Sepsis Organ Failure Research Articles

О роли ароматических микробных метаболитов

Интеграция метаболизма макроорганизма и его микробиоты, обеспечивающая в норме симбиоз и саногенез, нарушается при заболеваниях, травме, критическом состоянии, и вектор взаимодействия может изменяться в пользу прокариотов по принципу «метаболиты бактерий - против хозяина». Анализ литературы показал, что, с одной стороны, имеется живой интерес к ароматическим микробным метаболитам, с другой - отсутствует четкое представление об их роли в организме человека. Публикации, касающиеся ряда ароматических микробных метаболитов (фенилкарбоновых кислот, ФКК), как правило, не связаны между собой по тематике и направлены на решение тех или иных прикладных задач в разных областях биологии и медицины. Цель обзора - анализ информации о происхождении, биологических эффектах ФКК в экспериментах in vitro и in vivo , и клинических наблюдениях. Обобщая результаты приведенных в обзоре исследований на клеточном, субклеточном и молекулярном уровнях, логично предположить участие ароматических микробных метаболитов в патогенезе полиорганной недостаточности при сепсисе. Наиболее перспективным для раскрытия роли ароматических микробных метаболитов представляется изучение механизмов вторичной почечной недостаточности и септической энцефалопатии. Важным направлением для будущих исследований является изучение влияния продуктов микробной биодеградации ароматических соединений на развитие диссеминированного внутрисосудистого свертывания крови, артериальной гипотензии и септического шока. Результаты дальнейших исследований будут иметь не только фундаментальное значение, но и обогатят практическую медицину новыми диагностическими и лечебными технологиями. Significant increases in blood concentrations of some aromatic metabolites (phenylcarboxylic acids, PhCAs) in patients with sepsis have been previously shown. Enhanced bacterial biodegradation of aromatic compounds has been demonstrated to considerably contribute to this process. Integration of macroorganism metabolism and its microbiota, which provides normal symbiosis and sanogenesis, is disturbed in diseases, trauma, and critical conditions. Direction of this interaction may change in favor of prokaryotes according to the principle, “bacterial metabolites are against the host”. Analysis of literature showed a particular interest of many investigators to aromatic microbial metabolites. However, there is no clear understanding of their role in the human body. Publications on PhCAs are generally not thematically interrelated and usually focus on solving applied tasks in different fields of biology and medicine. The aim of this work was to consolidate existing information about origin and biological effects of PhCAs in in vitro / in vivo experiments and some clinical findings. The presented summary of reported data from studies performed at cellular, sub-cellular, and molecular levels suggests participation of aromatic microbial metabolites in the pathogenesis of multiple organ failure in sepsis. Studying mechanisms of secondary renal failure and septic encephalopathy is most promising for discovering the function of aromatic microbial metabolites. Effects of microbial biodegradation products of aromatic substances on development of disseminated intravascular coagulation, hypotension, and septic shock are an important challenge for future studies. Results of further investigations will be not only fundamental, but will also enrich medical practice with new diagnostic and therapeutic technologies.

Mechanisms and treatment of organ failure in sepsis.

Sepsis is a dysregulated immune response to an infection that leads to organ dysfunction. Knowledge of the pathophysiology of organ failure in sepsis is crucial for optimizing the management and treatment of patients and for the development of potential new therapies. In clinical practice, six major organ systems - the cardiovascular (including the microcirculation), respiratory, renal, neurological, haematological and hepatic systems - can be assessed and monitored, whereas others, such as the gut, are less accessible. Over the past 2 decades, considerable amounts of new data have helped improve our understanding of sepsis pathophysiology, including the regulation of inflammatory pathways and the role played by immune suppression during sepsis. The effects of impaired cellular function, including mitochondrial dysfunction and altered cell death mechanisms, on the development of organ dysfunction are also being unravelled. Insights have been gained into interactions between key organs (such as the kidneys and the gut) and organ-organ crosstalk during sepsis. The important role of the microcirculation in sepsis is increasingly apparent, and new techniques have been developed that make it possible to visualize the microcirculation at the bedside, although these techniques are only research tools at present.

Parenteral Succinate Reduces Systemic ROS Production in Septic Rats, but It Does Not Reduce Creatinine Levels.

In sepsis, reactive oxygen species (ROS) production is increased. This process takes place mainly within the electron transport chain. ROS production is part of the pathophysiology of multiple organ failure in sepsis. Succinate yields Dihydroflavine-Adenine Dinucleotide (FADH2), which enters the chain through complex II, avoiding complex I, through which electrons are lost. The aim of this work is to determine if parenteral succinate reduces systemic ROS production and improves kidney function. Rats with cecal ligation and puncture were used as model of sepsis, and 4 groups were made: Control group; Succinate group, which only received parenteral succinate; Sepsis group; and Sepsis which received parenteral succinate. Systemic ROS are measured 24 hours after the procedure. Rats subjected to cecal puncture treated with succinate had less systemic ROS than Septic untreated rats (p = 0.007), while there were no differences in creatinine levels (p = 0.07). There was no correlation between creatinine and systemic ROS levels (p = 0.3). We concluded that parenteral succinate reduces ROS levels, but it does not reduce creatinine levels. Since there is no correlation between both levels, the processes would not be related.

Lipopolysaccharide-induced neutrophil extracellular trap formation in canine neutrophils is dependent on histone H3 citrullination by peptidylarginine deiminase

Neutrophils release neutrophil extracellular traps (NETs), which are extracellular chromatin decorated with histones and antimicrobial proteins. Although known for antimicrobial properties, overzealous production of NETs (NETosis) may lead to cytotoxicity and multiple organ failure in sepsis. Pathogen-induced NETosis has been extensively studied in mice but its importance in dogs remains largely unknown. This study sought to characterize in vitro NETosis induced by E.coli LPS, including assessing the role of peptidylarginine deiminase (PAD) in canine NETosis. Neutrophils (1×106 cells/ml) from healthy dogs were isolated and treated with 100μg/ml LPS, 100nM phorbol 12-myristate 13-acetate (PMA), or buffer for either 90 or 180min. NETs were assessed using fluorescence microscopy of living neutrophils and immunofluorescent microscopy. Supernatant and cellular debris were purified and cell-free DNA was quantified by spectrophotometry. The role of PAD was assessed by treating LPS- and PMA-activated neutrophils with 50, 100 or 200μM of the PAD inhibitor, Cl-amidine. In vitro NETosis was characterized by co-localization of cell-free DNA, citrullinated histone H3, and myeloperoxidase. LPS stimulation resulted in intracellular citrullination of histone H3. Compared to PMA chemically-induced NETosis, LPS resulted in smaller NETs with less extracellular citrullinated histone H3. Cl-amidine decreased citrullination of histones and NET production in either LPS- or PMA-stimulated neutrophils demonstrating that neutrophil PAD is essential for these cellular processes.

Melatonin and Neonatal Sepsis: A Promising Antioxidant Adjuvant Agent.

AbstractSepsis represents a major clinical problem in neonatal setting with elevated mortality rate related to multiple organ failure. Despite decades of research, the exact mechanism of organ failure in sepsis is still not completely understood. Oxidative stress (OS), derived from an imbalance between pro-oxidant and antioxidant factors, is involved in the pathogenesis of several neonatal diseases, including sepsis, and plays a particular role in systemic organ failure. Recently, it has been recognized that administration of antioxidants could be useful in septic patients. Among all antioxidants, melatonin has a characteristic role as an antioxidant, anti-inflammatory, and anti-apoptotic agent. In combination with other interventions, melatonin may contribute to an improvement in septic organ injury. Furthermore, melatonin has already been widely used in treating various diseases of neonatal population, including asphyxia, respiratory distress, and sepsis, and no significant toxicity or treatment-related side effects with long-term melatonin therapy have been reported. This review aims to summarize current knowledge concerning the potential beneficial role of melatonin in septic neonates, supporting its short-term adjuvant co-therapy to reduce complications during neonatal sepsis.

Endothelial glycocalyx biomarkers increase in patients with infection during Emergency Department treatment

PurposeEndothelial glycocalyx (EG) shedding may promote organ failure in sepsis. This study describes temporal changes in EG biomarkers from Emergency Department (ED) arrival, and associations with clinical characteristics. Materials and MethodsThis prospective observational study included 23 patients with simple infection, 86 with sepsis and 29 healthy controls. Serum EG biomarkers included syndecan-1, syndecan-4 and hyaluronan. Samples were taken on enrolment in the ED (T0), 1 hour (T1), 3 hours (T3) and 12 to 24 hours (T24) later. ResultsSyndecan-1 concentration increased incrementally over time (T0-T24, both patient groups, P < .001) whereas hyaluronan concentration peaked at T3 (T0-T3, sepsis group, P < .001). Hyaluronan was positively associated with cumulative fluid volumes (P < .001) at T0, T1, and T3, independent of illness severity. Both syndecan-1 (OR 1.04, 95% CI 1.01-1.07, P = .017) and hyaluronan (OR 1.83, 95% CI 1.46-2.30, P < .001) were associated with organ failure, independent of age and comorbidity.Syndecan-4 concentration was not different between groups or over time. ConclusionsIn contrast to previous ICU studies, EG biomarkers increased during the first 24 hours of sepsis treatment and were associated with fluid volumes and organ failure. Further investigation is required to determine if interventions delivered in the ED contribute to EG shedding.

Survival, bacterial clearance and thrombocytopenia are improved in polymicrobial sepsis by targeting nuclear transport shuttles.

The rising tide of sepsis, a leading cause of death in the US and globally, is not adequately controlled by current antimicrobial therapies and supportive measures, thereby requiring new adjunctive treatments. Severe microvascular injury and multiple organ failure in sepsis are attributed to a “genomic storm” resulting from changes in microbial and host genomes encoding virulence factors and endogenous inflammatory mediators, respectively. This storm is mediated by stress-responsive transcription factors that are ferried to the nucleus by nuclear transport shuttles importins/karyopherins. We studied the impact of simultaneously targeting two of these shuttles, importin alpha 5 (Imp α5) and importin beta 1 (Imp β1), with a cell-penetrating Nuclear Transport Modifier (NTM) in a mouse model of polymicrobial sepsis. NTM reduced nuclear import of stress-responsive transcription factors nuclear factor kappa B, signal transducer and activator of transcription 1 alpha, and activator protein 1 in liver, which was also protected from sepsis-associated metabolic changes. Strikingly, NTM without antimicrobial therapy improved bacterial clearance in blood, spleen, and lungs, wherein a 700-fold reduction in bacterial burden was achieved while production of proinflammatory cytokines and chemokines in blood plasma was suppressed. Furthermore, NTM significantly improved thrombocytopenia, a prominent sign of microvascular injury in sepsis, inhibited neutrophil infiltration in the liver, decreased L-selectin, and normalized plasma levels of E-selectin and P-selectin, indicating reduced microvascular injury. Importantly, NTM combined with antimicrobial therapy extended the median time to death from 42 to 83 hours and increased survival from 30% to 55% (p = 0.022) as compared to antimicrobial therapy alone. This study documents the fundamental role of nuclear signaling mediated by Imp α5 and Imp β1 in the mechanism of polymicrobial sepsis and highlights the potential for targeting nuclear transport as an adjunctive therapy in sepsis management.

Endothelial barrier dysfunction, loss of microcirculatory flow and organ failure in sepsis: current clinical view of sepsis and links to basic research

Sepsis and septic shock are major healthcare problems, affecting millions of people around the world each year, with an increasing incidence. In the last decades clinical and basic research have significantly improved the understanding of the complex pathophysiology of sepsis. This led to the new sepsis definition (“Sepsis-3”) which abandoned the view that sepsis is predominately defined the various immunological responses. Rather, sepsis is now defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. This view with a focus on the establishment of organ failure warrants the intensified research for therapeutic attempts to prevent and treat organ failure in sepsis. In this context, it is increasingly recognized that microvascular endothelial barrier dysfunction followed by loss of microcirculatory flow are key events leading to organ failure that should be therapeutically targeted. This review summarizes the current clinical view of the novel sepsis definition and connects it to basic research aspects of endothelial barrier regulation and loss of microcirculatory flow and thus organ protection.

Mechanical Ventilation in Sepsis: A Reappraisal.

Sepsis is the main cause of close to 70% of all cases of acute respiratory distress syndromes (ARDS). In addition, sepsis increases susceptibility to ventilator-induced lung injury. Therefore, the development of a ventilatory strategy that can achieve adequate oxygenation without injuring the lungs is highly sought after for patients with acute infection and represents an important therapeutic window to improve patient care. Suboptimal ventilatory settings cannot only harm the lung, but may also contribute to the cascade of organ failure in sepsis due to organ crosstalk.Despite the prominent role of sepsis as a cause for lung injury, most of the studies that addressed mechanical ventilation strategies in ARDS did not specifically assess sepsis-related ARDS patients. Consequently, most of the recommendations regarding mechanical ventilation in sepsis patients are derived from ARDS trials that included multiple clinical diagnoses. While there have been important improvements in general ventilatory management that should apply to all critically ill patients, sepsis-related lung injury might still have particularities that could influence bedside management.After revisiting the interplay between sepsis and ventilation-induced lung injury, this review will reappraise the evidence for the major components of the lung protective ventilation strategy, emphasizing the particularities of sepsis-related acute lung injury.

Celecoxib administration reduced mortality, mesenteric hypoperfusion, aortic dysfunction and multiple organ injury in septic rats.

The cyclooxygenase (COX)-2 overexpression is associated with vascular injury and multiple organ failure in sepsis. However, constitutive COX-1 and basal COX-2 expressions have physiological effects. We aimed to investigate the effects of partial and selective COX-2 inhibition without affecting constitutive COX-1 and basal COX-2 activities by celecoxib on mesenteric artery blood flow (MABF), vascular reactivity, oxidative and inflammatory injuries, and survival in septic rats accomplished by cecal ligation and puncture (CLP). Wistar rats were allocated into Sham, CLP, Sham+celecoxib, CLP+celecoxib subgroups. 2h after Sham and CLP operations, celecoxib (0.5mg/kg) or vehicle (saline; 1mL/kg) was administered orally to rats. 18h after drug administrations, MABF and responses of isolated aortic rings to phenylephrine were measured. Tissue samples were obtained for biochemical and histopathological examinations. Furthermore, survival rate was monitored throughout 96h. Celecoxib ameliorated mesenteric hypoperfusion and partially improved aortic dysfunction induced by CLP. Survival rate was%0 at 49th h in CLP group, but in CLP+celecoxib group it was 42.8% at the end of 96h. Serum AST, ALT, LDH, BUN, Cr and inflammatory cytokine (tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6) levels were increased in CLP group that were prevented by celecoxib. The decreases in liver and spleen glutathione levels and the increases in liver, lung, spleen and kidney malondialdehyde levels in CLP group were blocked by celecoxib. The histopathological protective effects of celecoxib on organ injury due to CLP were also observed. Celecoxib has protective effects on sepsis due to its preservative effects on mesenteric perfusion, aortic function and its anti-inflammatory and antioxidative effects.

Serum Soluble Fms-Like Tyrosine Kinase 1 (sFlt-1) Predicts the Severity of Acute Pancreatitis.

Organ failure is the most important determinant of the severity of acute pancreatitis (AP). Soluble fms-like tyrosine kinase 1 (sFlt-1) is positively associated with organ failure in sepsis. Our aim was to evaluate the diagnostic utility of automated sFlt-1 measurements for early prediction of AP severity. Adult patients (66) with AP were recruited, including 46 with mild (MAP), 15 with moderately-severe (MSAP) and 5 with severe AP (SAP). Serum and urine samples were collected twice. Serum sFlt-1 was measured with automated electrochemiluminescence immunoassay. Serum concentrations of sFlt-1 were significantly higher in patients with MSAP and SAP as compared to MAP. SAP patients had the highest concentrations. At 24 and 48 h, sFlt-1 positively correlated with inflammatory markers (leukocyte count, C-reactive protein), kidney function (creatinine, urea, cystatin C, serum and urine neutrophil gelatinase-associated lipocalin, urine albumin/creatinine ratio), D-dimer and angiopoietin-2. sFlt-1 positively correlated with the bedside index of severity in AP (BISAP) score and the duration of hospital stay. Serum sFlt-1 above 139 pg/mL predicted more severe AP (MSAP + SAP). In the early phase of AP, sFlt-1 is positively associated with the severity of AP and predicts organ failure, in particular kidney failure. Serum sFlt-1 may be a practical way to improve early assessment of AP severity.

Alert cell strategy in SIRS-induced vasculitis: sepsis and endothelial cells.

Sepsis refers to systemic inflammatory response syndrome and organ failure resulting from infection. Inflammatory receptors (e.g., Toll-like receptors and nucleotide oligomerization domain) recognize bacterial components as inflammatory ligands. These are expressed not only in leukocytes but also in major organs and vascular endothelial cells. “Alert cell” is defined as the cell that expresses the inflammatory receptor and intracellular signaling system to produce inflammatory mediators such as inflammatory cytokines, chemokines, nitric oxide, and prostanoids in organs and the vasculature. NF-κB and AP-1, which are the transcriptional factors of these inflammatory molecules, are important regulators of multiple organ failure in sepsis and systemic inflammation. The vascular endothelial injury would induce multiple organ failure as tissue ischemia and organ death. Drug discovery targeted at alert cells holds a promise for therapy of inflammation including sepsis.

The Human Host Defense Ribonucleases 1, 3 and 7 Are Elevated in Patients with Sepsis after Major Surgery—A Pilot Study

Sepsis is the most common cause of death in intensive care units and associated with widespread activation of host innate immunity responses. Ribonucleases (RNases) are important components of the innate immune system, however the role of RNases in sepsis has not been investigated. We evaluated serum levels of RNase 1, 3 and 7 in 20 surgical sepsis patients (Sepsis), nine surgical patients (Surgery) and 10 healthy controls (Healthy). RNase 1 and 3 were elevated in Sepsis compared to Surgery (2.2- and 3.1-fold, respectively; both p < 0.0001) or compared to Healthy (3.0- and 15.5-fold, respectively; both p < 0.0001). RNase 1 showed a high predictive value for the development of more than two organ failures (AUC 0.82, p = 0.01). Patients with renal dysfunction revealed higher RNase 1 levels than without renal dysfunction (p = 0.03). RNase 1 and 3 were higher in respiratory failure than without respiratory failure (p < 0.0001 and p = 0.02, respectively). RNase 7 was not detected in Healthy patients and only in two patients of Surgery, however RNase 7 was detected in 10 of 20 Sepsis patients. RNase 7 was higher in renal or metabolic failure than without failure (p = 0.04 and p = 0.02, respectively). In conclusion, RNase 1, 3 and 7 are secreted into serum under conditions with tissue injury, such as major surgery or sepsis. Thus, RNases might serve as laboratory parameters to diagnose and monitor organ failure in sepsis.

Decreased serum concentrations of sphingosine-1-phosphate in sepsis.

IntroductionSphingosine-1-phosphate (S1P) is a signaling lipid that regulates pathophysiological processes involved in sepsis progression, including endothelial permeability, cytokine release, and vascular tone. The aim of this study was to investigate whether serum-S1P concentrations are associated with disease severity in patients with sepsis.MethodsThis single-center prospective-observational study includes 100 patients with systemic inflammatory response syndrome (SIRS) plus infection (n = 40), severe sepsis (n = 30), or septic shock (n = 30) and 214 healthy blood donors as controls. Serum-S1P was measured by mass spectrometry. Blood parameters, including C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), lactate, and white blood cells (WBCs), were determined by routine assays. The Sequential Organ Failure Assessment (SOFA) score was generated and used to evaluate disease severity.ResultsSerum-S1P concentrations were lower in patients than in controls (P < 0.01), and the greatest difference was between the control and the septic shock groups (P < 0.01). Serum-S1P levels were inversely correlated with disease severity as determined by the SOFA score (P < 0.01) as well as with IL-6, PCT, CRP, creatinine, lactate, and fluid balance. A receiver operating characteristic analysis for the presence or absence of septic shock revealed equally high sensitivity and specificity for S1P compared with the SOFA score. In a multivariate logistic regression model calculated for prediction of septic shock, S1P emerged as the strongest predictor (P < 0.001).ConclusionsIn patients with sepsis, serum-S1P levels are dramatically decreased and are inversely associated with disease severity. Since S1P is a potent regulator of endothelial integrity, low S1P levels may contribute to capillary leakage, impaired tissue perfusion, and organ failure in sepsis.

Adsorption of histones on natural polysaccharides: The potential as agent for multiple organ failure in sepsis

Histones are intracellular proteins that are structural elements of nuclear chromatin and regulate gene transcription. However, the extracellular histones released in response to bacterial challenges have been identified as mediators contributing to endothelial dysfunction, organ failure, and death during sepsis. In the present study, the adsorption of histones as well as plasma proteins (α1-acid glycoprotein (AGP), albumin, and γ-globulin) on alginic acid, pectin, dextran, and chitosan was examined in order to evaluate the potential of natural polysaccharides as therapeutic agents for multiple organ failure in sepsis. Alginic acid and pectin strongly adsorbed histones, whereas the adsorption abilities of dextran and chitosan toward histones were very low or negligible. Among the natural polysaccharides examined, only alginic acid did not adsorb any of the plasma proteins. These results demonstrated that alginic acid strongly adsorbed histones, but not plasma proteins; therefore, it has potential as a candidate drug for the treatment of multiple organ failure in sepsis.

Lack of cyclophilin D protects against the development of acute lung injury in endotoxemia

Sepsis caused by LPS is characterized by an intense systemic inflammatory response affecting the lungs, causing acute lung injury (ALI). Dysfunction of mitochondria and the role of reactive oxygen (ROS) and nitrogen species produced by mitochondria have already been proposed in the pathogenesis of sepsis; however, the exact molecular mechanism is poorly understood. Oxidative stress induces cyclophilin D (CypD)-dependent mitochondrial permeability transition (mPT), leading to organ failure in sepsis. In previous studies mPT was inhibited by cyclosporine A which, beside CypD, inhibits cyclophilin A, B, C and calcineurin, regulating cell death and inflammatory pathways. The immunomodulatory side effects of cyclosporine A make it unfavorable in inflammatory model systems. To avoid these uncertainties in the molecular mechanism, we studied endotoxemia-induced ALI in CypD−/− mice providing unambiguous data for the pathological role of CypD-dependent mPT in ALI. Our key finding is that the loss of this essential protein improves survival rate and it can intensely ameliorate endotoxin-induced lung injury through attenuated proinflammatory cytokine release, down-regulation of redox sensitive cellular pathways such as MAPKs, Akt, and NF-κB and reducing the production of ROS. Functional inhibition of NF-κB was confirmed by decreased expression of NF-κB-mediated proinflammatory genes. We demonstrated that impaired mPT due to the lack of CypD reduces the severity of endotoxemia-induced lung injury suggesting that CypD specific inhibitors might have a great therapeutic potential in sepsis-induced organ failure. Our data highlight a previously unknown regulatory function of mitochondria during inflammatory response.

Intra-abdominal pressure monitoring in postoperative period in patients with diffuse peritonitis

Epidemiology, etiology, pathologic and morphologic changes associated with increased intra-abdominal pressure are described. The most common ways of its measuring and monitoring are presented. Intra-abdominal pressure is increased by more than 15 mm Hg in patients with diffuse peritonitis. Increased intra-abdominal pressure is associated with the disease severity: the higher the intra-abdominal pressure, the more severe is the disease. If intra-abdominal pressure is increased over 20 mm Hg, treatment strategy depends on the signs of organ failure. In the absence of organ failure, intra-abdominal pressure should be monitored every 4 hours as long as the patient is in critical condition. Intra-abdominal pressure monitoring in case of peritonitis must be attributed to the mandatory manipulation, as pressure changes precede the clinical manifestations of intra-abdominal complications. Measurement of intra-abdominal pressure allows to detect the early signs of multiple organ failure, which is essential for the correction of systemic complications in pancreatogenic peritonitis. In this case, monitoring of intra-abdominal pressure in diffuse postoperative peritonitis should be considered only as a screening test for assessing of the organ dysfunction severity, as the development of multiple organ dysfunction syndrome involves complex pathophysiological mechanisms. Predictions that are more accurate can be made using such integrated indicators as APACHE II (Acute Physiology And Chronic Health Evaluation scale, which is used for assessing various acute and chronic diseases), SAPS (Simplified Acute Physiology Score - a simplified scale for acute functional changes assessment), SOFA (Sepsis-related Organ Failure Assessments Score - scale for dynamic assessment of organ failure in sepsis), MPI (Mannheim Peritonitis Index) scales.

Pathogenesis of Multiple Organ Failure in Sepsis.

Sepsis is a severe critical illness syndrome that arises from infectious insults. While the host immune system is generally beneficial, an overshooting and unregulated immune response can cause serious organ tissue injury. During sepsis, systemic hypotension, disturbed perfusion of the microcirculation, and direct tissue-toxicity caused by inflammatory immune reaction can occur and contribute to organ failure. The failure of two or more vital organ systems is termed multi-organ dysfunction syndrome (MODS) and resembles a very critical condition associated with high morbidity and mortality. Importantly, no specific treatment strategy exists to efficiently prevent the development of MODS during sepsis. In this review, we aim to identify the relevant molecular immunological pathways involved in the pathogenesis of MODS during sepsis. We believe that a detailed understanding of this mechanism is necessary for the development of new treatment approaches for septic patients. In particular, knowledge of the endogenous regulators keeping the balance between necessary immune system activation to combat infections and prevention of host tissue damage would greatly improve the chances for the development of effective interventions.

Recent advances in disseminated intravascular coagulation: endothelial cells and fibrinolysis in sepsis-induced DIC.

Endothelial cells are highly active, sensing and responding to signals from extracellular environments. They act as gatekeepers, mediating the recruitment and extravasation of proinflammatory leukocytes to the sites of tissue damage or infection. Endothelial cells participate in fibrinolysis by secreting tissue-type plasminogen activator, which converts plasminogen to active enzyme plasmin through constitutive and regulated pathways. Fibrinolysis systems and inflammation are tightly linked, as both responses are major host defense systems against both healing processes of tissue repair as well as pathogenic microorganisms. Endothelial cell dysfunction is one of the early signs of systemic inflammation, and it is a trigger of multiple organ failure in sepsis. The marked increase in plasminogen activator inhibitor-1 level causes fibrinolytic shutdown in endotoxemia or sepsis and is one of the most important predictors of multiple organ dysfunction during sepsis-induced disseminated intravascular coagulation (DIC). Leukocytes exhibit the first-line response to microorganisms. Leukocyte-derived elastase degrades cross-linked fibrin to yield molecular species distinct from those generated by plasmin. The alternative systems for fibrinolysis that interact with the plasminogen activator-plasmin systems may play crucial roles in the lysis of fibrin clots in sepsis-induced DIC.

Transcriptomic correlates of organ failure extent in sepsis

Sepsis is characterised by the frequent presence of organ failure and marked immunologic alterations. We studied the association between the extent of organ failure and the transcriptomic response of septic patients. Gene expression profiles in the blood of 74 surgical patients with sepsis were compared with those of 30 surgical patients with no sepsis. Differentially expressed genes were assessed for their correlation with the sequential organ failure (SOFA) score. The expression levels of a group of genes participating in the cell cycle (HIST1H1C, CKS2, CCNA2, CDK1, CCNB2, CIT, CCNB1, AURKA, RAD51), neutrophil protease activity (ELANE, ADORA3, MPO, MMP8, CTSG), IL-1R and IL-18R response correlated directly with SOFA and mortality. Genes involved in T cell (LCK, CD3G, CD3D, ZAP70, ICOS, CD3E, CD28, IL2RB, CD8B, CD8A, CD40LG, IL23A, CCL5, SH2D1A, ITK, CD247, TBX21, GATA3, CCR7, LEF1, STAT4) and NK cell immunity (CD244, KLRK1, KLRD1) were inversely associated with SOFA and mortality. The extent of organ failure in sepsis correlates directly with the existence of imbalanced innate and adaptive responses at the transcriptomic level. Quantification of the expression levels of the genes identified here could contribute to the simultaneous assessment of disease severity and immunological alterations in sepsis.