and healthy controls. This difference could not be detected on mRNA-level so that a physiological degranulation of neutrophils during the inflammatory process might be a reason for the increased Cathelicidin-LL-37-level. Because of the increased level of Cathelicidin-LL-37, a negative correlation was observed between the vitamin D and Cathelicidin-LL-37 levels. No measurable correlation between the severity of sepsis and the vitamin D level, re-spectively the Cathelicidin-LL-37 level was found. SIRS-patients had significant higher alpha-1-antitrypsin-levels. This study cannot answer questions about the mechanisms of the observations. Whether vitamin D levels and/or Cathelicidin-LL-37 levels could be used as prognostic markers has to be answered in further studies.
building Medizin
title Identifikation von prognostischen Markern bei Patienten mit Sepsis
title_short Identifikation von prognostischen Markern bei Patienten mit Sepsis
title_full Identifikation von prognostischen Markern bei Patienten mit Sepsis
title_fullStr Identifikation von prognostischen Markern bei Patienten mit Sepsis
title_full_unstemmed Identifikation von prognostischen Markern bei Patienten mit Sepsis
title_sort Identifikation von prognostischen Markern bei Patienten mit Sepsis
thumbnail http://archiv.ub.uni-marburg.de/diss/z2015/0457/cover.png
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The human antim- icrobial peptide LL-37 is a multifunctional modulator of innate immune re- sponses. The Journal of Immunology. 2002;169:3883–3891. 2002 The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses Tretli S, Hernes E, Berg JP, Hestvik UE, Robsahm TE. Association between se- rum 25(OH)D and death from prostate cancer. British Journal of Cancer. 2009;100:450–454. 2009 Association between serum 25(OH)D and death from prostate cancer Tanaka H, Abe E, Miyaura C, Kuribayashi T, Konno K, Nishii Y, Suda T la. 1 al- pha, 25-Dihydroxycholecalciferol and a human myeloid leukaemia cell line (HL- 60). Biochem. j. 1982;204:713–719. 1982 1 alpha , 25-Dihydroxycholecalciferol and a human myeloid leukaemia cell line (HL- 60) Oren Z, Lerman J, Gudmundsson G, Agerberth B, Shai Y. Structure and organiza- tion of the human antimicrobial peptide LL-37 in phospholipid membranes: rele- vance to the molecular basis for its non-cell-selective activity. Biochem. J. 1999;341:501–513. 1999 Structure and organization of the human antimicrobial peptide LL-37 in phospholipid membranes: relevance to the molecular basis for its non-cell-selective activity Schauber J, Dorschner RA, Coda AB, Büchau AS, Liu PT, Kiken D, Helfrich YR, Kang S, Elalieh HZ, Steinmeyer A, Zügel U, Bikle DD, Modlin RL, Gallo RL. In- jury enhances TLR2 function and antimicrobial peptide expression through a vi- tamin D–dependent mechanism. Journal of Clinical Investigation. 2007;117:803–811. 2007 Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D–dependent mechanism Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, Gallo RL, Leung DY. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. New England Journal of Medicine. 2002;347:1151–1160. 2002 Endogenous antimicrobial peptides and skin infections in atopic dermatitis Zanetti M, Gennaro R, Romeo D. Cathelicidins: a novel protein family with a common proregion and a variable C-terminal antimicrobial domain. FEBS let- ters. 1995;374:1–5. 1995 Cathelicidins: a novel protein family with a common proregion and a variable C-terminal antimicrobial domain Pramanik R, Asplin JR, Lindeman C, Favus MJ, Bai S, Coe FL. Lipopolysaccha- ride negatively modulates vitamin D action by down-regulating expression of vi- tamin D-induced VDR in human monocytic THP-1 cells. Cellular Immunology. 2004;232:137–143. 2004 Lipopolysaccharide negatively modulates vitamin D action by down-regulating expression of vitamin D-induced VDR in human monocytic THP-1 cells Sørensen O, Cowland JB, Askaa J, Borregaard N. An ELISA for hCAP-18, the cathelicidin present in human neutrophils and plasma. Journal of immunological methods. 1997;206:53–59. 1997 An ELISA for hCAP-18, the cathelicidin present in human neutrophils and plasma Watkins RR, Yamshchikov AV, Lemonovich TL, Salata RA. The role of vitamin D deficiency in sepsis and potential therapeutic implications. Journal of Infection. 2011;63:321–326. 2011 The role of vitamin D deficiency in sepsis and potential therapeutic implications Yousefzadeh P, Shapses SA, Wang X. Vitamin D Binding Protein Impact on 25- Hydroxyvitamin D Levels under Different Physiologic and Pathologic Condi- tions. International Journal of Endocrinology. 2014;2014:1–6. 2014 Vitamin D Binding Protein Impact on 25- Hydroxyvitamin D Levels under Different Physiologic and Pathologic Conditions 2015-09-03 Die Sepsis ist trotz der Fortschritte der modernen Medizin noch immer mit einer hohen Morbidität und Mortalität behaftet. Durch die Identifikation von protektiven Faktoren, die eine schwere Verlaufsform verhindern und kausale Therapieansätze, die nicht nur Pathogene eliminieren, sondern auch das nachfolgende Immungeschehen beeinflussen, könnte das Outcome verbessert werden. Vitamin D hat eine große Bedeutung für das angeborene und erworbene Immunsystem. Mindestens 28 % der gesunden Bevölkerung sind von einem Vitamin-D-Mangel betroffen. Vitamin D reguliert unter anderem die Expression von antimikrobiellen Peptiden wie Cathelicidine, die ebenfalls eine Rolle bei der angeborenen Immunabwehr spielen. Ziel der vorliegenden Arbeit war es, die Serumkonzentration von 25-Hydroxycholecalciferol, Cathelicidin-LL-37 (zusätzlich auch Expressionsstudien auf mRNA-Ebene)- und von Alpha-1-Antitrypsin bei SIRS bzw. Sepsis zu untersuchen und so mögliche protektive Faktoren und prognostische Marker zu identifizieren. Dazu wurden Blutentnahmen bei SIRS-Patienten und Intensivpatienten ohne SIRS (Intensiv-Kontrolle) sowie bei gesunden Kontrollen durchgeführt und daraus die Parameter bestimmt. Weiterhin wurden bei den Intensivpatienten der APACHE-II-Score, SOFA-Score und MODS-Score erhoben, um die Schwere der Erkrankung einzuschät-zen. Die SIRS-Patienten zeigten eine ausgeprägte Vitamin-D-Defizienz und signifikant nied-rigere Spiegel (8,921 ± 6,812 ng/ml) als Patienten der Intensiv-Kontrolle und als ge-sunde Probanden. Auch unter den gesunden Kontrollen waren nur 28% suffizient mit Vitamin D versorgt. Entgegen der Annahme, dass SIRS-Patienten einen erniedrigten Cathelicin LL-37-Spiegel aufweisen, wurden verglichen mit den Patienten der Intensivkontrolle und mit gesunden Probanden signifikant erhöhte Werte (12,39 ± 9,775 ng/ml) gemessen. Auf mRNA-Ebene war dieser Unterschied nicht zu detektieren, daher ist eine im Rahmen von Entzündungsprozessen stattfindende Degranulierung von Neutrophilen eine mögliche Ursache für die Erhöhung der Cathelicidin-LL-37-Spiegel. Es bestand eine negative Korrelation zwischen den Vitamin-D- und Cathelicidin-LL-37-Spiegeln. Ein messbarer Zusammenhang zwischen der Schwere der Sepsis und dem Vitamin-D-Spiegel bzw. dem Cathelicidin-LL-37-Spiegel ließ sich nicht beobachten. Darüber hinaus zeigten die SIRS-Patienten signifikant erhöhte Alpha-1-Antitrypsin-Spiegel. Die vorliegenden Ergebnisse erlauben keine Aussagen zu den Mechanismen der beobachteten Veränderungen. Ob sich Vitamin-D- und/oder Cathelicidn LL-37 als prognostische Faktoren eignen, muss in weiterführenden Studien mit größerer Probandenzahl untersucht werden. 2015 Despite many efforts in modern medicine, systemic inflammatory response syndrome (SIRS) and sepsis are still linked to high morbidity and mortality. Identification of protective factors that prevent a severe course of the disease and new therapeutic strategies that do not only eliminate pathogens but support the balance between pro-inflammatory and immunosuppressive phases could improve the outcome. Vitamin D has a great importance for the innate and adaptive immune system. Vitamin D deficiency is a widespread problem. 28% of the healthy population are affected. The aim of this study was to examine serum levels of vitamin D (25-Hydroxycholecalciferol), Cathelicidin-LL-37 (protein and mRNA-level) and alpha-1-antitrypsin during SIRS and to identify potential protective factors and prognostic mark-ers. For this purpose, blood samples were taken from SIRS patients and control patients from the intensive care unit as well as from healthy controls. Serum levels were measured and clinical data, particularly APACHE-II-Score, SOFA-Score and MODS-Score were collected to define the severity of sepsis. The main finding was that SIRS patients are vitamin D deficient and have significant lower vitamin D levels than controls from the intensive care unit and healthy controls. Even among the healthy controls, only 28% had sufficient vitamin D levels. Contrary to the hypothesis that Cathelicidin-LL-37 is decreased during SIRS, increased levels (12,39 ± 9,775 ng/ml) were measured compared to controls from the intensive care unit and healthy controls. This difference could not be detected on mRNA-level so that a physiological degranulation of neutrophils during the inflammatory process might be a reason for the increased Cathelicidin-LL-37-level. Because of the increased level of Cathelicidin-LL-37, a negative correlation was observed between the vitamin D and Cathelicidin-LL-37 levels. No measurable correlation between the severity of sepsis and the vitamin D level, re-spectively the Cathelicidin-LL-37 level was found. SIRS-patients had significant higher alpha-1-antitrypsin-levels. This study cannot answer questions about the mechanisms of the observations. Whether vitamin D levels and/or Cathelicidin-LL-37 levels could be used as prognostic markers has to be answered in further studies. 2015-07-24 opus:6279 urn:nbn:de:hebis:04-z2015-04574 Identifikation von prognostischen Markern bei Patienten mit Sepsis Philipps-Universität Marburg ths Prof. Dr. Dr. Bals Robert Bals, Robert (Prof. Dr. Dr.) Regner, Wiebke Regner Wiebke
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