Novel erythropoiesis stimulating protein (darbepoetin alfa) alleviates anemia associated with chronic inflammatory disease in a rodent model.
OBJECTIVE
We developed a rodent model of noninfectious systemic inflammation to examine the pathogenesis of the associated anemia of chronic disorders (ACD), to evaluate the similarity of this ACD model to human ACD, and to evaluate the potential efficacy of novel erythropoiesis stimulating protein (darbepoetin alfa) as an ACD therapy.


METHODS
Lewis rats were immunized with peptidoglycan-polysaccharide polymers (PG-APS), the chronic inflammation and associated ACD were characterized, and the effects of darbepoetin alfa treatment on complete blood counts (CBC), red blood cell (RBC) indices, and iron metabolism were analyzed weekly.


RESULTS
Acutely inflamed rats had reduced peripheral blood (PB) RBC counts and hemoglobin (Hb) concentrations and increased reticulocyte counts. PB RBC numbers normalized during chronic inflammation, but RBC remained hypochromic and microcytic. Consequently, the rats remained chronically anemic. Anemic rats had fluctuating serum erythropoietin (EPO) concentrations, but mean EPO concentrations never varied significantly from baseline control levels. Histology of anemic rat spleen sections revealed reticuloendothelial siderosis. Total serum iron concentrations were chronically low. Peritoneal exudate cells (PEC) isolated from anemic rats and stimulated with PG-APS in vitro produced more interleukin (IL)-1alpha and interferon (IFN)-gamma, and significantly more tumor necrosis factor (TNF)-alpha and IL-10 than control cultures. Darbepoetin alfa restored Hb concentrations to baseline levels within 2 to 7 weeks, depending on dosage. A refined treatment strategy restored Hb to baseline and maintained those levels with reduced dosing.


CONCLUSIONS
ACD in this rodent model closely replicates human ACD. Darbepoetin alfa treatment reversed ACD in this model by increasing RBC production and RBC hemoglobinization while reducing siderosis and hypoferremia.
Coccia
M A
MA
Pharmacology & Pathology Department, Amgen Inc., Thousand Oaks, Calif. 91320, USA. mcoccia@amgen.com
Cooke
K
K
Stoney
G
G
Pistillo
J
J
Del Castillo
J
J
Duryea
D
D
Tarpley
J E
JE
Molineux
G
G
D000740:Anemia / Q000188:drug therapy* / Q000209:etiology; D000818:Animals; D001202:Ascitic Fluid / Q000276:immunology / Q000503:physiopathology; D001772:Blood Cell Count; D002908:Chronic Disease; D004195:Disease Models, Animal; D004906:Erythrocyte Count; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000097:blood* / Q000494:pharmacology*; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D007249:Inflammation / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D012157:Mononuclear Phagocyte System / Q000187:drug effects / Q000473:pathology; D010457:Peptidoglycan / Q000494:pharmacology; D011134:Polysaccharides / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D017701:Reticulocyte Count; D012806:Siderosis / Q000209:etiology / Q000473:pathology
D006454:Hemoglobins; D010457:Peptidoglycan; D011134:Polysaccharides; D004921:Erythropoietin