Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kenya Medical Research Institute, University of New Mexico, Kisumu, Kenya.
Am J Hematol. 2012 Aug;87(8):782-9. doi: 10.1002/ajh.23253. Epub 2012 Jun 23.
In holoendemic Plasmodium falciparum transmission areas, severe malaria primarily occurs in children aged <48 months and manifests as severe malarial anemia [SMA; hemoglobin (Hb) < 6.0 g/dL]. Induction of high levels of prostaglandin-E(2) (PGE(2)) through inducible cyclooxygenase-2 (COX-2) is an important host-defense mechanism against invading pathogens. We have previously shown that COX-2-derived PGE(2) levels are reduced in children residing in hyperendemic transmission regions with cerebral malaria and in those with mixed sequelae of anemia and hyperparasitemia. Our in vitro studies further demonstrated that reduced PGE(2) was due to downregulation of COX-2 gene products following phagocytosis of malarial pigment (hemozoin, PfHz). However, as COX-2-PGE(2) pathways and the impact of naturally acquired PfHz on erythropoietic responses have not been determined in children with SMA, plasma and urinary bicyclo-PGE(2)/creatinine and leukocytic COX-2 transcripts were determined in parasitized children (<36 months) stratified into SMA (n = 36) and non-SMA (Hb ≥ 6.0 g/dL; n = 38). Children with SMA had significantly reduced plasma (P = 0.001) and urinary (P < 0.001) bicyclo-PGE(2)/creatinine and COX-2 transcripts (P = 0.007). There was a significant positive association between Hb and both plasma (r = 0.363, P = 0.002) and urinary (r = 0.500, P = 0.001)] bicyclo-PGE(2)/creatinine. Furthermore, decreased systemic bicyclo-PGE(2)/creatinine was associated with inefficient erythropoiesis (i.e., reticulocyte production index; RPI < 2.0, P = 0.026). Additional analyses demonstrated that plasma (P = 0.031) and urinary (P = 0.070) bicyclo-PGE(2)/creatinine and COX-2 transcripts (P = 0.026) progressively declined with increasing concentrations of naturally acquired PfHz by monocytes. Results presented here support a model in which reduced COX-2-derived PGE(2), driven in part by naturally acquired PfHz by monocytes, promotes decreased erythropoietic responses in children with SMA.
在恶性疟原虫流行传播地区，重症疟疾主要发生在 48 个月以下的儿童中，表现为严重的疟疾性贫血[SMA；血红蛋白（Hb）<6.0g/dL]。诱导高水平的前列腺素 E（2）（PGE（2））通过诱导型环氧化酶-2（COX-2）是一种对抗入侵病原体的重要宿主防御机制。我们之前已经表明，在患有脑型疟疾和混合性贫血和高寄生虫血症后遗症的高流行传播地区居住的儿童中，COX-2 衍生的 PGE（2）水平降低。我们的体外研究进一步表明，由于吞噬疟色素（血影蛋白，PfHz）后 COX-2 基因产物的下调，导致 PGE（2）减少。然而，由于 COX-2-PGE（2）途径和天然获得的 PfHz 对红细胞生成反应的影响在 SMA 儿童中尚未确定，因此在寄生虫感染的儿童（<36 个月）中，根据 SMA（n=36）和非-SMA（Hb≥6.0g/dL；n=38）进行了血浆和尿双环 PGE（2）/肌酐和白细胞 COX-2 转录本的测定。患有 SMA 的儿童的血浆（P=0.001）和尿（P<0.001）双环 PGE（2）/肌酐和 COX-2 转录本显著降低（P=0.007）。Hb 与血浆（r=0.363，P=0.002）和尿（r=0.500，P=0.001）双环 PGE（2）/肌酐均呈显著正相关。此外，全身双环 PGE（2）/肌酐减少与红细胞生成效率低下有关（即网织红细胞生成指数；RPI<2.0，P=0.026）。进一步的分析表明，血浆（P=0.031）和尿（P=0.070）双环 PGE（2）/肌酐和 COX-2 转录本（P=0.026）随着单核细胞中天然获得的 PfHz 浓度的增加而逐渐降低。本文的研究结果支持一种模型，即部分由单核细胞中天然获得的 PfHz 驱动的 COX-2 衍生的 PGE（2）减少，促进了 SMA 儿童红细胞生成反应的减少。
