Animal Models of Anemia of Inflammation(1)
Anemia of inflammation (AI), also known as anemia of chronic disease or anemia of chronic disorders (ACD), is a common syndrome complicating many infectious, non-infectious inflammatory, and neoplastic disorders. Understanding the diverse mechanisms that could be involved requires a variety of animal models that illuminate specific individual mechanisms. It is important to recognize that there are important differences between human and murine pathophysiology that could lead to profound differences in the anemic response to inflammation. The lifespan of the mouse erythrocyte is much shorter than that of humans.
Infectious models
Anemia is a common feature of a broad spectrum of infectious diseases. The inflammatory response to different infections is diverse, as is the involvement of additional mechanisms that contribute to anemia. It will be difficult to establish a bacterial peritonitis model.
Intestinal Perforation
Cecal ligation and puncture (CLP), traditionally, has been used to model severe sepsis or septic shock. Tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in a CLP model of AI played a significant role in the pathogenesis of AI in this model. In experienced hands, CLP-induced anemia is an informative model of the anemia in the setting of severe infections.
Pyrogenic Bacterial infections
AI is a common feature of most chronic infections with pyogenic bacteria (gram positives and enteric gram negatives) such as osteomyelitis, indwelling catheter infections and endocarditis. Coated dextran microbeads with Staphylococcus aureus and Streptococcus pyogenes and injection subcutaneously induced large abscesses in proportion to the number of bacteria Injected in mice. Mice were statistically more anemic than controls but the anemia was very mild.
Mycobacterial Infections
Mycobacterial infections, especially Mycobacterium tuberculosis (MTB), are exceedingly prevalent in the world, responsible for widespread morbidity and mortality and frequently associated with anemia. MTB causes infection in several strains of mice including BALB/c, C57BL/6 and DBA/2J. The inflammatory response to components of MTB causes AI so it is likely that MTB infections would be a good model of AI.
Parasitic Infections
Trypanosomes cause a wide variety of diseases in humans and animals, many of which are associated with anemia. T. brucei, the cause of sleeping sickness in humans, causes anemia in mice. Many Plasmodium species are able to infect mice and cause anemia. P. chabaudi infected red blood cells injected IP causes anemia after about five days that reaches a nadir at 10 days. P. berghei causes severe anemia but is rapidly fatal without treatment. P. yoelii infects mice, has not been shown to be a human pathogen and different strains produce differing severities of anemia and mortality.
Pseudo-infectious Models
Complete Freund’s Adjuvant (CFA) is an emulsion of dried and inactivated mycobacteria (Mycobacterium butyricum) in oil. Intraperitoneal CFA injection increases hepcidin production and induces hypoferremia in mice. A single IP injection of 0.2 ml CFA emulsified with an equal amount of saline induces lower hemoglobin in one week that reaches its maximum at 3 weeks. A single injection of the Brucella ring test antigen produces anemia in C57Bl/6 mice and that this anemia was iron restricted and partially prevented by anti-hepcidin antibody. Lipopolysaccharides (LPS) are components of the outer cell membrane of Gram-negative bacteria and elicit a potent inflammatory response when administered intravenously or IP. LPS induces hepcidin and causes hypoferremia within hours of administration in both humans and mice.
Non-infectious Models
Collagen induced arthritis (CIA) is a model of rheumatoid arthritis created by sensitizing mice to their own collagen by injecting them with heterologous type II collagen in the presence of an adjuvant . CIA, like active rheumatoid arthritis in humans, causes AI in mice. Oral feeding of dextran sulfate sodium (DSS) for several days induces a colitis in mice that is a model of inflammatory bowel disease (IBD) in humans. DSS colitis, like IBD, is associated with anemia that resembles AI more than it does simple colonic bleeding.
Transgenic Models
A key pathway proposed to cause AI is the IL-6 – hepcidin – ferroportin axis. In this model, AI is caused by overproduction of IL-6 inducing the production of hepcidin that then causes the internalization and degradation of the iron export protein ferroportin. According to this model, increase in IL-6 or hepcidin should cause a condition that resembles AI. In another transgenic model, overexpression of hepcidin also induces an iron-restricted anemia similar to AI . Such models query whether a specific individual mediator can produce AI, or at least an iron-restricted anemia.
NON-MOUSE MODELS
Other Mammals
CFA-induced anemia in rats has long been used as a model of AI . Peptidoglycan (PG), from the cell wall of gram positive bacteria and carrageenan, isolated from red seeweeds, also cause AI in rats. The PG model would appear to be a good model of the anemia seen in RA, as a single injection of PG in susceptible rats (Lewis) induces relapsing arthritis and anemia that lasts almost a year. Cynomolgus monkeys develop anemia in response to CIA.
1. S. Rivera, T. Ganz, Animal models of anemia of inflammation. Semin. Hematol. 46, 351–357 (2009).