Tissue repair and metabolic dysfunction in sepsis
Thesis event information
Date and time of the thesis defence
Place of the thesis defence
Oulu University Hospital, Auditorium 1. Remote access: https://oulu.zoom.us/j/64960512595?pwd=YWg3dDJvQUl1allaZUMvVHg3M0dyUT09
Topic of the dissertation
Tissue repair and metabolic dysfunction in sepsis
Doctoral candidate
Medical Doctor Henna Jaurila
Faculty and unit
University of Oulu Graduate School, Faculty of Medicine, Research Group of Surgery, Anesthesia and Intensive Care; Cancer and Translational Medicine Research Unit
Subject of study
Surgery
Opponent
Docent Pirkka Vikatmaa, Helsinki University Hospital
Custos
Professor Tero Ala-Kokko, Oulu University Hospital
Alterations in metabolism, cell signaling, and interplay of cytokines and ECM cause impaired wound healing in sepsis
The skin is the largest organ of the body. Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The protective function of the skin is compromised in sepsis, and septic patients are susceptible to wound healing complications such as infection, skin necrosis, blistering and pressure ulcers. However, the explaining mechanisms of impaired wound healing in sepsis are mostly unknown.
In this study we observed skin wound healing and the molecular mechanisms behind it in septic patients and healthy controls. From sepsis and healthy sera, metabolites were analyzed with proton nuclear magnetic spectroscopy, and cytokines using multiplex assay. The effect of sepsis and healthy sera was tested in vitro on keratinocyte proliferation, migration and viability. Skin suction blister wounds were induced and biopsied for immunohistochemical analyses.
Serum levels of glucose, glycine, 3-hydroxybutyrate, creatinine and glycoprotein acetyls were significantly higher in sepsis patients compared to healthy controls, whereas levels of histidine and citrate were significantly lower in sepsis. Keratinocyte viability, proliferation and migration were reduced in sepsis in vitro. Sepsis sera supplemented with epithelial growth factor (EGF) or tumor necrosis factor alpha (TNF-α) improved and EGF receptor inhibition reduced keratinocyte migration in healthy and septic wounds. Extracellular vesicles added to healthy or sepsis serum media inhibited keratinocyte migration. Higher serum concentrations of TNF-α and vascular endothelial growth factor (VEGF) and lower levels of EGF were detected in sepsis sera compared to healthy sera. In skin immunohistochemistry samples, the levels of EGF, VEGF and transforming growth factor beta as well as integral membrane protein syndecan-1 were increased in septic patients compared to healthy controls. Extracellular matrix (ECM) components tenascin-C and laminin-332 had lower expression in septic skin compared to healthy skin.
The results of this study support the clinical findings concerning impaired wound healing in sepsis and provide new information about the underlying mechanisms: hypermetabolism, catabolism and organ dysfunction as well as altered cell signaling and interplay of cytokines and ECM. Understanding the cell level details of wound healing and skin homeostasis in sepsis provides opportunities to improve surgical treatments and their timing.
In this study we observed skin wound healing and the molecular mechanisms behind it in septic patients and healthy controls. From sepsis and healthy sera, metabolites were analyzed with proton nuclear magnetic spectroscopy, and cytokines using multiplex assay. The effect of sepsis and healthy sera was tested in vitro on keratinocyte proliferation, migration and viability. Skin suction blister wounds were induced and biopsied for immunohistochemical analyses.
Serum levels of glucose, glycine, 3-hydroxybutyrate, creatinine and glycoprotein acetyls were significantly higher in sepsis patients compared to healthy controls, whereas levels of histidine and citrate were significantly lower in sepsis. Keratinocyte viability, proliferation and migration were reduced in sepsis in vitro. Sepsis sera supplemented with epithelial growth factor (EGF) or tumor necrosis factor alpha (TNF-α) improved and EGF receptor inhibition reduced keratinocyte migration in healthy and septic wounds. Extracellular vesicles added to healthy or sepsis serum media inhibited keratinocyte migration. Higher serum concentrations of TNF-α and vascular endothelial growth factor (VEGF) and lower levels of EGF were detected in sepsis sera compared to healthy sera. In skin immunohistochemistry samples, the levels of EGF, VEGF and transforming growth factor beta as well as integral membrane protein syndecan-1 were increased in septic patients compared to healthy controls. Extracellular matrix (ECM) components tenascin-C and laminin-332 had lower expression in septic skin compared to healthy skin.
The results of this study support the clinical findings concerning impaired wound healing in sepsis and provide new information about the underlying mechanisms: hypermetabolism, catabolism and organ dysfunction as well as altered cell signaling and interplay of cytokines and ECM. Understanding the cell level details of wound healing and skin homeostasis in sepsis provides opportunities to improve surgical treatments and their timing.
Last updated: 1.3.2023