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Protracted Anemia Associated with Chronic, Relapsing Systemic Inflammation Induced by Arthropathic Peptidoglycan-Polysaccharide Polymers in Rats R

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Protracted Anemia Associated with Chronic, Relapsing Systemic Inflammation Induced by Arthropathic Peptidoglycan-Polysaccharide Polymers in Rats R INFECTION AND IMMUNITY, Apr. 1989, p. 1177-1185 Vol. 57, No. 4 0019-9567/89/041177-09$02.00/0 Copyright © 1989, American Society for Microbiology Protracted Anemia Associated with Chronic, Relapsing Systemic Inflammation Induced by Arthropathic Peptidoglycan-Polysaccharide Polymers in Rats R. BALFOUR SARTOR,l.2* SONIA K. ANDERLE,3 NADER RIFAI,4 DAVID A. T. GOO,4 WILLIAM J. CROMARTIE,3 AND JOHN H. SCHWAB2'3 Department of Medicine,1 Department of Microbiology and Immunology,3 Department ofPathology,4 and Core Center for Diarrheal Disease,2 University of North Carolina, Chapel Hill, North Carolina 27599-7080 Received 3 October 1988/Accepted 6 January 1989 Mild hypoproliferative anemia with abnormal iron metabolism frequently accompanies chronic inflamma- tion and infection in humans. To determine whether anemia is associated with chronic relapsing arthritis induced by bacterial cell wall polymers, serial determinations of the hematocrit were measured in rats injected intraperitoneally with sonicated peptidoglycan-polysaccharide fragments from group A streptococci. Acute anemia peaked 5 to 10 days after injection, and chronic, spontaneously relapsing anemia persisted for 309 days. 51Cr labeling demonstrated decreased erythrocyte survival, i.e., a half-life of 8.4 days in cell wall-injected rats versus 11.8 days in controls. Erythrocytes were mildly microcytic, and leukocyte counts were elevated during early spontaneous reactivation of arthritis, 15 days after injection of peptidoglycan-polysaccharide. Bone marrow myeloid/erythroid precursor ratios were elevated in arthritic rats (P < 0.0001). Purified peptidoglycan produced an acute anemia lasting 10 days, while injection of group A streptococcal polysaccharide and mutanolysin-digested cell wall did not affect the hematocrit. The minimal effective dose of peptidoglycan- polysaccharide was 5 ,ug of rhamnose per g (body weight). Serum iron and transferrin levels were decreased in cell wall-injected rats (P < 0.005) and were closely correlated with hematocrit values and joint inflammatory scores. Stainable iron was increased in the liver, spleen, and mesenteric lymph nodes and unchanged in the bone marrow of cell wall-injected rats. Anemia accompanying chronic, relapsing systemic inflammation induced by peptidoglycan-polysaccharide polymers appears to be an excellent animal model of the anemia of chronic disease. Mild nonprogressive anemia accompanies chronic inflam- group A streptococci induce an acute and chronic systemic mation of diverse etiologies, including chronic bacterial and inflammatory response characterized by hepatic granulomas fungal infections (42), rheumatoid arthritis (43), Crohn's (20, 47) and spontaneously relapsing arthritis (8) that can disease (10), and widespread malignancies (13). The anemia persist at least 1 year after a single intraperitoneal (i.p.) of chronic disease (inflammation) is characterized by mildly injection into susceptible rat strains. Macrophages are acti- decreased circulating erythrocyte (RBC) survival, lack of an vated to secrete increased amounts of interleukin-1 (IL-1) by appropriate bone marrow compensatory response, and dis- both in vitro and in vivo exposure to PG-APS (L. A. Bristol ordered iron kinetics (13, 24, 48). Typically, the serum iron, and J. H. Schwab, submitted for publication). total iron-binding capacity (TIBC), and marrow sideroblasts This study is designed to determine whether a single i.p. are decreased in spite of normal-to-increased bone marrow injection of PG-APS would produce protracted anemia and and tissue iron stores. Recent studies have suggested that to determine whether this well-characterized and reproduc- monokines secreted by activated macrophages may be re- ible chronic, systemic inflammatory response in genetically sponsible for suppression of bone marrow erythroid precur- susceptible rats could serve as a reliable model of the anemia sors (33, 37). Anemia accompanies several experimental of chronic disease. We demonstrate that PG-APS produces a inflammatory states associated with macrophage activation, chronic, spontaneously relapsing anemia that persists at including adjuvant arthritis (25), arthritis induced by viable least 10 months after a single i.p. injection and whose course BCG (26) and Mycoplasma arthritidis (11), and turpentine closely parallels activity of peripheral arthritis. PG is the abscesses (32). These experimental models have been pro- moiety of PG-APS responsible for the anemia and arthritis. posed as animal models of the anemia of chronic inflamma- tion, however, none of the models produce protracted ane- PG-APS-induced anemia resembles human anemia of mia nor exactly reproduce the bone marrow suppression and chronic disease in the following respects: it is mild to disordered iron metabolism found in the anemia of chronic moderate, RBC survival is decreased, RBCs are slightly disease (48). microcytic, serum iron and transferrin concentrations are Bacterial cell wall polymers induce well-characterized decreased, and reticuloendothelial iron stores are normal or acute and chronic granulomatous inflammation in a variety increased. of organs after local and systemic injection (35, 41). Pepti- (A portion of this work was presented as a poster at the doglycan-polysaccharide (PG-APS) polymers derived from 87th Annual Meeting of the American Society for Microbi- ology in Atlanta, Ga., 1 to 6 March 1987, and was published as an abstract [R. B. Sartor, S. K. Anderle, W. J. Cromar- tie, and J. H. Schwab, Abstr. Annu. Meet. Am. Soc. Micro- * Corresponding author. biol. 1987, B-146, p. 49].) 1177 1178 SARTOR ET AL. INFECT. IMMUN. MATERIALS AND METHODS injection of PG-APS or PBS. Serial determinations of hema- tocrit (HCT), 51Cr counts per minute, or sedimentation rates Animals. Female inbred Lewis rats were purchased from were obtained at intervals outlined in individual experiments Charles River Breeding Laboratories, Inc., Wilmington, from blood derived from transection of the tip of the tail. A Mass., and were housed 2 or 3 per cage with free access to minimal volume of blood was obtained to prevent iron Purina rat chow and water at all times. Rats weighed 140 to deficiency. Bleeding was controlled by digital pressure on 160 g at the time of injection. the tail above the transection and by cauterization immedi- Cell wall polymer preparation. PG-APS polymers were ately after blood collection. Blood was collected directly isolated under aseptic conditions from the cell walls of strain into D58 of group A streptococci (Streptococcus pyogenes) as two heparinized 75-mm-long microhematocrit capillary previously described in detail (40). Briefly, streptococci tubes (approximately 70 [LI of operational volume; Fisher grown in Todd-Hewitt broth (BBL Microbiology Systems, Scientific, Pittsburgh, Pa.) for duplicate HCT and sedimen- Cockeysville, Md.) were disrupted in a Braun MSK cell tation rate determinations and into heparinized microcentri- homogenizer (Bronwell Scientific, Inc., Rochester, N.Y.), fuge tubes (approximately 200-pL volume) for 51Cr or auto- and the cell wall fraction was separated by filtration and mated cell counting. Serum for iron and transferrin levels centrifugation. The cell walls were extracted three times in was obtained at necropsy by cardiac puncture. All injections 2% sodium dodecyl sulfate (Sigma Chemical Co., St. Louis, and blood collections were done under ether inhalation Mo.) at 56°C and then washed extensively and dialyzed to anesthesia to minimize discomfort, and animals were killed remove the sodium dodecyl sulfate. Purified PG-APS poly- by CO2 overdose. mers (400 mg) were suspended in 20 ml of sterile phosphate- Measurement of laboratory and clinical parameters. HCT buffered saline (PBS) (pH 7.2) and sonicated for 35 min using values were determined in duplicate microhematocrit tubes a 0.5-in. (1.27-cm) probe and a setting of 8 (model 350; immediately after centrifugation at 12,600 x g for 3 min. Branson Sonic Power Co., Danbury, Conn.). The suspen- Spontaneous sedimentation of RBCs was measured in mi- sion was centrifuged at 10,000 x g for 30 min to remove large crohematocrit capillary tubes allowed to stand upright for 30 particles. PG-APS fragments prepared by this method have min after collection at room temperature. The percent molecular weights ranging from 5 x 106 to 5 x 108 (16). plasma relative to total volume was read with a microhema- Sterility was confirmed by culturing 0.1 ml on sheep blood tocrit capillary tube reader (Lancer, Brunswick Co., St. agar. PG-APS concentrations for injections were calculated Louis, Mo.). The amount of 51Cr within 0.1 ml of heparin- on the basis of rhamnose values determined by the method ized blood was determined in a gamma counter (1197 series; of Dische and Shettles (9). Immediately before injection, Automatic Gamma Counting System; Searle Analytic, Inc., PG-APS was diluted to appropriate concentrations in PBS Des Plains, Ill.). Counts per minute at each time point were (pH 7.2) and sonicated for 3 min with a 9-kilocycle Sonic corrected for the spontaneous decay in 51Cr activity (phys- oscillator (Raytheon Co., Waltham, Mass.) to disperse ag- ical half-life, 27.7 days). An automated cell counter (150 gregates. series; Baker Instruments Corp., Allentown, Pa.), pro- Preparation of PG-APS fractions. Group-specific APS and grammed for rat blood cells, was used for hemoglobin, RBC PG were prepared by hot formamide treatment of cell walls. and leukocyte (WBC) counts, and mean corpuscular volume APS was purified from the
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