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Identifier 000416854
Title Συσχέτιση της κατανάλωσης ενέργειας με τη μιτοχονδριακή λειτουργία και τη διέγερση του iNOS και των πρωτεϊνών στρες Hsp 70, Hsp 90 σε ασθενείς ΜΕΘ με σήψη
Alternative Title Correlation of energy consumption with mitochondrial function and stimulation of iNOS and stress proteins Hsp70, Hsp90 in ICU patients with sepsis
Author Ταβλαδάκη, Θεονύμφη
Thesis advisor Μπριασούλης, Γεώργιος
Reviewer Κονδύλη, Ευμορφία
Βενυχάκη, Μαρία
Γεωργόπουλος, Δημήτριος
Δημητρίου, Ελένη
Γαλανάκης, Εμμανουήλ
Σαμώνης, Γεώργιος
Abstract Despite the fact that sepsis was already known as a serious condition since Hippocrates, the debate about what sepsis represents and how it should be delimited continues until today. While the definitions of sepsis, severe sepsis, septic shock and multi-organ failure have remained unchanged for more than 2 decades, a new definition emerged in 2016 called SEPSIS -3. This process was based on the recent knowledge that sepsis has implications in organ function , morphology, cell biology, biochemistry, immunology and circulation that all together constitute the pathobiology of sepsis. The prevailing severity score scale is the Sequential Organ Failure Assessment (SOFA). The higher SOFA scale is associated with higher mortality. Regarding children, there are corresponding definitions. Over the past 2 decades, case mortality has dropped whereas overall mortality increased. The term "systemic inflammatory response syndrome (SIRS)" was introduced to describe the host's hyperflammatory response to pathogen invasion, which was considered the hallmark of sepsis. Later, Bone et al. promoted the idea that the initial inflammatory response is followed by "compensatory anti-inflammatory response syndrome (CARS)", characterized by the induction of various anti-inflammatory mechanisms. In recent years, it has become apparent that the infection contributes both pro-inflammatory and anti-inflammatory mechanisms. Along with cytokines and chemokines, the term lipokines is used in the literature to describe protein molecules involved in inflammation and insulin resistance. Resistin as a proinflammatory lipokine increases in severe inflammation. Adiponectin is reduced in obese and severely affected patients. It is well known that all organisms respond to adverse environmental conditions by producing a set of specific stress-resistance proteins called heat shock proteins (Hsps) or chaperones. With regard to Hsp90, it has been shown that elevated levels of Hsp90 in plasma are associated with worse outcome in critically ill children with septic shock. Many researchers assume that moderate levels of stress, such as sepsis, increase the expression of intracellular HSP and secretion of extracellular HSP. Increased extracellular Hsp72 is associated with poor outcome in septic shock patients. Since HSP72 gene polymorphisms are also correlated with HSP72 production, polymorphisms of a nucleotide (SNPs) may be determinants of the sensitivity of the individual.The dysfunction of organs observed in sepsis appears to be due, at least in part, to mitochondrial dysfunction due to the developing strong oxidative stress and consequent failure of energy production confirmed in animal models of sepsis. Oxidative stress occurs when ROS / RNS production and antioxidant mechanisms are not in equilibrium. Nitrogen Oxide (NO) is produced by three different synthases (NO synthases, NOS). The enzyme, the inducible NOS (iNOS ), is synthesized in response to inflammation and produces large amounts of NO for prolonged periods of time. Different interpretations can be proposed for the dual personality of NO during a septic shock. Mitochondrial biogenesis involves the production of mitochondrial proteins encoded by either nuclear or mitochondrial DNA, thus replacing damaged proteins and improving the energy production potential, as there is increased demand for energy.The inflammation observed in Sepsis further increases metabolic needs due to intense catabolism. Past and recent studies in adults have shown that the organism responds to sepsis with a hypometabolic 'ebb' phase. Early changes in metabolic profile in sepsis are characterized by mitochondrial deficiency, suppressed energy consumption and multiple cellular dysfunctions. Caloric overdose at the wrong time may disproportionately increase sepsis-induced inflammatory, immune and hormonal deregulation. Recently, HSP72 and HSP90α have been shown to be associated with a low-LDL / HDL submetabolic model of sepsis accompanying the acute stress phase and associated with increased mortality. Possible correlations of the metabolic hormones Adiponectin and Resistin, which regulate insulin action, energy and homeostasis of glucose and lipids, with HSP, have not yet been evaluated. In this study, we showed that sepsis is similarly manifested in adults and children, involving early changes in specific pathways of inflammation, endocrinology, inherent immunity, metabolism and myocardial contractility. We also showed that the studied "window" of sepsis pathobiology differs from SIRS in adults and children, regardless of whether the definition of adult or pediatric sepsis is used. Our preliminary results indicate that early pathobiology in sepsis is unique in all age groups. For the first time in the literature, the results of this study showed that Resistin and eHSP90a were higher while mHSP72, VO2, VCO2, EE, and metabolic patterns were lower in sepsis than in SIRS in both adults and pediatric patients. Similar differences between the groups in terms of severity score, temperature, HR, CRP, lactate, albumin and EF are indicated. It has been previously shown that HSP72 exhibits substantial molecular and biological protective effects in experimental sepsis models, but not in clinical studies. Our findings of suppressed mHSP72 expression in septic adults and children broaden the results of recent adult studies showing suppressed expression of intracellular HSP72 and HSP90α in sepsis. Reduced HSP expression due to autophagia has been shown to aggravate the experimental progression of the disease. In recent in vitro studies, iHSP72 was higher in sepsis and SIRS compared to healthy controls, whereas HSP72 increased and HSP90α remained stable in septic serum. In the present study, besides lactate and Resistin, eHSP90a better distinguished sepsis and SIRS in children and adults. Extracellular HSP72 was also a strong distinctive sepsis factor in children. In such a state of stress, alarmins eHSP72 and eHSP90a are released from damaged cells as "hazard signals" that activate the innate, acquired and hormonal response of the host. Although precursory studies had assumed that HSP72 genotypes are likely to affect the outcome of sepsis, our analysis of the HSP72 genotype did not show differences in the groups rs6457452 and rs1061581 in terms of predisposition to sepsis or poor outcome. In the present study, Resistin was higher and able to distinguish sepsis independently from SIRS in both adults and pediatric patients. In particular, Resistin was associated with disease severity scores, eHSP90a in children and negative with metabolic patterns in adults. On the other hand, Adiponectin, a polypeptide hormone secreted by adipocytes regulating metabolic processes and energy homeostasis, did not appear to be related to any of the variables studied. Thus, although plasma levels of Adiponectin and Resistin have been shown to be elevated in septic shock, in the present series we have shown that only Resistin has been associated with metabolic profiles in sepsis. In agreement with previous studies, the estimated EE, VO2 and VCO2 values were lower among non-survivors in both groups. For the first time, we showed that low metabolic profiles, VO2, VCO2, albumin, and increasing lactate levels, could predict mortality among ICU patients with similar accuracy in children and adults. A hypometabolic model has also been shown to predominate in the acute phase of severe sepsis in children related to mortality. In our series, malnourished septic children had higher mortality, while septic adults, which were more obese than patients with SIRS, did not show increased mortality. Also, the results of the aminographs of this study confirm those previous studies that showed that acute phase of a critical disease the amino acid levels are not correlated with a particular plasma amino acid mobility pattern as their levels decrease, increase or do not change compared to the values recorded in healthy individuals. TBARS levels were also elevated relative to the SIRS group. In the current study, ATP levels were decreased while NO3 levels were increased in patients with sepsis compared to healthy controls or SIRS patients. In the inflammatory response, inducible NO synthase (iNOS) is stimulated leading to excessive NO production. Thereafter, ATP synthesis and ATP levels are inhibited in septic patients. In a previous study, BVR found to be increased in septic patients in our study showed strong antioxidant capacity and that BVR in plasma effectively protects endothelial cells from the death caused by hydrogen peroxide and nitrogen peroxide. In addition, elevated TBARS levels in septic patients indicate the strong oxidative stress in this group of patients. Further clarification is required as to whether there are other pathobiological similarities or unexplored yet crucial biomolecules or bioenergy significant differences in sepsis between adults and children. CONCLUSIONS Critically ill adult and pediatric ICU patients at high risk of mortality have similar inflammatory, immunological and metabolic profiles not affected by the SNSs rs6457452 and rs1061581 HSP72. These important disorders of metabolism and endogenous immunity in the acute phase of stress in sepsis are accompanied by characteristic changes in the bioenergetic profile and aminogram not observed in SIRS. Resistin and eHSP90α may play a dominant role in the sepsis and design of a common profile for adult and child sepsis, distinct from SIRS. Suppressed intracellular HSPs and malnutrition may also contribute to the development of sepsis. However, age-related differences and various indicators of suspected identification and management of early sepsis may paradoxically translate these similarities into different adult-child results. It is therefore urgent to quantify specific pathobiological processes taking place in septic patients with a variety of metabolic and genetic abnormalities.
Language Greek
Issue date 2018-07-18
Collection   Faculty/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
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