Expression of placental glycans and its role in regulating peripheral blood NK cells during preeclampsia: a perspective.

Preeclampsia is a pregnancy-related multisystem disorder characterized by altered trophoblast invasion, oxidative stress, exacerbation of systemic inflammatory response, and endothelial damage. The pathogenesis includes hypertension and mild-to-severe microangiopathy in the kidney, liver, placenta, and brain. The main mechanisms involved in its pathogenesis have been proposed to limit trophoblast invasion and increase the release of extracellular vesicles from the syncytiotrophoblast into the maternal circulation, exacerbating the systemic inflammatory response. The placenta expresses glycans as part of its development and maternal immune tolerance during gestation. The expression profile of glycans at the maternal-fetal interface may play a fundamental role in physiological pregnancy changes and disorders such as preeclampsia. It is unclear whether glycans and their lectin-like receptors are involved in the mechanisms of maternal-fetal recognition by immune cells during pregnancy homeostasis. The expression profile of glycans appears to be altered in hypertensive disorders of pregnancy, which could lead to alterations in the placental microenvironment and vascular endothelium in pregnancy conditions such as preeclampsia. Glycans with immunomodulatory properties at the maternal-fetal interface are altered in early-onset severe preeclampsia, implying that innate immune system components, such as NK cells, exacerbate the systemic inflammatory response observed in preeclampsia. In this article, we discuss the evidence for the role of glycans in gestational physiology and the perspective of glycobiology on the pathophysiology of hypertensive disorders in gestation.

Increased TNF-α production in response to IL-6 in patients with systemic inflammation without infection.

Acute systemic inflammation can lead to life-threatening organ dysfunction. In patients with sepsis, systemic inflammation is triggered in response to infection, but in other patients, a systemic inflammatory response syndrome (SIRS) is triggered by non-infectious events. IL-6 is a major mediator of inflammation, including systemic inflammatory responses. In homeostatic conditions, when IL-6 engages its membrane-bound receptor on myeloid cells, it promotes pro-inflammatory cytokine production, phagocytosis, and cell migration. However, under non-physiologic conditions, such as SIRS and sepsis, leucocyte dysfunction could modify the response of these cells to IL-6. So, our aim was to evaluate the response to IL-6 of monocytes from patients diagnosed with SIRS or sepsis. We observed that monocytes from patients with SIRS, but not from patients with sepsis, produced significantly more TNF-α than monocytes from healthy volunteers, after stimulation with IL-6. Monocytes from SIRS patients had a significantly increased baseline phosphorylation of the p65 subunit of NF-κB, with no differences in STAT3 phosphorylation or SOCS3 levels, compared with monocytes from septic patients, and this increased phosphorylation was maintained during the IL-6 activation. We found no significant differences in the expression levels of the membrane-bound IL-6 receptor, or the serum levels of IL-6, soluble IL-6 receptor, or soluble gp130, between patients with SIRS and patients with sepsis. Our results suggest that, during systemic inflammation in the absence of infection, IL-6 promotes TNF-α production by activating NF-κB, and not the canonical STAT3 pathway.

Peptide VSAK maintains tissue glucose uptake and attenuates pro-inflammatory responses caused by LPS in an experimental model of the systemic inflammatory response syndrome: a PET study.

The present investigation using Positron Emission Tomography shows how peptide VSAK can reduce the detrimental effects produced by lipopolysaccharides in Dutch dwarf rabbits, used to develop the Systemic Inflammatory Response Syndrome (SIRS). Animals concomitantly treated with lipopolysaccharides (LPS) and peptide VSAK show important protection in the loss of radiolabeled-glucose uptake observed in diverse organs when animals are exclusively treated with LPS. Treatment with peptide VSAK prevented the onset of changes in serum levels of glucose and insulin associated with the establishment of SIRS and the insulin resistance-like syndrome. Treatment with peptide VSAK also allowed an important attenuation in the circulating levels of pro-inflammatory molecules in LPS-treated animals. As a whole, our data suggest that peptide VSAK might be considered as a candidate in the development of new therapeutic possibilities focused on mitigating the harmful effects produced by lipopolysaccharides during the course of SIRS.

Transient Receptor Potential Canonical Channels 4 and 5 Mediate Escherichia coli-Derived Thioredoxin Effects in Lipopolysaccharide-Injected Mice.

Thioredoxin plays an essential role in bacterial antioxidant machinery and virulence; however, its regulatory actions in the host are less well understood. Reduced human Trx activates transient receptor potential canonical 5 (TRPC5) in inflammation, but there is no evidence of whether these receptors mediate bacterial thioredoxin effects in the host. Importantly, TRPC5 can form functional complexes with other subunits such as TRPC4. Herein, E. coli-derived thioredoxin induced mortality in lipopolysaccharide- (LPS-) injected mice, accompanied by reduction of leukocyte accumulation, regulation of cytokine release into the peritoneum, and impairment of peritoneal macrophage-mediated phagocytosis. Dual TRPC4/TRPC5 blockade by ML204 increased mortality and hypothermia in thioredoxin-treated LPS mice but preserved macrophage's ability to phagocytose. TRPC5 deletion did not alter body temperature but promoted additional accumulation of peritoneal leukocytes and inflammatory mediator release in thioredoxin-administered LPS mice. Thioredoxin diminished macrophage-mediated phagocytosis in wild-type but not TRPC5 knockout animals. TRPC5 ablation did not affect LPS-induced responses. However, ML204 caused mortality associated with exacerbated hypothermia and decreased peritoneal leukocyte numbers and cytokines in LPS-injected mice. These results suggest that bacterial thioredoxin effects under LPS stimuli are mediated by TRPC4 and TRPC5, shedding light on the additional mechanisms of bacterial virulence and on the pathophysiological roles of these receptors.

Protein from Hevea brasiliensis "Hev b 13" latex attenuates systemic inflammatory response and lung lesions in rats with sepsis.

Sepsis induces a severe systemic inflammatory response that may result in multiple organ dysfunction and death. Studies using a protein derived from natural Hevea brasiliensis (rubber tree) latex, denominated Hev b 13, have demonstrated important anti-inflammatory effects, but no data have been published regarding its effects on sepsis. The aim of this study was to investigate the effects of Hev b 13 on the inflammatory response and lung lesions of septal rats. Male Wistar rats were submitted to cecal ligation and puncture (CLP), randomized into groups and treated with subcutaneously administered doses of 0.5/2.0/3.0 mg/Kg of Hev b 13. Next, animals were subdivided into three different points in time (1, 6 and 24 hours after treatments) for collection of blood samples and euthanasia accompanied by organ removal. Total and differential leukocyte counts, cytokine dosage and histological assessment were analyzed. Treatment with Hev b 13 resulted in a significant decline in total and differential leukocytes as well as suppression of TNF-α and IL-6 production, associated with the increase in IL-10 and IL-4 in plasma and lung tissue. Moreover, it reduced morphological and pathological changes found in the lungs, including neutrophil infiltration, edema and alveolar thickening. The present study concluded that Hev b 13 exerts anti-inflammatory effects and attenuates lung lesions in septal rats, showing potential for clinical application.

Estradiol Modulates Local Gut Injury Induced by Intestinal Ischemia-Reperfusion in Male Rats.

Intestinal ischemia and reperfusion (I/R) triggers a systemic inflammatory response characterized by leukocyte mobilization from the bone marrow, release of cytokines to the circulation, and increased microvascular permeability, leading to high mortality. Females have shown attenuated inflammatory response to trauma when compared with males, indicating a role for female sex hormones in this process. Here, we have evaluated the effect of estradiol on the local gut injury induced by I/R in male rats. I/R was induced by the clamping of the superior mesenteric artery for 45 min, followed by 2 h of reperfusion. A group received 17ß-estradiol (280 µg/kg, i.v., single dose) at 30 min of ischemia. Morphometric analysis of the gut showed I/R induced a reduction of villous height that was prevented by estradiol. White blood cells, notably granulocytes, were mobilized from the circulation to the intestine by I/R, which was also prevented by estradiol treatment. Groups had the intestine wrapped in a plastic bag to collect intestinal fluid, where leukocytes count, TNF-α, and IL-10 levels were increased by I/R. Serum chemokines (CINC-1, MIP-1α, MIP-2), ICAM-1 expression in the mesenteric tissue, and neutrophils spontaneous migration measured in vitro were also increased after I/R. Estradiol treatment reduced leukocytes numbers and TNF-α on intestinal fluid, serum chemokine release and also downregulated MIP-1α, MIP-2 gene expression, and spontaneous in vitro neutrophil migration. In conclusion, estradiol blunts intestinal injury induced by I/R by modulating chemokines release and leukocyte trafficking.

Interleukin-6 and C-reactive protein are overexpressed in the liver of perinatal deaths diagnosed with fetal inflammatory response syndrome.

Anatomopathologic studies have failed to define the fetal inflammatory response syndrome (FIRS) as a cause of fetal death. Here, liver fragments of perinatal autopsies were collected at a university hospital from 1990 to 2009 and classified according to the cause of death, perinatal stress, and gestational age (GA) of the fetus. IL-6, TNF-α, and C-reactive protein (CRP) expression were immunostained, respectively, with primary antibody. Cases with congenital malformation, ascending infection, and perinatal anoxia showed increased IL-6, CRP, and TNF-α, respectively. Prematures presented higher expression of IL-6 whereas term births showed higher expression of CRP. Cases classified as acute stress presented higher expression of IL-6 and TNF-α and cases with chronic stress presented higher expression of CRP. GA correlated negatively with IL-6 and positively with CRP and TNF-α. Body weight correlated negatively with IL-6 and positively with CRP and TNF-α. Despite the diagnosis of FIRS being clinical and based on serum parameters, the findings in the current study allow the inference of FIRS diagnosis in the autopsied infants, based on an in situ liver analysis of these markers.

Hypertonic saline solution reduces the inflammatory response in endotoxemic rats

OBJECTIVE: Volume replacement in septic patients improves hemodynamic stability. This effect can reduce the inflammatory response. The objective of this study was to evaluate the effect of 7.5% hypertonic saline solution versus 0.9% normal saline solution for volume replacement during an inflammatory response in endotoxemic rats. METHODS: We measured cytokines (serum and gut), nitrite, and lipid peroxidation (TBARS) as indicators of oxidative stress in the gut. Rats were divided into four groups: control group (C) that did not receive lipopolysaccharide; lipopolysaccharide injection without treatment (LPS); lipopolysaccharide injection with saline treatment (LPS +S); and lipopolysaccharide injection with hypertonic saline treatment (LPS +H). Serum and intestine were collected. Measurements were taken at 1.5, 8, and 24 h after lipopolysaccharide administration. RESULTS: Of the four groups, the LPS +H group had the highest survival rate. Hypertonic saline solution treatment led to lower levels of IL-6, IL-10, nitric oxide, and thiobarbituric acid reactive substances compared to 0.9% normal saline. In addition, hypertonic saline treatment resulted in a lower mortality compared to 0.9% normal saline treatment in endotoxemic rats. Volume replacement reduced levels of inflammatory mediators in the plasma and gut. CONCLUSION: Hypertonic saline treatment reduced mortality and lowered levels of inflammatory mediators in endotoxemic rats. Hypertonic saline also has the advantage of requiring less volume replacement.

Characterization of pulmonary and systemic inflammatory responses produced by lung re-expansion after one-lung ventilation.

OBJECTIVES: To characterize the pulmonary and systemic inflammatory responses of rats undergoing 1-hour or 3-hour one-lung ventilation (OLV) with subsequent 1-hour lung re-expansion. DESIGN: A prospective, randomized, controlled animal experiment. SETTING: University laboratory. PARTICIPANTS: Thirty male Wistar rats were used. INTERVENTIONS: Rats were subjected to 1- or 3-hour OLV followed or not by 1-hour lung re-expansion. Control rats received no ventilation. MEASUREMENTS AND MAIN RESULTS: Pulmonary protein extravasation, pulmonary myeloperoxidase (MPO) activity, cytokine levels in serum and bronchoalveolar lavage (BAL), counts of total and differential cells in BAL fluid, gasometric data, and mean arterial blood pressure (MABP) were all evaluated. Bronchial occlusion for 1 or 3 hours with no lung re-expansion did not significantly change the protein extravasation in the right and left lungs compared with the control group. However, rats submitted to 1- or 3-hour OLV followed by lung re-expansion exhibited pulmonary edema formation and neutrophil recruitment as well as a higher MPO activity in comparison with control rats. Increased levels of interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α in BAL fluid were observed. Increased levels of IL-6 and IL-10 in serum also were detected. Blood gas and MABP did not differ between groups. CONCLUSIONS: Lung re-expansion after bronchial occlusion evokes an acute lung inflammatory response, which has been shown to be more pronounced in long periods of bronchial occlusion in terms of cytokine inflammatory response. In addition, the magnitude of this inflammatory response also can be detected systemically.

Hypertonic saline solution reduces the inflammatory response in endotoxemic rats.

OBJECTIVE: Volume replacement in septic patients improves hemodynamic stability. This effect can reduce the inflammatory response. The objective of this study was to evaluate the effect of 7.5% hypertonic saline solution versus 0.9% normal saline solution for volume replacement during an inflammatory response in endotoxemic rats. METHODS: We measured cytokines (serum and gut), nitrite, and lipid peroxidation (TBARS) as indicators of oxidative stress in the gut. Rats were divided into four groups: control group (C) that did not receive lipopolysaccharide; lipopolysaccharide injection without treatment (LPS); lipopolysaccharide injection with saline treatment (LPS +S); and lipopolysaccharide injection with hypertonic saline treatment (LPS +H). Serum and intestine were collected. Measurements were taken at 1.5, 8, and 24 h after lipopolysaccharide administration. RESULTS: Of the four groups, the LPS +H group had the highest survival rate. Hypertonic saline solution treatment led to lower levels of IL-6, IL-10, nitric oxide, and thiobarbituric acid reactive substances compared to 0.9% normal saline. In addition, hypertonic saline treatment resulted in a lower mortality compared to 0.9% normal saline treatment in endotoxemic rats. Volume replacement reduced levels of inflammatory mediators in the plasma and gut. CONCLUSION: Hypertonic saline treatment reduced mortality and lowered levels of inflammatory mediators in endotoxemic rats. Hypertonic saline also has the advantage of requiring less volume replacement.

Lipopolysaccharide signaling in the carotid chemoreceptor pathway of rats with sepsis syndrome.

In addition to their role in cardiorespiratory regulation, carotid body (CB) chemoreceptors serve as sensors for inflammatory status and as a protective factor during sepsis. However, lipopolysaccharide-induced sepsis (LPS) reduces CB responsiveness to excitatory or depressant stimuli. We tested whether LPS exerts a direct effect on the carotid chemoreceptor pathway, the CB and its sensory ganglion. We determined that the rat CB and nodose-petrosal-jugular ganglion complex (NPJgc) express TLR4, TNF-α and its receptors (TNF-R1 and TNF-R2). LPS administration (15mg/kg intraperitoneally) evoked MyD88-mechanism pathway activation in CB and NPJgc, with NF-κB p65, p38 MAPK, and ERK activation. Consistently, LPS increased TNF-α and TNF-R2. Double-labeling studies showed that the aforementioned pathway occurs in TH-containing glomus cells and NPJgc neurons, components of the chemosensitive neural pathway. Thus, our results suggest that LPS acting directly through TLR4/MyD88-mechanism pathways increases TNF-α and TNF-R2 expression in the carotid chemoreceptor pathway. These results show a novel afferent pathway to the central nervous system during endotoxemia, and could be relevant in understanding sepsis pathophysiology and therapy.

[Selenium in critically ill patients with systemic inflammatory response]. / Selenio en los pacientes críticos con Respuesta Inflamatoria sistémica.

Selenium is an essential micronutrient for humans. Critically ill patients with Systemic Inflammatory Response Syndrome (SIRS) and Multiple Organ Dysfunction (MOD) -such as severe sepsis, trauma, severe pancreatitis and critical burns- are exposed to severe oxidative stress. These patients exhibit decreased serum Selenium and selenoenzymes like Glutathione Peroxidase and Selenoprotein P. Selenoenzymes play a major role in protecting cells against lipid peroxidation and they are involved in the inflammatory response regulation. The degree of selenium deficiency correlates with disease severity and the incidence of mortality. In the past years, some clinical trials have studied Selenium supplementation effects in critical illness with SIRS-MOD. This therapeutic strategy could improve the outcome and prognosis in critically ill patients. Few small trials have demonstrated Selenium supplementation beneficial effects, reducing the rate of infectious complications and length of hospital stay. However, no clinical trials using Selenium supplementation in high doses have yet demonstrated significant improvement in mortality. The aims of this review are to evaluate: a) Selenium metabolism, b) the role of selenoenzymes during critical illness, c) clinical studies using Selenium alone or in combination with other antioxidants in critically ill patients and d) to analyze current parenteral Selenium replacement strategies and their results. Further multicentre, well designed randomized, double blind clinical trials about Selenium supplementation in critically ill patients with SIRS and MODS are required and appear to be attractive, necessary and challenging.

Increased susceptibility to septic and endotoxic shock in monocyte chemoattractant protein 1/cc chemokine ligand 2-deficient mice correlates with reduced interleukin 10 and enhanced macrophage migration inhibitory factor production.

The chemokine monocyte chemoattractant protein 1/CC chemokine ligand 2 (MCP-1/CCL2) is a potent chemoattractant of mononuclear cells and a regulatory mediator involved in a variety of inflammatory diseases. In the present study, we demonstrate that mcp-1/ccl2-deficient mice are more susceptible to systemic inflammatory response syndrome induced by lipopolysaccharide and to polymicrobial sepsis induced by cecum ligation and puncture (CLP) when compared with wild-type mice. Interestingly, in the CLP model, mcp-1/ccl2-deficient mice efficiently cleared the bacteria despite an impaired recruitment of leukocytes, especially mononuclear cells. The increased lethality rate in these models correlates with an impaired production of interleukin (IL) 10 in vivo. Furthermore, macrophages from mcp-1/ccl2-deficient mice activated with lipopolysaccharide also produced lower amounts of IL-10 and similar tumor necrosis factor compared with wild-type mice. We observed a drastic increase in the amounts of macrophage migration inhibitory factor at 6 and 24 h after CLP in mcp-1/ccl2-deficient mice. These results indicate that endogenous MCP-1/CCL2 positively regulates IL-10 but negatively controls macrophage migration inhibitory factor during peritoneal sepsis, thus suggesting an important immunomodulatory role for MCP-1/CCL2 in controlling the balance between proinflammatory and anti-inflammatory factors in sepsis.

Cytokine elaboration in critically ill infants with bacterial sepsis, necrotizing entercolitis, or sepsis syndrome: correlation with clinical parameters of inflammation and mortality.

OBJECTIVE: To test the hypothesis that cytokines might distinguish critically ill infants with bacterial sepsis or necrotizing enterocolitis (NEC) from those with sepsis syndrome and that these elevations would be correlated with clinical variables of inflammation and mortality. STUDY DESIGN: We measured plasma and tracheal aspirate (TA) levels of interleukin-8 (IL-8), epithelial neutrophil activating peptide (ENA-78), IL-10, and IL-18 in 84 neonates with suspected sepsis or NEC. Thirty-one infants had bacterial sepsis, 19 had NEC, and 34 infants with negative results on cultures had sepsis syndrome. RESULTS: Plasma IL-8 and IL-10 levels were significantly increased in infants with bacterial sepsis compared with those in infants with sepsis syndrome. Plasma IL-8, ENA-78, and IL-10 levels were elevated in infants with NEC compared with those in infants with sepsis syndrome. TA IL-8 and IL-10 levels were also increased in infants with bacterial sepsis; TA ENA-78, and IL-18 were not elevated in infants with sepsis or NEC when compared with infants with sepsis syndrome. Plasma and TA cytokine levels correlated with hematologic parameters. Plasma cytokine levels were higher in infants who did not survive than in infants who did survive. CONCLUSIONS: Plasma and TA cytokine levels are elevated in critically ill infants with bacterial sepsis or NEC compared with those in infants with sepsis syndrome. Our results suggest distinct patterns of cytokine elaboration in different disease states.

Alteraciones metabólicas asociadas a la sepsis: proteínas, lípidos y carbohidratos / Metabolic disorders associated with sepsis: proteins, lipids and carbohydrates

Para garantizar la función vital orgánica normalmente ofrecida por la absorción dietética es necesario disponer de un sustrato energético adecuado para mantener la homeostasis. Cuando los ingresos dietéticos no son adecuados, el organismo acude a fuentes alternativas de obtención de energía dadas por la gluconeogénesis, lipólisis y cetogénesis. A la interrupción de estas fuentes provisionales de sustratos de energía se asocia la sepsis. Se altera durante la sepsis la función de la vía glucolítica, cuya integridad es necesaria para utilizar adecuadamente la glucosa en la obtención de energía. Todas estas anomalías, unidas a las interrupciones de la maquinaria productora de energía intracelular (enzimas glucolíticas, gluconeogénesis y mitocondria) producen una reducción del adenosintrifosfato intracelular, cuestión que socava todas las funciones consumidoras de energía celular, incluyendo la formación de sustratos energéticos (gluconeogénesis fallida), producción antioxidante y homeostasis del calcio. Asimismo se conoce que el aumento de los niveles de calcio intracelular activa vías enzimáticas potencialmente destructivas, las cuales disminuyen más la función celular y logran provocar la muerte a este nivel. Puede así desempeñar la acumulación de calcio intracelular un importante rol en el progreso de la sepsis temprana a una disfunción múltiple de órganos, la causa más frecuente de mortalidad en las unidades de cuidados intensivos(AU)

Alteraciones metabólicas asociadas a la sepsis: proteínas, lípidos y carbohidratos / Metabolic disorders associated with sepsis: proteins, lipids and carbohydrates

Para garantizar la función vital orgánica normalmente ofrecida por la absorción dietética es necesario disponer de un sustrato energético adecuado para mantener la homeostasis. Cuando los ingresos dietéticos no son adecuados, el organismo acude a fuentes alternativas de obtención de energía dadas por la gluconeogénesis, lipólisis y cetogénesis. A la interrupción de estas fuentes provisionales de sustratos de energía se asocia la sepsis. Se altera durante la sepsis la función de la vía glucolítica, cuya integridad es necesaria para utilizar adecuadamente la glucosa en la obtención de energía. Todas estas anomalías, unidas a las interrupciones de la maquinaria productora de energía intracelular (enzimas glucolíticas, gluconeogénesis y mitocondria) producen una reducción del adenosintrifosfato intracelular, cuestión que socava todas las funciones consumidoras de energía celular, incluyendo la formación de sustratos energéticos (gluconeogénesis fallida), producción antioxidante y homeostasis del calcio. Asimismo se conoce que el aumento de los niveles de calcio intracelular activa vías enzimáticas potencialmente destructivas, las cuales disminuyen más la función celular y logran provocar la muerte a este nivel. Puede así desempeñar la acumulación de calcio intracelular un importante rol en el progreso de la sepsis temprana a una disfunción múltiple de órganos, la causa más frecuente de mortalidad en las unidades de cuidados intensivos

Intestinal permeability and systemic infections in critically ill patients: effect of glutamine.

OBJECTIVE: This article provides a critical review of the evidence indicating that an increase in intestinal permeability is associated with the installation of bacteremia, sepsis, and the multiple organ failure syndrome and that glutamine in pharmacologic doses reduces the acute increase of intestinal permeability and the infection frequency in critically ill patients. DATA SOURCE: All studies published until December 2004 about intestinal permeability, bacterial translocation, and glutamine were located by search of PubMed and Web of Science. The reference lists of review articles and primary publications were also examined to identify references not detected in the computer search. STUDY SELECTION: Clinical and experimental studies investigating the correlation between intestinal permeability, bacterial translocation, and frequency of infections, associated or not with the effect of glutamine administration. DATA EXTRACTION: Information regarding patient population, experimental design, glutamine doses and routes of administration, nutritional therapy prescribed, methods used to assess intestinal permeability, metabolic variables, and the frequency of infections were obtained from the primary literature. DATA SYNTHESIS: Intestinal permeability is increased in critically ill patients. The results have not always been consistent, but the studies whose results support the association between intestinal permeability and systemic infections have had better design and more appropriate controls. The administration of glutamine by the intravenous or oral route and at the doses recommended before or immediately after surgery, burns, or the administration of parenteral nutrition has a protective effect that prevents or reduces the intensity of the increase in intestinal permeability. Glutamine reduces the frequency of systemic infections and may also reduce the translocation of intestinal bacteria and toxins, but this has not been demonstrated. CONCLUSIONS: Glutamine administration improves the prognosis of critically ill patients presumably by maintaining the physiologic intestinal barrier and by reducing the frequency of infections.

Síndrome da resposta inflamatória sistêmica na circulaçäo extracorpórea: papel das interleucinas / Systemic inflammatory response syndrome in the extracorporeal circulation: role of the interleukins

A síndrome da resposta inflamatória sistêmica (SIRS) na cirurgia cardíaca ocorre, com maior freqüência, com o uso da CEC. Isto se deve ao contato do sangue com superfícies näo endoteliais e, mais tarde, à reperfusäo. Esse contato leva à liberaçäo de componentes moleculares, dos quais as anafilotoxinas ativadas pelo fator de complemento, que estimulam a liberaçäo de citocinas pró-inflamatórias, tais como a IL-1, IL-6, FNT-a. Estas interleucinas säo responsáveis por induçäo de febre, neutrofilia, com aumento da adesividade entre neutrófilos e miócitos e/ou endotélio, e agem de forma sinergética estimulando a produçäo de outras interleucinas pelos monócitos e leucócitos (IL-6, IL-8). Observa-se que a isquemia intestinal, decorrente do uso da CEC, ocasiona a produçäo de IL-6, FNT-a, IL-1 no epitélio intestinal, e a reperfusäo pós-CEC provoca a expressäo de IL-1 e FNT-a no endotélio microvascular e pode gerar uma disfunçäo que danifica os cardiomiócitos. Seguindo a cascata de reaçöes pós- CEC, a síndrome do distress respiratório do adulto é mediada pela IL-8, encontrada a nível alveolar. Cérebro e fígado também podem ser afetados pelos fenômenos causados pela isquemia/reperfusäo e se demonstra que as interlucinas, uma vez mais (IL-8 e IL-13, respectivamente), têm um papel importante na série de eventos que ocorre. As técnicas de CEC bem como a anestesia podem influenciar a atividade das interleucinas. Näo há um consenso sobre terapias preventivas ou de tratamento das complicaçöes advindas da SIRS. Intervençäo a nível dos mediadores da inflamaçäo, procedimento de descontaminaçäo digestiva, uso de drogas como a indometacina ou esteróides säo opçöes possíveis. A regulaçäo do processo inflamatório, de um modo geral, depende do equilíbrio entre citocinas pró- e anti-inflamatórias. Estas últimas säo detectáveis no indivíduo normal, enquanto que as pró-inflamatórias apenas se manifestam localmente ou säo quase inexistentes. Conclui-se que, o aumento da concentraçäo das interleucinas pró-inflamatórias no organismo é um fato esperado, em grandes cirurgias, e que trará complicaçöes se este aumento for exacerbado e se o organismo estiver muito debilitado

[Study of cytokines kinetics in severe sepsis and its relationship with mortality and score of organic dysfunction]. / Estudio de la cinética de citoquinas en sepsis grave y su relación con mortalidad y score de disfunción orgánica.

BACKGROUND: The Infectious Systemic Inflammatory Response syndrome and multiple organic dysfunction have common physiopathological mechanisms. Multiple organic dysfunction can be assessed using severity scores. AIM: To relate cytokine kinetics with a multiple organic dysfunction score during sepsis. MATERIAL AND METHODS: Tumor necrosis factor alpha (TNF alpha) and interleukin 6 (IL6) kinetics were studied in 25 patients with severe sepsis with less than 48 h of evolution and interleukin 1 beta (IL beta) kinetics was studied in 13 patients. Measurements were made at 0, 12, 24 and 48 hours after admission to the study, using an ELISA technique. These parameters were correlated with the Marshall multiple organic dysfunction score and survival. RESULTS: Mean age of study subjects was 70 years, the APACHE II score was 16.9 +/- 6 and the Marshall score was 6.8 +/- 3.6. Sepsis was of pulmonary origin in 56% of patients and intra abdominal in 32%. Mortality was 36%. TNF alpha increased during the study period (24.1 pg/ml initially and 37.8 pg/ml at 24 hours, with a slight posterior reduction, p < 0.02). These levels had no association with mortality or organic dysfunction. IL6 remained elevated during the first hours and had a tendency to decrease thereafter. Decreased patients had higher values than survivors (306 pg/ml and 55.4 pg/ml respectively, p = 0.011). Its values were tightly correlated with Marshall score, with the number of failing organs, with the presence of shock and with probability of dying during hospitalization. IL1 beta remained low and was not associated with clinical parameters. CONCLUSIONS: There is a tight correlation between the elevation of IL6 and the severity of the Systemic Inflammatory Response and mortality in these patients with sepsis.