Sepsis is a systemic inflammatory condition following bacterial infection with a high mortality rate and limited therapeutic options. Here we show that interleukin-33 (IL-33) reduces mortality in mice with experimental sepsis from cecal ligation and puncture (CLP). IL-33-treated mice developed increased neutrophil influx into the peritoneal cavity and more efficient bacterial clearance than untreated mice. IL-33 reduced the systemic but not the local proinflammatory response, and it did not induce a T helper type 1 (T(H)1) to T(H)2 shift. The chemokine receptor CXCR2 is crucial for recruitment of neutrophils from the circulation to the site of infection. Activation of Toll-like receptors (TLRs) in neutrophils downregulates CXCR2 expression and impairs neutrophil migration. We show here that IL-33 prevents the downregulation of CXCR2 and inhibition of chemotaxis induced by the activation of TLR4 in mouse and human neutrophils. Furthermore, we show that IL-33 reverses the TLR4-induced reduction of CXCR2 expression in neutrophils via the inhibition of expression of G protein-coupled receptor kinase-2 (GRK2), a serine-threonine protein kinase that induces internalization of chemokine receptors. Finally, we find that individuals who did not recover from sepsis had significantly more soluble ST2 (sST2, the decoy receptor of IL-33) than those who did recover. Together, our results indicate a previously undescribed mechanism of action of IL-33 and suggest a therapeutic potential of IL-33 in sepsis.

This article reports the spread of bla KPC-2 in the Sao Paulo and Rio de Janeiro states, facilitated by globally spread K. pneumoniae clonal complex 258 (CC258) clones (ST258, ST11, and ST437) and a diversity of plasmids (IncFII, IncN, and IncL/M, two untypeable plasmids carrying Tn4401a or Tn4401b) successfully disseminated among species of the Enterobacteriaceae (Enterobacter cloacae, Serratia marcescens, and Citrobacter freundii). It also constitutes the first description of sequence type 258 (ST258) in Brazil, which was associated with a nosocomial hospital outbreak in Ribeirao Preto city.

Collectively, these data identify CCR2 as a key receptor that drives the inappropriate infiltration of neutrophils into remote organs during sepsis. Therefore, CCR2 blockade is a novel potential therapeutic target for treatment of sepsis-induced MODS.

The deregulation of inflammatory response during sepsis seems to reflect the overproduction of mediators, which suppress leukocyte functions. We investigated the intracellular mechanisms underlying the inability of neutrophils from severe septic patients to migrate toward chemoattractants. Patients IntroductionSepsis is a complex clinical syndrome resulting from a damaging host response to infection. 1 In the United States, more than 700 000 patients per year develop sepsis, with mortality rates reported to vary between 30% and 70%, despite the best available supportive care. 2 Polymorphonuclear neutrophils (PMNs) play the first line in the host defense against microorganisms, being recruited to the inflammatory sites by chemoattractants such as leukotriene B 4 (LTB 4 ) and chemokines. 3,4 Once emigrated, these leukocytes are able to phagocytose and to generate large amounts of reactive oxygen and nitrogen species, such as hydrogen peroxide and nitric oxide, which are crucial products for the microbicidal activity of these cells. 5,6 As neutrophils appear to play a crucial role in the control of the infectious process, one can hypothesize that a deficient migratory ability of neutrophils may aggravate infections. Indeed, impairment of neutrophil migration has been reported in leukemia, 7 diabetes, 8 and AIDS, 9 diseases associated with high susceptibility to infection. Furthermore, previous studies from our group showed that failure of neutrophil migration is observed in severe sepsis induced by cecal ligation and puncture and Staphylococcus aureus administration. 10,11 In these lethal models, failure of neutrophil migration to the site of infection was accompanied by increased numbers of bacteria in the peritoneal fluid and blood. Conversely, in sublethal infection in which massive neutrophil migration was observed, bacterial infection was restricted to the peritoneal cavity, and the animals exhibited a low mortality rate. 10,11 More recently, we have also reported that blood neutrophils obtained from patients with sepsis failed to respond in vitro to the chemotactic stimuli FMLP and LTB 4 . This unresponsiveness was directly associated to a poor prognosis. 12 Evidence from literature suggests that the high levels of circulating cytokines/chemokines observed in severe sepsis may mediate the impairment of neutrophil migration, in addition to being involved in the deleterious physiopathologic findings of the disease, such as coagulation disorders, cardiovascular collapse, and organ failure. 13 The intravenous administration of tumor necrosis factor-␣ (TNF-␣) or interleukin-8 (IL-8) inhibited neutrophil migration to mouse peritoneal cavity and anti-TNF-␣ antibody partially prevented the inhibition of neutrophil migration in endotoxemia model. 14 However, the molecular mechanisms involved in the reduced ability of neutrophils to migrate during sepsis were not completely clarified.Independent of their chemical nature, most chemoattractants exert their action via binding to specific G protein-coupled receptors (GP...

Brazilian Clinical Trials Registry, affiliated with the World Health Organization's International Clinical Trial Registry Platform: U1111-1152-2671.

Oral application of a 0.12% solution of chlorhexidine does not prevent respiratory tract infections among ICU patients, although it may retard their onset.

The reduction of circulating neutrophil migration to infection sites is associated with a poor outcome of severe sepsis. ␣-1-Acid glycoprotein (AGP) was isolated from the sera of severely septic patients by HPLC and acrylamide gel electrophoresis and identified by mass spectrometry. Both the isolated protein and commercial AGP inhibited carrageenin-induced neutrophil migration into the rat peritoneal cavity when administered i.v. at a dose of 4.0 g per rat (95 pmol per rat). Analysis by intravital microscopy demonstrated that both proteins inhibited the rolling and adhesion of leukocytes in the mesenteric microcirculation. The inhibitory activity was blocked by 50 mg/kg aminoguanidine, s.c., and was not demonstrable in inducible nitric oxide synthase (iNOS) knockout mice. Incubation of AGP with neutrophils from healthy subjects induced the production of NO and inhibited the neutrophil chemotaxis by an iNOS/NO/cyclic guanosine 3,5-monophosphatedependent pathway. In addition, AGP induced the L-selectin shedding by neutrophils. The administration of AGP to rats with mild cecal ligation puncture sepsis inhibited neutrophil migration and reduced 7-day survival from Ϸ80% to 20%. These data demonstrate that AGP, an acute-phase protein, inhibits neutrophil migration by an NO-dependent process and suggest that AGP also participates in human sepsis.

Several prognostic indices have been employed to predict the outcome of surgical critically ill patients. Among them, acute physiology and chronic health evaluation (APACHE) II, sequential organ failure assessment (SOFA) and simplified acute physiology score (SAPS 3) are widely used. It seems that biological markers such as C-reactive protein (CRP), albumin, and blood lactate levels correlate with the degree of inflammation during the immediate postoperative phase and could be used as independent predictors. The objective of this study is to compare the different predictive values of prognostic indices and biological markers in the outcome of 847 surgical patients admitted to the intensive care unit (ICU) in the postoperative phase. The patients were divided into survivors (n = 765, 57.4% males, age 61, interquartile range 51–71) and nonsurvivors (n = 82, 57.3% males, age 70, interquartile range 58–79). APACHE II, APACHE II death probability (DP), SOFA, SAPS 3, SAPS 3 DP, CRP, albumin, and lactate were recorded on ICU admission (first 24 hours). The area under the ROC curve (AUROC) and 95% confidence interval (95% CI) were used to measure the index accuracy to predict mortality. The AUROC and 95% CI for APACHE II, APACHE II DP, SOFA, SAPS 3, SAPS 3 DP, CRP/albumin ratio, CRP, albumin, and lactate were 0.850 (0.824–0.873), 0.855 (0.829–0.878), 0.791 (0.762–0.818), 0.840 (0.813–0.864), 0.840 (0.813–0.864), 0.731 (0.700–0.761), 0.708 (0.676–0.739), 0.697 (0.665–0.728), and 0.601 (0.567–0.634), respectively. The ICU and overall in-hospital mortality were 6.6 and 9.7%, respectively. The APACHE II, APACHE II DP, SAPS 3, SAPS 3 DP, and SOFA scores showed a better performance than CRP/albumin ratio, CRP, albumin, or lactate to predict in-hospital mortality of surgical critically ill patients. Even though all indices were able to discriminate septic from nonseptic patients, only APACHE II, APACHE II DP, SOFA and to a lesser extent SAPS 3, SAPS 3 DP, and blood lactate levels could predict in the first 24-hour ICU admission surgical patients who have survived sepsis.