title: Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats.
abstract: Anemia of chronic inflammation (ACI) is the most frequent anemia in hospitalized patients and is associated with significant morbidity. A major underlying mechanism of ACI is the retention of iron within cells of the reticuloendothelial system (RES), thus making the metal unavailable for efficient erythropoiesis. This reticuloendothelial iron sequestration is primarily mediated by excess levels of the iron regulatory peptide hepcidin down-regulating the functional expression of the only known cellular iron export protein ferroportin resulting in blockade of iron egress from these cells. Using a well-established rat model of ACI, we herein provide novel evidence for effective treatment of ACI by blocking endogenous hepcidin production using the small molecule dorsomorphin derivative LDN-193189 or the protein soluble hemojuvelin-Fc (HJV.Fc) to inhibit bone morphogenetic protein-Smad mediated signaling required for effective hepcidin transcription. Pharmacologic inhibition of hepcidin expression results in mobilization of iron from the RES, stimulation of erythropoiesis and correction of anemia. Thus, hepcidin lowering agents are a promising new class of pharmacologic drugs to effectively combat ACI.
authors: Department of Internal Medicine I, Clinical Immunology and Infectious Diseases, Medical University, Innsbruck, Austria.
authors: Igor
authors: I
authors: Theurl
authors: Andrea
authors: A
authors: Schroll
authors: Thomas
authors: T
authors: Sonnweber
authors: Manfred
authors: M
authors: Nairz
authors: Milan
authors: M
authors: Theurl
authors: Wolfgang
authors: W
authors: Willenbacher
authors: Kathrin
authors: K
authors: Eller
authors: Dominik
authors: D
authors: Wolf
authors: Markus
authors: M
authors: Seifert
authors: Chia Chi
authors: CC
authors: Sun
authors: Jodie L
authors: JL
authors: Babitt
authors: Charles C
authors: CC
authors: Hong
authors: Tracey
authors: T
authors: Menhall
authors: Patrick
authors: P
authors: Gearing
authors: Herbert Y
authors: HY
authors: Lin
authors: Guenter
authors: G
authors: Weiss
mesh_terms: D000740:Anemia / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D058851:GPI-Linked Proteins; D015870:Gene Expression / Q000187:drug effects; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D007141:Immunoglobulin Fc Fragments / Q000627:therapeutic use; D007249:Inflammation / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D008565:Membrane Proteins / Q000276:immunology; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D012074:Remission Induction
chemical_list: D023181:Antimicrobial Cationic Peptides; D058851:GPI-Linked Proteins; C578703:Hamp protein, rat; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C513726:Hjv protein, rat; D007141:Immunoglobulin Fc Fragments; C554430:LDN 193189; D008565:Membrane Proteins; D011720:Pyrazoles; D011743:Pyrimidines