학술논문
Role of the lectin-like domain of thrombomodulin in septic cardiomyopathy.
Document Type
Academic Journal
Author
Voelker MT; Department of Anaesthesiology and Critical Care Medicine, University Hospital Leipzig, Germany. Electronic address: theresa.voelker@medizin.uni-leipzig.de.; Hechaichi N; Center for Sepsis Control and Care, University Hospital Jena, Germany.; Ndongson-Dongmo B; Institute of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University, Jena, Germany.; Lemm J; Center for Sepsis Control and Care, University Hospital Jena, Germany.; Heller R; Institute of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University, Jena, Germany.; Bauer R; Institute of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University, Jena, Germany.; Conway EM; UBC Centre for Blood Research, Faculty of Medicine, Division of Haematology, Life Sciences Institute, Vancouver, British Columbia, Canada.; Theilmeier G; Division of Perioperative Inflammation and Infection, Faculty of Medicine and Health Sciences, Oldenburg, Germany.; Stehr SN; Department of Anaesthesiology and Critical Care Medicine, University Hospital Leipzig, Germany; Center for Sepsis Control and Care, University Hospital Jena, Germany.
Source
Publisher: Elsevier Country of Publication: Netherlands NLM ID: 0375521 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0631 (Electronic) Linking ISSN: 00243205 NLM ISO Abbreviation: Life Sci Subsets: MEDLINE
Subject
Language
English
Abstract
Aims: Septic cardiomyopathy is a severe complication of sepsis and septic shock. This study aimed to evaluate the role of thrombomodulin and its lectin-like domain (LLD-TM) in the development of septic cardiomyopathy and the link between LLD-TM, HMGB-1, and toll-like receptors 2/4 (TLR 2/4) to intracellular mechanisms resulting in reduced cardiac function.
Materials and Methods: Sepsis was induced using a polymicrobial peritoneal infection model in wildtype and mice lacking the lectin-like domain of thrombomodulin (TMLeD/LeD ), and severity of disease and cardiac function was compared. Cell cultures of cardiomyocytes were prepared from hearts harvested from wildtype and TM LeD/LeD mice. Cultures of neonatal cardiomyocytes were transfected with complete human thrombomodulin or human thrombomodulin deficient of LLD-TM and when TLR-2 and/or TLR-4 were blocked. All cultures were challenged with inflammatory stimuli.
Key Findings: Lack of the LLD-TM results in a significant increase in severity of disease, decreased survival and impaired cardiac function in septic mice. In vivo and in vitro analyses of cardiomyocytes displayed high levels of inflammatory cytokines causing cardio-depression. In vitro results showed a strong correlation between elevated HMGB-1 levels and elevated troponin-1 levels. No connection was found between HMGB-1 and TLR-2 and/or -4 signalling pathways. Phospholamban mediated dysregulation of calcium homeostasis resulted in a general impairment after sepsis induction, but showed no connection to LLD-TM.
Significance: Lack of LLD-TM results in an increase in general severity of disease, decreased survival and impaired cardiac function in sepsis. TLR-2 and TLR 4 do not participate as mediating factors in the development of septic cardiomyopathy.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Materials and Methods: Sepsis was induced using a polymicrobial peritoneal infection model in wildtype and mice lacking the lectin-like domain of thrombomodulin (TM
Key Findings: Lack of the LLD-TM results in a significant increase in severity of disease, decreased survival and impaired cardiac function in septic mice. In vivo and in vitro analyses of cardiomyocytes displayed high levels of inflammatory cytokines causing cardio-depression. In vitro results showed a strong correlation between elevated HMGB-1 levels and elevated troponin-1 levels. No connection was found between HMGB-1 and TLR-2 and/or -4 signalling pathways. Phospholamban mediated dysregulation of calcium homeostasis resulted in a general impairment after sepsis induction, but showed no connection to LLD-TM.
Significance: Lack of LLD-TM results in an increase in general severity of disease, decreased survival and impaired cardiac function in sepsis. TLR-2 and TLR 4 do not participate as mediating factors in the development of septic cardiomyopathy.
(Copyright © 2022 Elsevier Inc. All rights reserved.)