The host immune system plays a critical role in the development and progression of sepsis, but the mechanisms that lead to cellular dysfunction, organ failure and death remain poorly defined. Peripheral blood monocytes are a major source of the effector molecules that are closely correlated with sepsis development and clinical outcomes. We aim to dissect the signalling pathways and transcription factor networks that control monocyte function in human sepsis. We will also use a newly-developed 3D organoid model to assess how patient monocyte signalling is influenced by lung tissue, which is the most common site of infection in sepsis and serves as a reservoir of monocytes for release into the blood. Given that sepsis-linked changes in monocyte function alter the metabolite content of blood, we will also use a metabolomic approach to identify novel biomarkers within the volatile fraction of patient serum. This project will better define the molecular determinants of monocyte activity in human sepsis and assist the identification of new prognostic biomarkers for use in the clinic.

Imunitní systém hraje klíčovou úlohu ve vývoji a kontrole sepse, avšak mechanismus buněčné disfunkce, selhání orgánů a smrt nejsou dostatečně pochopeny. Monocyty periferní krve jsou hlavním zdrojem efektorových molekul, které jsou úzce propojeny s rozvojem a klinickým výsledkem sepse. Hlavním cílem projektu je pochopení nevysvětlených událostí v signalizaci monocytů během sepse, především spolupráce sítě klíčových transkripčních faktorů řídících funkce monocytů v sepsi. Použijeme nový model trojrozměrných plicních organoidů, ve kterém budeme zjistíme jak monocyty pacientů signalizují v kontextu plicní tkáně, která je běžným místem infekce a slouží jako rezervoár monocytů. Protože se sepsí spojené změny v monocytech mění množství metabolitů v krvi, použijeme také měření metabolitů k identifikaci nových biomarkerů mezi těkavými látkami séra pacientů. Výsledky projektu povedou k lepšímu pochopení procesů kontrolujících osud monocytů v septických stavech, a také možnost rychlé validace diagnostických znaků sepse.

• MeSH
• metabolismus MeSH
• monocyty MeSH
• NF-kappa B MeSH
• sepse imunologie   metabolismus   MeSH
• signální transdukce MeSH
• transkripční faktory NFATC MeSH
• zánět MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• alergologie a imunologie
• infekční lékařství
• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

Tryptophan is an essential amino acid whose metabolites play key roles in diverse physiological processes. Due to low reserves in the body, especially under various catabolic conditions, tryptophan deficiency manifests itself rapidly, and both the serotonin and kynurenine pathways of metabolism are clinically significant in critically ill patients. In this review, we highlight these pathways as sources of serotonin and melatonin, which then regulate neurotransmission, influence circadian rhythm, cognitive functions, and the development of delirium. Kynurenines serve important signaling functions in inter-organ communication and modulate endogenous inflammation. Increased plasma kynurenine levels and kynurenine-tryptophan ratios are early indicators for the development of sepsis. They also influence the regulation of skeletal muscle mass and thereby the development of polyneuromyopathy in critically ill patients. The modulation of tryptophan metabolism could help prevent and treat age-related disease with low grade chronic inflammation as well as post intensive care syndrome in all its varied manifestations: cognitive decline (including delirium or dementia), physical impairment (catabolism, protein breakdown, loss of muscle mass and tone), and mental impairment (depression, anxiety or post-traumatic stress disorder).

• MeSH
• delirium etiologie   MeSH
• deprese etiologie   MeSH
• indolamin-2,3,-dioxygenasa metabolismus   MeSH
• kosterní svaly metabolismus   MeSH
• kritický stav * MeSH
• kynurenin metabolismus   MeSH
• lidé MeSH
• melatonin biosyntéza   MeSH
• sepse metabolismus   MeSH
• serotonin biosyntéza   MeSH
• tryptofan nedostatek   MeSH
• zánět metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND AND OBJECTIVES: Renal elimination of amikacin and other aminoglycosides is slowed down in sepsis-induced acute kidney injury increasing the risk of adverse effects. Since neutrophil gelatinase-associated lipocalin (NGAL) and aminoglycosides share the mechanisms for renal excretion, the predictive power of NGAL was examined towards the changes in amikacin pharmacokinetics during early endotoxemia in anesthetized Wistar rats. METHODS: Endogenous biomarkers of inflammation and acute kidney injury were assessed including NGAL in saline-injected controls and two groups of rats challenged with an intravenous injection of bacterial lipopolysaccharide (5 mg/kg)-a fluid-resuscitated group (LPS) and a fluid-resuscitated group infused intravenously with 8 μg/kg/h terlipressin (LPS-T). Sinistrin and amikacin were infused to measure glomerular filtration rate (GFR) and amikacin clearance (CLam). The investigations included blood gas analysis, chemistry and hematology tests and assessment of urine output, creatinine clearance (CLcr) and sinistrin clearance (CLsini). RESULTS: Within 3 h of injection, systemic and renal inflammatory responses were induced by lipopolysaccharide. Gene and protein expression of NGAL was increased in the kidneys and the concentrations of NGAL in the plasma (pNGAL) and urine rose 4- to 38-fold (P < 0.01). The decreases in CLam and the GFR markers (CLcr, CLsini) were proportional, reflecting the extent to which endotoxemia impaired the major elimination mechanism for the drug. Terlipressin attenuated lipopolysaccharide-induced renal dysfunction (urine output, CLcr, CLsini) and accelerated CLam. The pNGAL showed a strong association with the CLsini (rs = - 0.77, P < 0.0005). Concerning prediction of CLam, pNGAL was comparable to CLcr (mean error - 24%) and inferior to CLsini (mean error - 6.4%), while the measurement of NGAL in urine gave unsatisfactory results. CONCLUSIONS: During early endotoxemia in the rat, pNGAL has a moderate predictive ability towards CLam. Clinical studies should verify whether pNGAL can support individualized dosing of aminoglycosides to septic patients.

• MeSH
• akutní poškození ledvin krev   MeSH
• amikacin krev   metabolismus   farmakokinetika   MeSH
• biologické markery krev   MeSH
• cytokiny MeSH
• endotoxemie chemicky indukované   MeSH
• hodnoty glomerulární filtrace fyziologie   MeSH
• krysa rodu rattus MeSH
• ledviny patofyziologie   MeSH
• lipokalin-2 krev   metabolismus   moč   MeSH
• lipopolysacharidy farmakologie   MeSH
• metabolická clearance MeSH
• moč MeSH
• modely u zvířat MeSH
• oligosacharidy farmakokinetika   MeSH
• potkani Wistar * MeSH
• prediktivní hodnota testů MeSH
• sepse farmakoterapie   metabolismus   MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Myristic acid was identified as a metabolite with the highest diagnostic sensitivity and specificity in the metabolome of patients with bacteraemia. Subsequently, its significant decrease was observed in patients in septic shock not responding to treatment. In our study we have captured myristic acid serum level kinetics in 96 hours following accidental intravenous self-administration of eubiotic Hylak forte causing infection-like systemic inflammatory response syndrome (SIRS). To our knowledge, this is the first time the kinetics of myristic acid levels is presented in a septic patient. Myristic acid was evaluated in comparison with other inflammatory biomarkers and with its level in a control group of healthy subjects. Myristic acid levels during septic response were significantly elevated in comparison with the control group. The peak level was recorded almost immediately after the insult with a gradual decrease within 96 hours. Myristic acid appears to be a promising biomarker in sepsis diagnostics, further research by our group into this topic is ongoing.

• MeSH
• biologické markery analýza   metabolismus   MeSH
• kinetika MeSH
• kyselina myristová metabolismus   MeSH
• lidé MeSH
• sepse metabolismus   MeSH
• septický šok metabolismus   MeSH
• syndrom MeSH
• zánět metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• antioxidancia metabolismus   MeSH
• cytokiny * fyziologie   metabolismus   MeSH
• lidé MeSH
• rány a poranění * metabolismus   patofyziologie   MeSH
• rizikové faktory MeSH
• sepse * metabolismus   patofyziologie   MeSH
• zánět metabolismus   patofyziologie   MeSH
• Check Tag
• lidé MeSH

The fused quinazolinone derivative, RX-207, is chemically and functionally related to small molecule inhibitors of protein binding to glycosaminoglycans (SMIGs). Composed of a planar aromatic amine scaffold, it inhibits protein binding to glycosaminoglycans (GAGs). RX-207 reduced neutrophil migration in thioglycollate-induced peritonitis (37%), inhibited carrageenan-induced paw edema (32%) and cerulein-induced pancreatitis (28%), and increased animal survival in the mouse model of cecal ligation and puncture (CLP)-induced sepsis (60%). The mechanism of RX-207 action, analyzed by UV spectroscopy, confirmed that which was elucidated for chemically related anti-inflammatory SMIGs. RX-207 binding to cell surface GAGs can account for the inhibition of neutrophil recruitment via the micro-vasculature and as a consequence, the reduction of neutrophil mediated tissue damage in the animal models of inflammation and improved survival of mice in CLP-induced sepsis.

• MeSH
• antiflogistika farmakologie   MeSH
• buněčná adheze účinky léků   MeSH
• cékum mikrobiologie   chirurgie   MeSH
• chinazolinony farmakologie   MeSH
• edém chemicky indukované   metabolismus   patologie   prevence a kontrola   MeSH
• glykosaminoglykany metabolismus   MeSH
• infiltrace neutrofily účinky léků   MeSH
• ligace MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední BALB C MeSH
• neutrofily účinky léků   metabolismus   mikrobiologie   MeSH
• pankreatitida chemicky indukované   metabolismus   patologie   prevence a kontrola   MeSH
• peritonitida chemicky indukované   metabolismus   patologie   prevence a kontrola   MeSH
• punkce MeSH
• sepse metabolismus   mikrobiologie   patologie   prevence a kontrola   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The microbial etiology and source of sepsis influence the inflammatory response. Therefore, the plasma levels of cytokines (IL-6, IL-8, and IL-10), chemokines (CCL2/MCP-1, MIP-1β), heparin-binding protein (HBP), soluble CD14 (sCD14), and cortisol were analyzed in blood from septic patients obtained during the first 96 hours of intensive care unit hospitalization. The etiology was established in 56 out of a total of 62 patients enrolled in the study. Plasma concentrations of MCP-1, sCD14, IL-6, and IL-10 were significantly higher in patients with community-acquired pneumonia (CAP; n = 10) and infective endocarditis (IE; n = 11) compared to those with bacterial meningitis (BM; n = 18). Next, cortisol levels were higher in IE patients than in those with BM and CAP, and at one time point, cortisol was also higher in patients with gram-negative sepsis when compared to those with gram-positive infections. Furthermore, cortisol and MCP-1 levels correlated positively with the daily measured SOFA score. In addition, HBP levels were significantly higher in patients with IE than in those with BM. Our findings suggest that MCP-1, sCD14, IL-6, IL-10, cortisol, and HBP are modulated by the source of sepsis and that elevated MCP-1 and cortisol plasma levels are associated with sepsis-induced organ dysfunction.

• MeSH
• antigeny CD14 metabolismus   MeSH
• biologické markery metabolismus   MeSH
• chemokin CCL2 metabolismus   MeSH
• chemokin CCL4 metabolismus   MeSH
• hydrokortison metabolismus   MeSH
• interleukin-10 metabolismus   MeSH
• interleukin-6 metabolismus   MeSH
• interleukin-8 metabolismus   MeSH
• kationické antimikrobiální peptidy metabolismus   MeSH
• krevní proteiny metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• péče o pacienty v kritickém stavu MeSH
• senioři MeSH
• sepse metabolismus   MeSH
• transportní proteiny metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Ample experimental evidence suggests that sepsis could interfere with any mitochondrial function; however, the true role of mitochondrial dysfunction in the pathogenesis of sepsis-induced multiple organ dysfunction is still a matter of controversy. This review is primarily focused on mitochondrial oxygen consumption in various animal models of sepsis in relation to human disease and potential sources of variability in experimental results documenting decrease, increase or no change in mitochondrial respiration in various organs and species. To date, at least three possible explanations of sepsis-associated dysfunction of the mitochondrial respiratory system and consequently impaired energy production have been suggested: 1. Mitochondrial dysfunction is secondary to tissue hypoxia. 2. Mitochondria are challenged by various toxins or mediators of inflammation that impair oxygen utilization (cytopathic hypoxia). 3. Compromised mitochondrial respiration could be an active measure of survival strategy resembling stunning or hibernation. To reveal the true role of mitochondria in sepsis, sources of variability of experimental results based on animal species, models of sepsis, organs studied, or analytical approaches should be identified and minimized by the use of appropriate experimental models resembling human sepsis, wider use of larger animal species in preclinical studies, more detailed mapping of interspecies differences and organ-specific features of oxygen utilization in addition to use of complex and standardized protocols evaluating mitochondrial respiration.

• MeSH
• buněčné dýchání fyziologie   MeSH
• hypoxie buňky fyziologie   MeSH
• lidé MeSH
• mitochondrie metabolismus   patologie   MeSH
• multiorgánové selhání metabolismus   patologie   MeSH
• sepse metabolismus   patologie   MeSH
• spotřeba kyslíku fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

This study analyzes fatty acid (FA) composition in plasma lipids and erythrocyte phospholipids while comparing septic and non-septic critically ill patients. The aim was to describe impacts of infection and the inflammatory process. Patients with severe sepsis (SP, n = 13); age-, sex- and APACHE II score-matched non-septic critically ill with systemic inflammatory response syndrome (NSP, n = 13); and age-/sex-matched healthy controls (HC, n = 13) were included in a prospective case-control study during the first 24 h after admission to the intensive care unit. In both SP and NSP, lower n-6 polyunsaturated FA (PUFA) accompanied by higher proportions of monounsaturated FA (MUFA) in plasma phospholipids (PPL) was observed relative to HC. MUFA proportion was negatively correlated with n-6 PUFA, high density lipoprotein cholesterol (HDL-C), and albumin. MUFA was positively correlated with C-reactive protein (CRP), procalcitonin (PCT), interleukins (IL-6, IL-10), oxidized low density lipoproteins (ox-LDL), and conjugated dienes (CD). In both SP and NSP, inflammatory and lipid peroxidation markers were significantly higher-CRP (p < 0.001; p = 0.08), IL-6, IL-10, TNF-α (p < 0.01, p = 0.06), ox-LDL, and CD while total cholesterol, HDL-C, LDL-C albumin, and 20:4n-6/22:6n-3 and n-6/n-3 ratios were lower compared to HC. In conclusion, the changes in plasma lipid FA profile relate to the intensity of inflammatory and peroxidative response regardless of insult etiology. The lower MUFA and higher n-6 PUFA proportions in PPL were inversely correlated with cholesterol and albumin levels.

• MeSH
• biologické markery krev   MeSH
• C-reaktivní protein metabolismus   MeSH
• fosfolipidy krev   MeSH
• interleukiny metabolismus   MeSH
• kalcitonin metabolismus   MeSH
• kritický stav * MeSH
• kyseliny mastné mononenasycené krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mastné kyseliny krev   MeSH
• prospektivní studie MeSH
• senioři MeSH
• sepse imunologie   metabolismus   MeSH
• studie případů a kontrol MeSH
• syndrom systémové zánětlivé reakce imunologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

Sepse byla zprvu chápána jako nemoc způsobená invazivní bakteriální infekcí spojenou se zaplavením organizmu bakteriálními zplodinami (otrava krve). Schottmüllerova definice položila důraz na existenci ložiska jako zdroje invadujících bakterií. Další výzkumy vedly k objevu cytokinové kaskády a k poznání, že projevy sepse jsou indukovány našimi vlastními endogenními mediátory. Příčinu selhávání různých orgánů při sepsi lze vysvětlit jednak poruchami hemodynamiky, které mají původ ve změněné funkci kapilárního řečiště, ale současně i komplexní přestavbou metabolizmu. Pro vysvětlení metabolických změn byla postulována teorie hibernace tkání; podle alternativní teorie vznikají metabolické změny v důsledku útlumu funkce mitochondrií, který se vyvíjí jako součást komplexní protibakteriální odpovědi. V článku jsou popsány jednotlivé definice sepse od poloviny 19. století po současnost.

Sepsis was understood as a disease caused by an invasive bacterial infection associated with deluging of organism with bacterial toxins (blood poisoning). Schottmüller's definition emphasized the existence of a focus as the source of invading bacteria. Further research led to the discovery of the cytokine cascade and to the recognition that sepsis is induced by our own endogenous mediators. The dysfunction or failure of various organs in sepsis can be explained both by hemodynamic disorders which originate in the altered microcapillars but also by a complex transformation of metabolism. To explain metabolic changes, the theory of tissue hibernation was postulated. According to the alternative theory, metabolic changes arise due to attenuation of mitochondrial function, which develops as part of a complex antibacterial response. Definitions of sepsis from the mid-19th century to the present are described.

• MeSH
• dějiny 19. století MeSH
• dějiny 20. století MeSH
• dějiny lékařství MeSH
• hemodynamika MeSH
• lidé MeSH
• mediátory zánětu MeSH
• multiorgánové selhání patofyziologie   MeSH
• sepse * dějiny   etiologie   metabolismus   patofyziologie   MeSH
• septický šok * etiologie   patofyziologie   MeSH
• stupeň závažnosti nemoci MeSH
• syndrom systémové zánětlivé reakce patofyziologie   MeSH
• terminologie jako téma * MeSH
• TNF-alfa MeSH
• Check Tag
• dějiny 19. století MeSH
• dějiny 20. století MeSH
• lidé MeSH
• Publikační typ
• historické články MeSH
• přehledy MeSH