Human body reacts to physical, chemical and biological insults with a complex inflammatory reaction. Crucial components and executors of this response are endothelial cells, platelets, white blood cells, plasmatic coagulation system, and complement. Endothelial injury and inflammation are associated with elevated blood levels of cell membrane-derived microvesicles. Increased concentrations of microvesicles were found in several inflammatory reactions and diseases including acute coronary syndromes, stroke, vasculitis, venous thromboembolism, multiple sclerosis, rheumatoid arthritis, systemic lupus ery-thematosus, anti-phospholipid antibody syndrome, inflammatory bowel disease, thrombotic thrombocy-topenic purpura, viral myocarditis, sepsis, dissemi-nated intravascular coagulation, polytrauma, and burns. Microvesicles can modulate a variety of cellular processes, thereby having an impact on pathogenesis of diseases associated with inflammation. Microvesicles are important mediators and potential biomarkers of systemic inflammation. Measurement of inflammatory cell-derived microvesicles may be utilized in diagnostic algorithms and used for detection and determination of severity in diseases associated with inflammatory responses, as well as for prediction of their outcome. This review focuses on the mechanisms of release of microvesicles in diseases associated with systemic inflammation and their potential role in the regulation of cellular and humoral interactions. and Corresponding author: Jan Janota
Enteral nutrition (EN) is a preferred way of feeding in critically ill patients unless obvious contraindications such as ileus or active gastrointestinal bleeding are present. Early enteral nutrition as compared to delayed EN or total parenteral nutrition decreases morbidity in postsurgical and trauma patients. The hepatosplanchnic region plays a pivotal role in the pathophysiology of sepsis and multiple organ dysfunction syndrome. The beneficial effects of EN on splanchnic perfusion and energy metabolism have been documented both in healthy volunteers and animal models of sepsis, hemorrhagic shock and burns. By contrast, EN may increase splanchnic metabolic demands, which in turn may lead to oxygen and/or energy demand/supply mismatch, especially when hyperemic response to EN is not preserved. Therefore, the timing of initiation and the dose of EN in patients with circulatory failure requiring vasoactive drugs are a matter of controversy. Interestingly, the results of recent clinical studies suggest that early enteral nutrition may not be harmful even in patients with circulatory compromise. Nevertheless, possible onset of serious complications, the non-occlusive bowel necrosis in particular, have to be kept in mind. Unfortunately, there is only a limited number of clinically applicable monitoring tools for the effects of enteral nutrition in critically ill patients., R. Rokyta Jr., M. Matějovič, A. Kroužecký, I. Novák., and Obsahuje bibliografii
Disturbance of capillary perfusions due to leukocyte adhesion, disseminated intravascular coagulat ion, tissue edema is critical components in the pathophysiology of sepsis. Alterations in brain microcirculation during sepsis are not clearly understood. The aim of this study is to gain an improved understanding of alterations through direct visualization of brain microcirculations in an experimental endotoxemi a using intravital microscopy (IVM). Endotoxemia was induced in Lewis rats with Lipopolysaccharide (LPS, 15 mg/kg i.v.). The dura mater was removed via a cranial window to expose the pial vessels on the brain surface. Using fluorescence dyes, plasma extravasation of pial venous vessels and leukocyte-endothelial interaction were visualized by intravital microscopy 4 h after LPS administration. Plasma cytokine levels of IL1-β, IL-6, IFN-γ, TNF-α and KC/GRO were evaluated after IVM. A sign ificant plasma extravasation of the pial venous vessels was found in endotoxemia rats compared to control animals. In addition , a significantly increased number of leukocytes adherent to the pial venous endothelium was observed in septic animals. Endotoxemia also induced a significant elevation of plasma cytokine levels of IL1-β, IL-6, IFN-γ, TNF-α and KC/GRO. Endotoxemia increased permeability in the brain pial vessels accompanied by an increase of leukocyte-endothelium interactions and an increase of inflammatory cytokines in the plasma., J. Zhou ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
To investigate the effect of hydrogen sulfide (H2S) on myocardial injury in sepsis-induced myocardial dysfunction (SIMD), male C57BL/6 mice were intraperitoneally injected with lipopolysaccharide (LPS) (10 mg/kg, i.p.) to induce cardiac dysfunction without or with the H2S donor sodium hydrosulfide (NaHS) (50 µmol/kg, i.p.) administration 3 h after LPS injection. Six hours after the LPS injection, echocardiography, cardiac hematoxylin and eosin (HE) staining, myocardial damage and inflammatory biomarkers and Western blot results were analyzed. In mice, the administration of LPS decreased left ventricular ejection fraction (LVEF) by 30 % along with lowered H2S levels (35 % reduction). It was observed that cardiac troponin I (cTnI), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) levels were all increased (by 0.22-fold, 2000-fold and 0.66-fold respectively). HE staining revealed structural damage and inflammatory cell infiltration in the myocardial tissue after LPS administration. Moreover, after 6 h of LPS treatment, toll-like receptor 4 (TLR4) and nod-like receptor protein 3 (NLRP3) expressions were up-regulated 2.7-fold and 1.6-fold respectively. When compared to the septic mice, NaHS enhanced ventricular function (by 0.19-fold), decreased cTnI, TNF-α, and IL-1β levels (by 11 %, 33 %, and 16 % respectively) and downregulated TLR4 and NLRP3 expressions (by 64 % and 31 % respectively). Furthermore, NaHS did not further improve cardiac function and inflammation in TLR4-/- mice or mice in which NLRP3 activation was inhibited by MCC950, after LPS injection. In conclusion, these findings imply that decreased endogenous H2S promotes the progression of SIMD, whereas exogenous H2S alleviates SIMD by inhibiting inflammation via the TLR4-NLRP3 pathway suppression.
Our study explored the role of extrapituitary prolactin (PRL) and toll-like receptors (TLR)2 and TLR4 in defense reaction of immune system to bacterial infection. Forty-two patients diagnosed with sepsis were recruited and blood samples were withdrawn after patients’ admission to hospital, after the end of acute phase of sepsis and after the sepsis has been resolved, respectively. Seventeen patients died of sepsis; thus, only one sample collected just before death could be processed. PRL and TLR2/4 mRNA levels were measured in CD14+ blood monocytes by QPCR and PRL -1149 G/T SNP genotyped. The TLRs mRNA expression was markedly elevated in all patients groups in comparison to healthy controls mRNA levels; the highest upregulation of monocytic TLR2 in sepsis (16.4 times, P<0.0001) was detected in patients who did not survive septic complications. PRL mRNA expression in monocytes from nonsurvivors tended to be lower (4.5 fold decrease, P=NS) compared to control levels and it was 6.2 times reduced compared to PRL mRNA expression in second blood sample from survivors (P<0.05). The PRL -1149 G/T SNP had no effect on PRL mRNA response during sepsis. Our data suggest that increased prolactin mRNA expression in monocytes is associated with better outcome and improved survival rate in sepsis with no apparent effect of PRL -1149 G/T SNP on monocytic prolactin response., P. Čejková ... [et al.]., and Obsahuje seznam literatury
The kidney is a common “victim organ” of various insults in critically ill patients. Sepsis and septic shock are the dominant causes of acute kidney injury, accounting for nearly 50 % of episodes of acute renal failure. Despite our substantial progress in the understanding of mechanisms involved in septic acute kidney injury there is still a huge pool of questions preclusive of the development of effective ther apeutic strategies. This review briefly summarizes our current knowledge of pathophysiological mechanisms of septic acute kidney injury focusing on hemodynamic alterations, peritubular dysfunction, role of inflammatory mediators and nitric oxide, mitochondrial dysfunction and structural chan ges. Role of proteomics, new promising laboratory method, is mentioned., J. Chvojka, R. Sýkora, T. Karvunidis, J. Raděj, A. Kroužecký, I. Novák, M. Matějovič., and Obsahuje bibliografii
Rats received an injection of [14C]leucine and were then divided into four groups. Groups I and II consisted of ad libitum fed rats were administered saline or endotoxin of Salmonella enteritidis eight and twenty-two h after the [14C]leucine treatment. Animals of Group III (saline) and Group IV (endotoxin) fasted after [14C]leucine injection. Twenty three hours after [14C]leucine treatment rats were injected with pHjleucine and sacrificed 20 min afterwards. Endotoxin administration decreased body weight in fed rats only. After endotoxin treatment, higher [3H]leucine specific activity in the blood plasma, decreased leucine incorporation into proteins and lowered plasma amino acid levels were observed. [14C]leucine radioactivity was significantly higher in the spleen and lower in skeletal muscles of endotoxin-treated rats. All changes were less expressed in fasted than in ad libitum fed animals. Our results indicate that endotoxin treatment results in (a) changes in host metabolism that are not mediated solely by anorexia; (b) a decrease of protein synthesis in the viscera and skeletal muscles; (c) an increase of protein degradation in skeletal muscles; (d) reutilization of leucine released from skeletal muscles in viscera, and (e) a slower disappearance rate of leucine from the blood.
Sepsis is a life threatening condition that arises when the body's response to an infection injures its own tissues and organs. Sepsis can lead to shock, multiple organ failure and death especially if not recognized early and treated promptly. Molecular mechanisms underlying the systemic inflammatory response syndrome associated with sepsis are still not completely defined and most therapies developed to target the acute inflammatory component of the disease are insufficient. In this s tudy we investigated a possibility of combating sepsis in a mouse model by intravenous treatment with recombinant human tissue non - specific alkaline phosphatase (rhTNAP) derived from transgenic rabbit milk. We induced sepsis in mice by intraperitoneal inje ction of LPS and three hours later treated experimental group of mice by intravenous injection with rhTNAP derived from transgenic rabbits. Such treatment was proved to be physiologically effective in this model, as administration of recombinant rhTNAP suc cessfully combated the decrease in body temperature and resulted in increased survival of mice (80 % vs. 30 % in a control group). In a control experiment, also the administration of bovine intestinal alkaline phosphatase by intravenous injection proved to be effective in increasing survival of mice treated with LPS. Altogether, present work demonstrates the redeeming effect of the recombinant tissue non -specific AP derived from milk of genetically modified rabbits in combating sepsis induced by LPS., B. Bender, M. Baranyi, A. Kerekes, L. Bodrogi, R. Brands, P. Uhrin, Z. Bösze., and Obsahuje bibliografii
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.