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Reduced systemic bicyclo‐prostaglandin‐E 2 and cyclooxygenase‐2 gene expression are associated with inefficient erythropoiesis and enhanced uptake of monocytic hemozoin in children with severe malarial anemia
Author(s) -
Anyona Samuel B.,
Kempaiah Prakasha,
Raballah Evans,
Davenport Gregory C.,
Were Tom,
Konah Stephen N.,
Vulule John M.,
Hittner James B.,
Gichuki Charity W.,
Ong'echa John M.,
Perkins Douglas J.
Publication year - 2012
Publication title -
american journal of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.456
H-Index - 105
eISSN - 1096-8652
pISSN - 0361-8609
DOI - 10.1002/ajh.23253
Subject(s) - cyclooxygenase , creatinine , medicine , prostaglandin e , erythropoiesis , endocrinology , anemia , immunology , biology , biochemistry , enzyme
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, Pf Hz). However, as COX‐2‐PGE 2 pathways and the impact of naturally acquired Pf Hz 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 Pf Hz by monocytes. Results presented here support a model in which reduced COX‐2‐derived PGE 2 , driven in part by naturally acquired Pf Hz by monocytes, promotes decreased erythropoietic responses in children with SMA. Am. J. Hematol., 2012. © 2012 Wiley Periodicals, Inc.