Effect of lysed and non-lysed sickle red cells on the activation of NLRP3 inflammasome and LTB4 production by mononuclear cells.

OBJECTIVE AND DESIGN: This study tested the hypothesis that sickle red blood cell (SS-RBC) can induce inflammasome NLRP3 components gene expression in peripheral blood mononuclear cells (PBMCs) as well as interleukin-1ß (IL-1ß) and leukotriene B4 (LTB4) production. Additionally, we investigated the effect of hydroxyurea (HU) treatment in these inflammatory markers. METHODS: PBMCs from healthy donors (AA-PBMC) were challenged with intact and lysed RBCs from SCA patients (SS-RBC) and from healthy volunteers (AA-RBC). NLRP3, IL-1ß, IL-18 and Caspase-1 gene expression levels were assessed by quantitative PCR (qPCR). IL-1ß protein levels and LTB4 were measured by ELISA. RESULTS: We observed that lysed SS-RBC induced the expression of inflammasome NLRP3 components, but this increase was more prominent for CASP1 and IL18 expression levels. Moreover, we observed that intact SS-RBC induced higher production of IL-1ß and LTB4 than lysed SS-RBC. Although SCA patients treated with HU have a reduction in NLRP3 gene expression and LTB4 production, this treatment did not modulate the expression of other inflammasome components or IL-1ß production. CONCLUSIONS: Thus, our data suggest that caspase-1, IL-1ß and IL-18 may contribute to the inflammatory status observed in SCA and that HU treatment may not interfere in this inflammatory pathway.

Elevated manganese exposure and school-aged children's behavior: a gender-stratified analysis.

High levels of waterborne manganese have been associated with problematic behavior in school-aged children, however to date this has not been reported for children exposed to airborne manganese. The objective of the present study was to examine behavioral traits among children with exposure to airborne manganese from a ferro-manganese alloy plant, located in the metropolitan region of Salvador, Brazil. The study included 34 boys and 36 girls, aged 7-12 years, living in two communities within a 3-km radius from the plant. For each child, hair manganese levels (MnH) and blood lead (PbB) levels were analyzed by graphite furnace atomic absorption spectrometry. The Children's Behavior Check List (CBCL) (Portuguese version validated in Brazil) was administered to parents or caregivers, providing scale scores of internalizing (withdrawn, somatic complaints, and anxious/depressed scales), externalizing (disruptive and aggressive) behaviors and a separate scale for attention problems. Median and range for MnH and PbB were 11.48 µg/g (range: 0.52-55.74); 1.1 µg/dL (range: 0.5-6.1), respectively. Spearman correlation analyses showed that several behavioral indices were significantly correlated with MnH levels for girls, but not for boys: total externalizing behavior (rho=0.484 vs rho=0.041) and attention problem scores (rho=0.542 vs rho=0.003) coefficients were significantly at p<0.001 level, respectively for girls and boys. No significant correlation was observed with any of the internalizing sub-scales. A linear regression model was fitted with the total externalizing behavior, inattention and total CBCL scores as dependent variables, with log transformed MnH stratified by sex, adjusting for age and maternal IQ. Total externalizing behaviors and attention problem scores were significantly associated with girls' MnH levels but not with boys'. Adjusting for maternal IQ, the ß-coefficients for LogMnH associations with total externalizing and attention problems are 8.85 (95%CI 2.44-15.24) and 4.03 (95%CI 1.50-6.56) for girls. For boys, after adjusting for age, the ß-coefficients are 0.08 (95%CI 11.51-11.66) and -0.05 (95%CI 4.34-4.25), respectively. The findings of this study suggest a positive association between elevated Mn exposure and externalizing behavioral problems and inattention, with girls presenting more pronounced effects. Future studies on Mn exposure in children should attempt to further elucidate sex and/or gender differences in Mn exposed populations.