5-lipoxygenase-dependent recruitment of neutrophils and macrophages by eotaxin-stimulated murine eosinophils.

The roles of eosinophils in antimicrobial defense remain incompletely understood. In ovalbumin-sensitized mice, eosinophils are selectively recruited to the peritoneal cavity by antigen, eotaxin, or leukotriene(LT)B4, a 5-lipoxygenase (5-LO) metabolite. 5-LO blockade prevents responses to both antigen and eotaxin. We examined responses to eotaxin in the absence of sensitization and their dependence on 5-LO. BALB/c or PAS mice and their mutants (5-LO-deficient ALOX; eosinophil-deficient GATA-1) were injected i.p. with eotaxin, eosinophils, or both, and leukocyte accumulation was quantified up to 24 h. Significant recruitment of eosinophils by eotaxin in BALB/c, up to 24 h, was accompanied by much larger numbers of recruited neutrophils and monocytes/macrophages. These effects were abolished by eotaxin neutralization and 5-LO-activating protein inhibitor MK886. In ALOX (but not PAS) mice, eotaxin recruitment was abolished for eosinophils and halved for neutrophils. In GATA-1 mutants, eotaxin recruited neither neutrophils nor macrophages. Transfer of eosinophils cultured from bone-marrow of BALB/c donors, or from ALOX donors, into GATA-1 mutant recipients, i.p., restored eotaxin recruitment of neutrophils and showed that the critical step dependent on 5-LO is the initial recruitment of eosinophils by eotaxin, not the secondary neutrophil accumulation. Eosinophil-dependent recruitment of neutrophils in naive BALB/c mice was associated with increased binding of bacteria.

Essential roles of endogenous glucocorticoids and TNF/TNFR1 in promoting bone-marrow eosinopoiesis in ovalbumin-sensitized, airway-challenged mice.

AIMS: Stress mechanisms paradoxically contribute to allergic episodes in humans and mice. Glucocorticoids (GC) and interleukin (IL)-5 synergically upregulate murine bone-marrow eosinophil production. Here we explored the role of endogenous GC in allergen-stimulated bone-marrow eosinophil production in ovalbumin-sensitized/challenged mice. MAIN METHODS: In BALB/c or C57BL/6 mice, sensitized and intranasally challenged with ovalbumin, we monitored eosinophil numbers in freshly harvested or cultured bone-marrow, and plasma corticosterone levels. Metyrapone (MET) was used to inhibit GC synthesis, and RU486 to block GC actions. In sensitized mice challenged intraperitoneally, we examined the relationship between eosinophilia of bone-marrow and peritoneal cavity, in the absence or presence of RU486. In experiments involving in vivo neutralization of tumor necrosis factor-α (TNF) by specific antibodies, or using mice which lack functional type I TNF receptors (TNFRI), we evaluated the relationship between TNF blockade, corticosterone levels, RU486 or MET treatment and challenge-induced bone-marrow eosinophilia. KEY FINDINGS: RU486 or MET pretreatments abolished challenge-induced increases in eosinophil numbers in bone-marrow (in vivo and ex vivo), and in the peritoneal cavity. MET, but not RU486, prevented the challenge-induced increase in corticosterone levels. Challenge-induced bone-marrow eosinophilia and corticosterone surge were abolished in TNFRI-deficient mice. Anti-TNF-treatment very effectively prevented challenge-induced bone-marrow eosinophilia, in the absence of RU486 or MET, but had no independent effect in the presence of either drug. SIGNIFICANCE: Endogenous GC was essential for allergen challenge-induced increases in eosinophil numbers inside bone-marrow. This effect required TNF and TNFRI, which suggests an immunoendocrine mechanism.

Prediction of sepsis-related outcomes in neonates through systematic genotyping of polymorphisms in genes for innate immunity and inflammation: a narrative review and critical perspective.

CONTEXT AND OBJECTIVE: Neonatal sepsis is associated with premature birth and maternal infection. Large-scale studies seek to define markers that identify neonates at risk of developing sepsis. Here, we examine whether the scientific evidence supports systematic use of polymorphism genotyping in cytokine and innate immunity genes, to identify neonates at increased risk of sepsis. DESIGN AND SETTING: Narrative literature review conducted at Fernandes Figueira Institute, Brazil. METHODS: The literature was searched in PubMed, Embase (Excerpta Medica Database), Lilacs (Literatura Latino-Americana e do Caribe em Ciências da Saúde), SciELO (Scientific Electronic Library Online) and Cochrane Library. From > 400,000 references, 548 were retrieved based on inclusion/exclusion criteria; 22 were selected for detailed analysis after quality assessment. RESULTS: The studies retrieved addressed the impact of gene polymorphisms relating to immune mechanisms (most often TNF-a, LT-a, IL-6, IL-1ß, IL-1ra, L-selectin, CD14 and MBL) or inflammatory mechanisms (ACE and angiotensin II receptors; secretory PLA2; and hemostatic factors). Despite initial reports suggesting positive associations between specific polymorphisms and increased risk of sepsis, the accumulated evidence has not confirmed that any of them have predictive power to justify systematic genotyping. CONCLUSIONS: Sepsis prediction through systematic genotyping needs to be reevaluated, based on studies that demonstrate the functional impact of gene polymorphisms and epidemiological differences among ethnically distinct populations.

Prediction of sepsis-related outcomes in neonates through systematic genotyping of polymorphisms in genes for innate immunity and inflammation: a narrative review and critical perspective / Previsao de desfechos relacionados a sepse em neonatos atraves da genotipagem sistematica de polimorfismos de genes da imunidade inata e inflamacao: uma revisao narrativa e perspectiva critica

CONTEXT AND OBJECTIVE: Neonatal sepsis is associated with premature birth and maternal infection. Large-scale studies seek to define markers that identify neonates at risk of developing sepsis. Here, we examine whether the scientific evidence supports systematic use of polymorphism genotyping in cytokine and innate immunity genes, to identify neonates at increased risk of sepsis. DESIGN AND SETTING: Narrative literature review conducted at Fernandes Figueira Institute, Brazil. METHODS: The literature was searched in PubMed, Embase (Excerpta Medica Database), Lilacs (Literatura Latino-Americana e do Caribe em Ciências da Saúde), SciELO (Scientific Electronic Library Online) and Cochrane Library. From > 400,000 references, 548 were retrieved based on inclusion/exclusion criteria; 22 were selected for detailed analysis after quality assessment. RESULTS: The studies retrieved addressed the impact of gene polymorphisms relating to immune mechanisms (most often TNF-a, LT-a, IL-6, IL-1β, IL-1ra, L-selectin, CD14 and MBL) or inflammatory mechanisms (ACE and angiotensin II receptors; secretory PLA2; and hemostatic factors). Despite initial reports suggesting positive associations between specific polymorphisms and increased risk of sepsis, the accumulated evidence has not confirmed that any of them have predictive power to justify systematic genotyping. CONCLUSIONS: Sepsis prediction through systematic genotyping needs to be reevaluated, based on studies that demonstrate the functional impact of gene polymorphisms and epidemiological differences among ethnically distinct populations. .

CONTEXTO E OBJETIVO: A sepse neonatal está associada ao parto prematuro e à infecção materna. Estudos em grande escala buscam marcadores que identifiquem neonatos em risco de desenvolver sepse. Examinamos aqui se a evidência científica apoia o uso sistemático de genotipagem dos polimorfismos em genes de citocinas e imunidade inata, para identificar neonatos com risco elevado de sepse. TIPO DE ESTUDO E LOCAL: Revis ão narrativa da literatura, Instituto Fernandes Figueira, Brasil. M ÉTODOS: Busca online da literatura foi feita no PubMed, Embase (Excerpta Medica Database), Lilacs (Literatura Latino-Americana e do Caribe em Ciências da Saúde), SciELO (Scientific Electronic Library Online) e Cochrane Library. De mais de 400.000 referências, 548 foram recuperadas com base nos critérios de inclusão/exclusão, e 22, selecionadas para análise detalhada após verificação da qualidade. RESULTADOS: Recuperamos estudos de impacto dos polimorfismos em genes relacionados com mecanismos imunes (mais frequentemente, TNF-a, LT-a, IL-6, IL-1 β, IL-1ra, L-selectin, CD14, e MBL) ou inflamatórios (ACE e receptores de angiotensina II; PLA2 secretória; fatores hemostáticos). Contrariando estudos que inicialmente sugeriram associação positiva entre polimorfismos específicos e risco aumentado de sepse, a evidência acumulada não confirmou, para qualquer deles, valor preditivo que justifique genotipagem sistemática para orientar antibioticoterapia. CONCLUSÕES: A previsão da sepse por meio de genotipagem sistemática precisa ser reavaliada, com base em estudos que demonstram o impacto funcional de polimorfismos gênicos e as diferenças epidemiológicas entre populações etnicamente distintas. .

Distribution of bioelectrical impedance vector values in multi-ethnic infants and pre-school children.

BACKGROUND & AIMS: Ethnicity may influence bioimpedance values. The goal of this study was to measure total body impedance vector in infants and pre-school children in Brazil and compare them with those reported in other countries. METHODS: We analyzed bioelectrical impedance from a sample of 255 healthy Brazilian children, aged 1-36 months, using the RXc graph method (tetrapolar analysis at 50 kHz frequency). The 95%, 75% and 50% tolerance ellipses were plotted by age group. RESULTS: The mean impedance vector showed migration across age groups, with progressive higher reactances and lower resistances as age increased. The mean bioimpedance vectors from the present sample of Brazilian children were different from those of European children of the same age ranges. CONCLUSIONS: Our results confirm the importance of defining reference values of total body impedance vector for each country in view of the considerable ethnic diversity among different geographical areas.