Plasmodium berghei NK65 in Combination with IFN-γ Induces Endothelial Glucocorticoid Resistance via Sustained Activation of p38 and JNK.

Malaria-associated acute respiratory distress syndrome (MA-ARDS) is an often lethal complication of malaria. Currently, no adequate therapy for this syndrome exists. Although glucocorticoids (GCs) have been used to improve clinical outcome of ARDS, their therapeutic benefits remain unclear. We previously developed a mouse model of MA-ARDS, in which dexamethasone treatment revealed GC resistance. In the present study, we investigated GC sensitivity of mouse microvascular lung endothelial cells stimulated with interferon-γ (IFN-γ) and Plasmodium berghei NK65 (PbNK65). Upon challenge with IFN-γ alone, dexamethasone inhibited the expression of CCL5 (RANTES) by 90% and both CCL2 (MCP-1) and CXCL10 (IP-10) by 50%. Accordingly, whole transcriptome analysis revealed that dexamethasone differentially affected several gene clusters and in particular inhibited a large cluster of IFN-γ-induced genes, including chemokines. In contrast, combined stimulation with IFN-γ and PbNK65 extract impaired inhibitory actions of GCs on chemokine release, without affecting the capacity of the GC receptor to accumulate in the nucleus. Subsequently, we investigated the effects of GCs on two signaling pathways activated by IFN-γ. Dexamethasone left phosphorylation and protein levels of signal transducer and activator of transcription 1 (STAT1) unhampered. In contrast, dexamethasone inhibited the IFN-γ-induced activation of two mitogen-activated protein kinases (MAPK), JNK, and p38. However, PbNK65 extract abolished the inhibitory effects of GCs on MAPK signaling, inducing GC resistance. These data provide novel insights into the mechanisms of GC actions in endothelial cells and show how malaria may impair the beneficial effects of GCs

Plasmodium berghei NK65 in combination with IFN-γ induces endothelial glucocorticoid resistance via sustained activation of p38 and JNK

Malaria-associated acute respiratory distress syndrome (MA-ARDS) is an often lethal complication of malaria. Currently, no adequate therapy for this syndrome exists. Although glucocorticoids (GCs) have been used to improve clinical outcome of ARDS, their therapeutic benefits remain unclear. We previously developed a mouse model of MA-ARDS, in which dexamethasone treatment revealed GC resistance. In the present study, we investigated GC sensitivity of mouse microvascular lung endothelial cells stimulated with interferon-γ (IFN-γ) and Plasmodium berghei NK65 (PbNK65). Upon challenge with IFN-γ alone, dexamethasone inhibited the expression of CCL5 (RANTES) by 90% and both CCL2 (MCP-1) and CXCL10 (IP-10) by 50%. Accordingly, whole transcriptome analysis revealed that dexamethasone differentially affected several gene clusters and in particular inhibited a large cluster of IFN-γ-induced genes, including chemokines. In contrast, combined stimulation with IFN-γ and PbNK65 extract impaired inhibitory actions of GCs on chemokine release, without affecting the capacity of the GC receptor to accumulate in the nucleus. Subsequently, we investigated the effects of GCs on two signaling pathways activated by IFN-γ. Dexamethasone left phosphorylation and protein levels of signal transducer and activator of transcription 1 (STAT1) unhampered. In contrast, dexamethasone inhibited the IFN-γ-induced activation of two mitogen-activated protein kinases (MAPK), JNK, and p38. However, PbNK65 extract abolished the inhibitory effects of GCs on MAPK signaling, inducing GC resistance. These data provide novel insights into the mechanisms of GC actions in endothelial cells and show how malaria may impair the beneficial effects of GCs.status: publishe

Eventos extremos de precipitação no estado do Ceará e suas relações com a temperatura dos oceanos tropicais Extreme rainfall events in Ceará state and its relationship with tropical oceans temperature

O principal objetivo deste trabalho é prover informações sobre as tendências recentes dos eventos extremos de precipitação sobre o Estado do Ceará, associando esses eventos extremos às anomalias de Temperatura da Superfície do Mar (TSM) nos Oceanos Pacífico e Atlântico. Foram utilizados dados pluviométricos de 18 postos de 1971 a 2006 e o método de Mann-Kendall foi utilizado na obtenção das tendências. Os resultados mostram que existem características de aumento nas intensidades das secas e diminuição dos eventos de precipitação forte, e que o aumento nas anomalias de TSM no Pacífico e ao norte do equador, no Oceano Atlântico, acarreta em um aumento do número de dias consecutivos secos no norte do Ceará. Os índices extremos de precipitação mostraram correlações negativas com as anomalias de TSM nas regiões do Pacífico do Atlântico Tropical Norte e positivas com a região do Atlântico Tropical Sul. Entretanto, para a região sul do Ceará, o comportamento dos dias consecutivos chuvosos indica que o período chuvoso é governado por outros sistemas atmosféricos, necessitando assim, ser melhor estudado para o entendimento desse comportamento.<br>The main objective of this study is to provide information about recent trends of extreme rainfall over Ceará State, associating these extreme events with Sea Surface Temperature (SST) anomalies in the Pacific and Atlantic Oceans. Mann-Kendall method is applied to rainfall data of 18 rain gauges from 1971 to 2006 to obtain the trends. The results show that the drought intensity is increasing and the heavy precipitation events are decreasing and that the increase in the Pacific and north of equator Atlantic Ocean SST anomalies lead to an increase in the number of consecutive dry days in northern Ceará. Rainfall extreme indices have shown negative correlations with SST anomalies on Pacific and Tropical North Atlantic regions and positive with Tropical South Atlantic region. However, in southern Ceará region, the consecutive wet day behavior indicates that the rainy season is governed by other atmospheric systems, which needs to be more studied for better understanding