Evaluation of the Erythroid Regenerative Response in Two Different Models of Experimentally Induced Iron Deficiency Anemia

Burkhard, Mary Jo; Brown, Diane E.; McGrath, John P.; Meador, Vince P.; Mayle, Douglas A.; Keaton, Meghan; Hoffman, Wherly; Zimmermann, John; Abbott, David L.; Sun, Steven C.

doi:10.1111/j.1939-165x.2001.tb00262.x

Cited by 25 publications

(29 citation statements)

References 29 publications

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“…These previous reports showed that the ability of erythropoiesis to respond to a demand persisted throughout the suppression of erythropoiesis by undernutrition. A high hematopoietic activity was shown in the phlebotomy group as well as in the above-mentioned 5-FU treatment group [1,22] as well as in animals fed an irondeficient diet [5]. Decreases in reticulocytes were apparent after undernutrition but were not observed in cases with both blood loss and a poor nutritional condition (phlebotomy groups).…”

Section: Discussionmentioning

confidence: 89%

“…These findings were not observed in a pair-feeding group in a 4-day study protocol, since concerns regarding the influence of secondary changes related to undernutrition were minimized for this short-term study protocol [2]. Burkhard et al [5] reported that anemia induced in weanling rats by feeding them an iron-deficient diet resulted in a decrease in reticulocytes with bone marrow erythroid hypoplasia, and an increase in reticulocytes was seen in these rats after a hemolytic event. These previous reports showed that the ability of erythropoiesis to respond to a demand persisted throughout the suppression of erythropoiesis by undernutrition.…”

Section: Discussionmentioning

confidence: 93%

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Feature on Erythropoiesis in Dietary Restricted Rats

Asanuma

Miyata

Iwaki

et al. 2011

The Journal of Veterinary Medical Science

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ABSTRACT. We attempted to characterize the influence of undernutrition on erythropoiesis in toxicity studies. Male rats were divided into the following 5 groups: dietary restriction groups in which feeding was restricted by 33% or 66% for 14 days (R33 and R66); phlebotomy groups in which 1% or 4% of total blood volume was removed by serial phlebotomy for 14 days (PB01 and PB04); and a nontreated group (NT). Toxicological parameters such as hematology and blood chemistry were evaluated. The body weight gains in the R33 and phlebotomy groups (PB01 and PB04) were similar and were less than that observed in the NT group. Decreases in peripheral blood reticulocytes, bone marrow erythroids and the unsaturated iron binding capacity (UIBC) were observed as changes that suppressed erythropoiesis in the R33 and R66 groups. However, increases in reticulocytes and UIBC were observed as opposite changes in the phlebotomy groups. In addition, an increase in the blood urea nitrogen level and a decrease in the serum alkaline phosphatase level were observed as changes reflecting poor nutrition in the phlebotomy groups. Decreased reticulocytes which are related to poor nutrition were not observed. However, increases in those cells as reflected by a loss of blood were observed in the phlebotomy groups. Even if undernutrition suppresses erythropoiesis, the ability of erythropoiesis to respond to a demand appears to be retained. In repeated dose toxicity studies, decreased food consumption is often observed in the drug administration groups. Our study results provide useful information for hematological evaluations in toxicity studies.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 93%

Feature on Erythropoiesis in Dietary Restricted Rats

Asanuma

Miyata

Iwaki

et al. 2011

The Journal of Veterinary Medical Science

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“…These changes occurred together with hypoferremia in all but one infected mouse at three weeks post-infection; this mouse had an appropriate macrocytic regenerative response consistent with its normal serum iron concentration (Table 2). Erythrocytosis, which can occur with microcytic anemia [36], [37], was present from weeks 6–10 (Table 2, 10-week study), and 5 – 14 ( P <0.05; 16-week study). Increased RDW at week six (Table 2) and weeks 3–14 ( P <0.05; 16-week study) demonstrated erythrocyte anisocytosis.…”

Section: Resultsmentioning

confidence: 96%

Chronic Murine Typhoid Fever Is a Natural Model of Secondary Hemophagocytic Lymphohistiocytosis

et al. 2010

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Hemophagocytic lymphohistiocytosis (HLH) is a hyper-inflammatory clinical syndrome associated with neoplastic disorders especially lymphoma, autoimmune conditions, and infectious agents including bacteria, viruses, protozoa and fungi. In both human and veterinary medicine, hemophagocytic histiocytic disorders are clinically important and frequently fatal. HLH in humans can be a primary (familial, autosomal recessive) or secondary (acquired) condition, with both types generally precipitated by an infectious agent. Previously, no mouse model for secondary HLH has been reported. Using Salmonella enterica serotype Typhimurium by oral gavage to mimic naturally-occurring infection in Sv129S6 mice, we characterized the clinical, hematologic and morphologic host responses to disease thereby describing an animal model with the clinico-pathologic features of secondary HLH as set forth by the Histiocyte Society: fever, splenomegaly, cytopenias (anemia, thrombocytopenia), hemophagocytosis in bone marrow and spleen, hyperferritinemia, and hypofibrinogenemia. Disease severity correlates with high splenic and hepatic bacterial load, and we show disease course can be monitored and tracked in live animals. Whereby secondary HLH is known to occur in human patients with typhoid fever and other infectious diseases, our characterization of a viable natural disease model of secondary HLH offers an important means to elucidate pathogenesis of poorly understood mechanisms of secondary HLH and investigation of novel therapies. We characterize previously unreported secondary HLH in a chronic mouse model of typhoid fever, and novel changes in hematology including decreased tissue ferric iron storage that differs from classically described anemia of chronic disease. Our studies demonstrate S. Typhimurium infection of mice is a natural infectious disease model of secondary HLH that may have utility for elucidating disease pathogenesis and developing novel therapies.

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“…Infected mice develop microcytic anemia that is most severe 1 to 3 weeks postinfection and persistent for 9 weeks, along with erythrocyte fragmentation and severely diminished tissue iron staining from 1 to 6 weeks postinfection (7,8). These hematopathological findings are characteristic features of systemic iron deficiency (22). The observation of decreased tissue iron in infected, anemic mice in the face of marked inflammatory disease was unexpected based on the welldescribed macrophage iron sequestration that occurs with anemia of inflammatory (or chronic) disease (AID) (23).…”

mentioning

confidence: 93%

Increased Ferroportin-1 Expression and Rapid Splenic Iron Loss Occur with Anemia Caused by Salmonella enterica Serovar Typhimurium Infection in Mice

et al. 2015

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e The Gram-negative intracellular bacterium Salmonella enterica serovar Typhimurium causes persistent systemic inflammatory disease in immunocompetent mice. Following oral inoculation with S. Typhimurium, mice develop a hematopathological syndrome akin to typhoid fever with splenomegaly, microcytic anemia, extramedullary erythropoiesis, and increased hemophagocytic macrophages in the bone marrow, liver, and spleen. Additionally, there is marked loss of iron from the spleen, an unanticipated result, given the iron sequestration reported in anemia of inflammatory disease. To establish why tissue iron does not accumulate, we evaluated multiple measures of pathology for 4 weeks following oral infection in mice. We demonstrate a quantitative decrease in splenic iron following infection despite increased numbers of splenic phagocytes. Infected mice have increased duodenal expression of the iron exporter ferroportin-1, consistent with increased uptake of dietary iron. Liver and splenic macrophages also express high levels of ferroportin-1. These observations indicate that splenic and hepatic macrophages export iron during S. Typhimurium infection, in contrast to macrophage iron sequestration observed in anemia of inflammatory disease. Tissue macrophage export of iron occurs concurrent with high serum concentrations of interferon gamma (IFN-␥) and interleukin 12 (IL-12). In individual mice, high concentrations of both proinflammatory (tumor necrosis factor alpha [TNF-␣])and anti-inflammatory (IL-10) cytokines in serum correlate with increased tissue bacterial loads throughout 4 weeks of infection. These in vivo observations are consistent with previous cell culture studies and suggest that the relocation of iron from tissue macrophages during infection may contribute to anemia and also to host survival of acute S. Typhimurium infection.T yphoid fever is acquired upon oral ingestion of food or water contaminated with Salmonella enterica serovar Typhi or Paratyphi and remains a serious threat to public health, especially in developing countries (1). Human typhoid fever causes a broad range of clinical signs, including splenomegaly, neuropathy, and hematopathology, such as cytopenias (2), that have been modeled in laboratory mice infected with Salmonella enterica serovar Typhimurium (3). Inbred mouse strains with differing genetic backgrounds are characterized as either sensitive or resistant to S. Typhimurium. Sensitivity to the intracellular bacterial infection is caused by genetic deficiencies in the innate or adaptive immune system (4, 5). For instance, mice lacking the cation transporter Nramp1 (Slc11a1), a regulator of cellular iron metabolism, are extremely sensitive to infection. Nramp1 ϩ mice are considered resistant to S. Typhimurium, because infection is generally nonfatal (6-8). Resistant mice infected by natural oral inoculation develop systemic infection with an acute hematopathological syndrome similar to that of humans with typhoid fever, including fever, anemia, inflammatory disease characterized by periph...

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Evaluation of the Erythroid Regenerative Response in Two Different Models of Experimentally Induced Iron Deficiency Anemia

Cited by 25 publications

References 29 publications

Feature on Erythropoiesis in Dietary Restricted Rats

Feature on Erythropoiesis in Dietary Restricted Rats

Chronic Murine Typhoid Fever Is a Natural Model of Secondary Hemophagocytic Lymphohistiocytosis

Increased Ferroportin-1 Expression and Rapid Splenic Iron Loss Occur with Anemia Caused by Salmonella enterica Serovar Typhimurium Infection in Mice

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