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Aging of red blood cells and impaired erythropoiesis following prolonged administration of dichloromethylene diphosphonate containing liposomes in rats
Author(s) -
Giuliani Anna Lisa,
Graldi Giuseppe,
Veronesi Massimo,
Unis Lorenza,
Previato Antonio,
Lorenzini Franco,
Gandini Gloria,
Bergamini Carlo,
Vanara Franco,
Wiener Edith,
Wickramasinghe Sunitha N.,
Berti Gilberto
Publication year - 2005
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/j.1600-0609.2005.00521.x
Subject(s) - erythropoiesis , medicine , liposome , pharmacology , endocrinology , chemistry , anemia , biochemistry
Objectives : To investigate whether macrophage‐depleted rats may serve as a model for studying red blood cell (RBC) aging. Methods : Rats were macrophage‐depleted by 4 weekly injections of dichloromethylene diphosphonate‐containing liposomes (Cl 2 MDP‐CL). The macrophage content of spleens and bone marrows (BMs) was investigated by immunohistochemistry and light microscopy and by flow cytometry, respectively, after staining with macrophage‐specific monoclonal antibodies. In addition, the ultrastructure of residual BM macrophages and their ability to phagocytose zymosan was studied. BM was also studied for apoptosis (by the TUNEL reaction) and for erythroid progenitor cell content. Furthermore, RBC indices, morphology, life span (by 51 Cr labeling) and aging features (MCV, density, 4.1a/4.1b membrane protein ratio, anti‐spectrin IgG binding, microvesiculation) were investigated. Serum TNF‐ α , iron, total iron‐binding capacity (TIBC) and ferritin were also determined. Results : Prolonged treatment with Cl 2 MDP‐CL caused an almost complete depletion of macrophages in the spleen and a 58% reduction of those in the BM; the residual BM macrophages were activated as judged by their ultrastructure and phagocytic capacity in vitro. These alterations were accompanied by an increase in RBC life span and age‐related RBC changes, as well as by mild anemia associated with a reduced reticulocyte count, reduced BM erythroid progenitors, increased numbers of apoptotic cells in the BM, low serum iron, high TIBC and increased serum TNF‐ α levels. Conclusions : Rats subjected to prolonged macrophage depletion showed an increased prevalence of senescent RBC in the circulation due to their impaired clearance by macrophages. Hence, these animals provide a model system in which mechanisms of RBC aging can be delineated. They also showed impaired erythropoiesis, presumably related to a reduction in BM macrophages and increased production of proinflammatory cytokines by residual activated marrow macrophages and other cells.