Patients who survive sepsis can develop long-term immune dysfunction, with expansion of the regulatory T (Treg) cell population. However, how Treg cells proliferate in these patients is not clear. ...Here we show that IL-33 has a major function in the induction of this immunosuppression. Mice deficient in ST2 (IL-33R) develop attenuated immunosuppression in cases that survive sepsis, whereas treatment of naive wild-type mice with IL-33 induces immunosuppression. IL-33, released during tissue injury in sepsis, activates type 2 innate lymphoid cells, which promote polarization of M2 macrophages, thereby enhancing expansion of the Treg cell population via IL-10. Moreover, sepsis-surviving patients have more Treg cells, IL-33 and IL-10 in their peripheral blood. Our study suggests that targeting IL-33 may be an effective treatment for sepsis-induced immunosuppression.
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Sepsis is one of the main causes of mortality in hospitalized patients. Despite the recent technical advances and the development of novel generation of antibiotics, severe sepsis ...remains a major clinical and scientific challenge in modern medicine. Unsuccessful efforts have been dedicated to the search of therapeutic options to treat the deleterious inflammatory components of sepsis. Recent findings on neuronal networks controlling immunity raised expectations for novel therapeutic strategies to promote the regulation of sterile inflammation, such as autoimmune diseases. Interesting studies have dissected the anatomical constituents of the so-called “cholinergic anti-inflammatory pathway”, suggesting that electrical vagus nerve stimulation and pharmacological activation of beta-2 adrenergic and alpha-7 nicotinic receptors could be alternative strategies for improving inflammatory conditions. However, the literature on infectious diseases, such as sepsis, is still controversial and, therefore, the real therapeutic potential of this neuroimmune pathway is not well defined. In this review, we will discuss the beneficial and detrimental effects of neural manipulation in sepsis, which depend on the multiple variables of the immune system and the nature of the infection. These observations suggest future critical studies to validate the clinical implications of vagal parasympathetic signaling in sepsis treatment.
Although antibiotic-induced dysbiosis has been demonstrated to exacerbate intestinal inflammation, it has been suggested that antibiotic prophylaxis may be beneficial in certain clinical conditions ...such as acute pancreatitis (AP). However, whether broad-spectrum antibiotics, such as meropenem, influence the dissemination of multidrug-resistant (MDR) bacteria during severe AP has not been addressed. In the currently study, a mouse model of obstructive severe AP was employed to investigate the effects of pretreatment with meropenem on bacteria spreading and disease outcome. As expected, animals subjected to biliopancreatic duct obstruction developed severe AP. Surprisingly, pretreatment with meropenem accelerated the mortality of AP mice (survival median of 2 days) when compared to saline-pretreated AP mice (survival median of 7 days). Early mortality was associated with the translocation of MDR strains, mainly
into the blood stream. Induction of AP in mice with guts that were enriched with
recapitulated the increased mortality rate observed in the meropenem-pretreated AP mice. Furthermore, naïve mice challenged with a mouse or a clinical strain of
succumbed to infection through a mechanism involving toll-like receptor-2. These results confirm that broad-spectrum antibiotics may lead to indirect detrimental effects during inflammatory disease and reveal an intestinal pathobiont that is associated with the meropenem pretreatment during obstructive AP in mice.
Sepsis is an overwhelming systemic inflammation resulting from an uncontrolled infection that causes extensive tissue damage, organ dysfunction and eventually death. A growing body of evidence ...indicates that impaired neutrophil migration to the site of infection is associated with poor outcome in sepsis. Here we show that galectin-3 (Gal-3), an endogenous glycan-binding protein, plays a critical role in sepsis outcome. We found that serum Gal-3 concentration increased in patients with septic shock and mice undergoing sepsis induced by cecal ligation and puncture (CLP). Mice deficient in Gal-3 (Gal-3 KO) are more resistant to sepsis induced by CLP, showing lower levels of biochemical markers and neutrophil infiltration for organ injury/dysfunction than those observed in wild-type mice (WT). Furthermore, Gal-3 KO mice show an increased number of neutrophils in the primary focus of infection and reduced bacterial loads in the peritoneal cavity, blood, and lungs. Mechanistically, blood neutrophils from septic mice show higher levels of surface-bound Gal-3 than neutrophils from naive mice. The deficiency of Gal-3 was associated with increased rolling and adhesion of these cells in mesenteric venules. Our results indicate that Gal-3, secreted during sepsis, inhibits neutrophil migration into the infectious focus, which promotes the bacterial spread and worsens the outcome of sepsis.
Several emerging lines of evidence support an anti-inflammatory role for nicotinamide and other vitamin B components. However, the mechanisms underlying their activity remain unclear. In the present ...study, we investigated the ability of nicotinamide to inhibit both neutrophil recruitment in IL-8-, LTB4- or carrageenan-induced pleurisy in mice and the rolling and adherence of neutrophils. Nicotinamide inhibited IL-8-, LTB4- and carrageenan-induced neutrophil migration, KC production and carrageenan-induced neutrophil rolling and adherence. We propose that the effects of nicotinamide in inhibiting neutrophil recruitment in carrageenan-induced pleurisy may be due to the ability of nicotinamide to inhibit the action of IL-8 and LTB4, decrease KC production, and inhibit early events that regulate leukocyte migration from blood vessels into tissue.
Sepsis is a lethal syndrome characterized by systemic inflammation and abnormal coagulation. Despite therapeutic advances, sepsis mortality remains substantially high. Herein, we investigated the ...role of the plasminogen/plasmin (Plg/Pla) system during sepsis. Plasma levels of Plg were significantly lower in mice subjected to severe compared with nonsevere sepsis, whereas systemic levels of IL-6, a marker of sepsis severity, were higher in severe sepsis. Plg levels correlated negatively with IL-6 in both septic mice and patients, whereas plasminogen activator inhibitor-1 levels correlated positively with IL-6. Plg deficiency render mice susceptible to nonsevere sepsis induced by cecal ligation and puncture (CLP), resulting in greater numbers of neutrophils and M1 macrophages, liver fibrin(ogen) deposition, lower efferocytosis, and increased IL-6 and neutrophil extracellular trap (NET) release associated with organ damage. Conversely, inflammatory features, fibrin(ogen), and organ damage were substantially reduced, and efferocytosis was increased by exogenous Pla given during CLP- and LPS-induced endotoxemia. Plg or Pla protected mice from sepsis-induced lethality and enhanced the protective effect of antibiotics. Mechanistically, Plg/Pla-afforded protection was associated with regulation of NET release, requiring Pla-protease activity and lysine binding sites. Plg/Pla are important host-protective players during sepsis, controlling local and systemic inflammation and collateral organ damage.
Although in vitro studies have shown that nicotinic acid inhibits some aspects of the inflammatory response, a reduced number of in vivo studies have investigated this activity. To the best of our ...knowledge, the effects induced by nicotinic acid in models of nociceptive and inflammatory pain are not known. Per os (p.o.) administration of nicotinic acid (250, 500 or 1000mg/kg, −1h) inhibited the first and the second phases of the nociceptive response induced by formalin in mice. Nicotinic acid (250 or 500mg/kg, −1 and 3h) also inhibited the mechanical allodynia induced by carrageenan in rats, a model of inflammatory pain. However, in a model of nociceptive pain, exposure of mice to a hot-plate, nicotinic acid was devoid of activity. In addition to inhibiting the nociceptive response in models of inflammatory pain, nicotinic acid (250 or 500mg/kg, p.o., −1 and 3h) inhibited paw edema induced by carrageenan in mice and rats. Picolinic acid (62.5 or 125mg/kg, p.o., −1h), a nicotinic acid isomer, inhibited both phases of the nociceptive response induced by formalin, but not paw edema induced by carrageenan in mice. The other nicotinic acid isomer, isonicotinic acid, was devoid of activity in these two models. In conclusion, our results represent the first demonstration of the activity of nicotinic acid in experimental models of nociceptive and inflammatory pain and also provide further support to its anti-inflammatory activity. It is unlikely that conversion to nicotinamide represents an important mechanism to explain the antinociceptive and anti-inflammatory activities of nicotinic acid. The demonstration of new activities of nicotinic acid, a drug that has already been approved for clinical use and presents a positive safety record, may contribute to raise the interest in conducting clinical trials to investigate its usefulness in the treatment of painful and inflammatory diseases.
► Nicotinic acid exhibits antinociceptive activity in a model of inflammatory pain. ► Nicotinic acid exhibits anti-inflammatory activity. ► Picolinic acid also exhibits antinociceptive activity.
O objetivo deste trabalho foi avaliar as principais características dendrométricas como o diâmetro, a altura e a forma e avaliar modelos para estimar o volume total de árvores de paricá (Schizolobium ...amazonicum Huber ex. Ducke) em plantios comerciais com idades de cinco, seis e sete anos, em espaçamento 4 x 4 m, na região de Paragominas, PA. A seleção dos modelos tomou como base medidas de qualidade de ajuste, como R2, erro padrão das estimativas, bem como a análise gráfica dos resíduos. Em relação às características dendrométricas, os resultados obtidos mostraram que o paricá apresentou medidas dendrométricas semelhantes quando comparado ao eucalipto em condições parecidas. A paricá teve um crescimento tanto em diâmetro quanto em altura semelhante a espécies de rápido crescimento. Quanto às equações de volume total, de modo geral, o modelo de Schumacher e Hall apresentou estimativas mais precisas na estimação do volume das árvores.
The aim of this study was to evaluate the main dendrometric characteristics of paricá (Schizolobium amazonicum Huber ex. Ducke), such as diameter, height and form, and also test models to estimate the total volume of paricá trees in commercial plantations with five, six and seven years of age, in a 4 m x 4 m spacing, in the region of Paragominas, Pará, Brazil. The models selection was based on goodness-of-fit indicators, such as R2, standard error of estimates, as well as the residual graphical analysis. Regarding the dendrometrical characteristics, results showed that the paricá trees presented similar dendrometrical measures when compared to eucalyptus in similar conditions. The paricá had a similar growth in both diameter and height to fast-growth species. As for the equations of total volume, generally, Schumacher and Hall’s model showed the best results to estimate the individual tree volume.
The natural ecosystems provide services that are crucial for our survival as climate control, food and water security. A very persistent pattern is loss of biodiversity caused by human activities all ...over the world, mainly due to deforestation and agricultural expansion. One very important challenge for human societies is to find the equilibrium between economic growth and environmental sustainability. In this contribution we address the role developed by spatial heterogeneity due to resource distribution and fragmentation on the species diversity. We propose a spatial model in which species compete on a lattice that is divided in habitats containing different amount of resources. The landscape here is a fractal structure which changes gradually from highly fragmented to highly clumped. Fractal landscapes are constructed through the use of fractional Brownian motion and characterized by the Hurst exponent. We found from our simulation results that there is an optimum number of habitats in which the fragmentation level has no effect. As habitat number drift away from optimal value, fragmentation has a growing effect on biodiversity promotion, mostly for small values of the Hurst exponent H. We observed two power law regimes describing the species–area relationship, in which the exponent for small areas is always smaller than the one observed for large areas. We also observe for the majority of the cases we studied, that the value of species–area exponent in both regimes grows with the number of habitats and then drops when the number of habitats becomes large. The number of habitats revealed to be the most important variable to foster and control the biodiversity in all scenarios.
•We use a spatial model with heterogeneity to study the effects of fragmentation on ecosystems.•Fragmentation is implemented by using fractal landscapes.•Fragmentation has little effect on diversity for intermediate heterogeneity.•The impact of fragmentation on diversity decreases when Hurst exponent is incremented.
Significance Methotrexate (MTX) is the first-line therapy for rheumatoid arthritis (RA). However, about 40% of patients are resistant to MTX. Furthermore, MTX resistance is only apparent after a ...prolonged continuous MTX treatment (>3 mo), by which time the disease of the nonresponders would have aggravated. Thus, there is a considerable unmet need for a biomarker to select MTX-resistant patients and place them immediately on alternative therapy. We found here that the low density of CD39 on peripheral regulatory T cells in RA patients is a rapid, convenient, and reliable ( P < 0.01) biomarker for MTX resistance. Our findings also provide previously unrecognized information on aspects of immune regulation in RA and the mechanism of action of MTX.
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by joint destruction and severe morbidity. Methotrexate (MTX) is the standard first-line therapy of RA. However, about 40% of RA patients are unresponsive to MTX treatment. Regulatory T cells (Tregs, CD4 ⁺CD25 ⁺FoxP3 ⁺) are thought to play an important role in attenuating RA. To investigate the role of Tregs in MTX resistance, we recruited 122 RA patients (53 responsive, R-MTX; 69 unresponsive, UR-MTX) and 33 healthy controls. Three months after MTX treatment, R-MTX but not UR-MTX showed higher frequency of peripheral blood CD39 ⁺CD4 ⁺CD25 ⁺FoxP3 ⁺ Tregs than the healthy controls. Tregs produce adenosine (ADO) through ATP degradation by sequential actions of two cell surface ectonucleotidases: CD39 and CD73. Tregs from UR-MTX expressed a lower density of CD39, produced less ADO, and had reduced suppressive activity than Tregs from R-MTX. In a prospective study, before MTX treatment, UR-MTX expressed a lower density of CD39 on Tregs than those of R-MTX or control ( P < 0.01). In a murine model of arthritis, CD39 blockade reversed the antiarthritic effects of MTX treatment. Our results demonstrate that MTX unresponsiveness in RA is associated with low expression of CD39 on Tregs and the decreased suppressive activity of these cells through reduced ADO production. Our findings thus provide hitherto unrecognized mechanism of immune regulation in RA and on mode of action of MTX. Furthermore, our data suggest that low expression of CD39 on Tregs could be a noninvasive biomarker for identifying MTX-resistant RA patients.
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