Intrauterine growth-restricted pregnant rats, from placental ischemic dams, display preeclamptic-like symptoms: A new rat model of preeclampsia.

Preeclampsia (PE) is characterized by de novo hypertension (HTN) and is often associated with intrauterine growth restriction (IUGR). Hallmarks of PE are placental ischemia, decreased nitric oxide (NO) bioavailability, oxidative stress (OS), and organ damage in the kidneys and brain. This study aims to characterize a new model of PE using pregnant IUGR rats from hypertensive placental ischemic dams.

Protracted anemia associated with chronic, relapsing systemic inflammation induced by arthropathic peptidoglycan-polysaccharide polymers in rats.

Mild hypoproliferative anemia with abnormal iron metabolism frequently accompanies chronic inflammation 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.

Immunosuppressive macrophages induced by arthropathic peptidoglycan-polysaccharide polymers from bacterial cell walls.

Rats injected with peptidoglycan-polysaccharide polymers derived from group A streptococcal cell walls (PG-APS) develop a chronic, remittant, erosive synovitis. Spleen cells from injected rats failed to proliferate when stimulated in vitro by Con A or PHA, unless nylon wool adherent cells were first removed. The suppression could also be reversed by removing phagocytic cells which had ingested carbonyl iron.

Lipopolysaccharide induces recurrence of arthritis in rat joints previously injured by peptidoglycan-polysaccharide.

Rat ankle joints injected intraarticularly with 5 micrograms of group A streptococcal peptidoglycan-polysaccharide (PG-APS) developed an acute course of arthritis. Recurrence of arthritis was induced in 100% of these joints by intravenous injection of as little as 10 micrograms of Salmonella typhimurium lipopolysaccharide (LPS) 3 wk after intraarticular injection. This reaction was similar in athymic and euthymic rats.

Effect of acetylation on arthropathic activity of group A streptococcal peptidoglycan-polysaccharide fragments.

Purified group A streptococcal peptidoglycan-polysaccharide (PG-PS) fragments were either de-O-acylated, or acetylated and then de-O-acylated to yield N-acetylated PG-PS. Native PG-PS was poorly degraded, N-acetylated PG-PS was extensively degraded, and de-O-acylated PG-PS was only slightly degraded by hen egg white lysozyme. N-acetylated PG-PS was also extensively degraded by human lysozyme and partially degraded by rat serum or rat liver extract.

Comparison of in vivo degradation of 125I-labeled peptidoglycan-polysaccharide fragments from group A and group D streptococci.

The in vivo degradation and persistence of 125I-labeled peptidoglycan-polysaccharide (PG-PS) fragments from the cell walls of group A and D streptococci were compared by group after intraperitoneal injection into rats. The quantity of PG-PS in the livers and spleens of group D PG-PS-injected rats was less than the quantity in rats injected with group A PG-PS throughout the course of the experiment. Gel filtration analyses of liver and spleen homogenates indicated that group A PG-PS was relatively resistant to degradation, whereas group D PG-PS was extensively degraded to yield a heterogeneous mixture of fragments of lower molecular weight.

Comparison of inflammatory reactions induced by intraarticular injection of bacterial cell wall polymers.

Cell wall polymers isolated from group A streptococci, as well as lipopolysaccharide from Salmonella typhimurium and synthetic muramyl dipeptide, were injected into the ankle joints of rats. The inflammatory responses were assessed by gross and histologic examination, and edema was measured by accumulation of radiolabeled albumin in the limbs. The isolated group-specific polysaccharide induced extensive edema of the articular and periarticular tissue immediately after injection, and this resolved in 24 hours.

Localized gut-associated lymphoid tissue hemorrhage induced by intravenous peptidoglycan-polysaccharide polymers.

A hemorrhage into gut-associated lymphoid tissue developed as early as 3 min after the intravenous injection of group A streptococcal peptidoglycan-polysaccharide polymers into rats. Extravasated erythrocytes were specifically located in the lamina propria and organized lymphoid follicles of the intestines and mesenteric lymph nodes and did not occur in the lungs, kidneys, liver, spleen, adrenal glands, or submandibular and popliteal lymph nodes, as determined by gross and histologic observations and measurement of radiolabeled erythrocytes. Petechial hemorrhage was preferentially located within the intestine to the distal ileum, Peyer's patches, and lymphoid aggregates of the colon.

Arthropathic properties of cell wall polymers from normal flora bacteria.

Peptidoglycan-polysaccharide (PG-PS) fragments were purified from cell walls of group D streptococci (Streptococcus faecium, strains ATCC 9790 and F-24) with a protocol which minimizes autolytic activity and tested for ability to induce arthritis in rats. PG-PS fragments from cell walls of other normal flora bacteria (Peptostreptococcus productus, and Propionibacterium acnes), group A streptococci, and pseudomurein-PS fragments from cell walls of Methanobacterium formicicum, were similarly purified and tested. Upon intraarticular injection into rat ankles, all PG-PS polymers induced acute inflammation; pseudomurein-PS fragments were approximately five times less active than the PG-PS preparations.

Reactivation of streptococcal cell wall-induced arthritis by homologous and heterologous cell wall polymers.

Joint inflammation initially induced by intraarticular injection of an aqueous suspension of peptidoglycan-polysaccharide (PG-PS) fragments isolated from Streptococcus pyogenes was reactivated by systemic injection of a normally subarthropathic dose of homologous or heterologous cell wall polymers, including muramyl dipeptide and lipopolysaccharide. Reactivation was not correlated with the severity of the initial inflammatory reaction. Results of studies utilizing 125I-labeled PG-PS fragments suggested that reactivation was associated with increased localization of PG-PS fragments in the joint following reinjection.

Inflammation induced by bacterial cell wall fragments in the rat air pouch. Comparison of rat strains and measurement of arachidonic acid metabolites.

Streptococcal cell wall fragments, suspended in phosphate-buffered saline, were injected into a preformed subcutaneous air pouch in rats. The advantage of the air pouch model is the capacity for quantitation of exudative, cellular, and proliferative responses and soluble mediators. Accumulation of pouch fluid containing many leukocytes occurred during the first 3 days.

Granulomatous enterocolitis induced in rats by purified bacterial cell wall fragments.

This study was designed to determine if poorly biodegradable bacterial cell wall components can produce chronic intestinal inflammation. A sterile aqueous suspension of sonically disrupted group A or group D streptococcal cell wall fragments was injected intramurally into the small intestine and cecum of 100 rats. Gross findings in rats killed at intervals of 1 day to 6 mo included intestinal thickening, adhesions, and mesenteric contraction.

Measurement of streptococcal cell wall in tissues of rats resistant or susceptible to cell wall-induced chronic erosive arthritis.

The quantity of streptococcal cell wall localized in the joints of rats of strains which are either susceptible (Sprague-Dawley, LEW/N, M520/N) or resistant (Buffalo, WKY/N, F344/N) to cell wall-induced chronic erosive arthritis was measured after intraperitoneal injection of group A streptococcal cell wall fragments. Susceptibility or resistance was not associated with a difference in the amount of cell wall localized in limbs or other tissues. It is concluded that although localization of cell wall in joint tissue is essential for development of arthritis, the relative resistance of certain rat strains reflects genetic regulation of inflammatory response rather than a quantitative difference in localization of cell wall in joints.

Treatment of experimental erosive arthritis in rats by injection of the muralytic enzyme mutanolysin.

A single intravenous injection into rats of 0.4 mg of the muralytic enzyme mutanolysin, given as long as 3 d after an arthropathic dose of peptidoglycan-polysaccharide polymers derived from group A streptococci (PG-APS), resulted in a complete resolution of acute arthritis and the prevention of chronic joint disease. When administration of mutanolysin was delayed until 14 d after the injection of PG-APS, a great reduction in the severity of chronic inflammation was still observed.

Microangiographic studies of experimental erosive synovitis in rats.

Chronic remittent erosive synovitis, which is clinically, radiologically and pathologically similar to rheumatoid arthritis in man, can be produced in rats by systemic injection of cell wall fragments isolated from Group A streptococci. Because of our desire to study the synovial microvasculature in this experimental model, we developed a reliable microangiographic technique to document these changes. This paper describes the first reported microangiographic studies of rat joints and discusses the microvascular changes that parallel the previously reported radiographic and histologic findings.

Measurement of bacterial cell wall in tissues by solid-phase radioimmunoassay: correlation of distribution and persistence with experimental arthritis in rats.

We have developed sensitive and specific solid-phase radioimmunoassays to quantitate the distribution and persistence of bacterial antigen in rats developing arthritis in response to a single injection of streptococcal cell wall material. Three separate assays were specific for either the A polysaccharide (N-acetyl-D-glucosamine), A-variant polysaccharide (polyrhamnose), or peptidoglycan (D-ala-D-ala) moieties of the streptococcal cell wall. Antigen was detected in all tissues surveyed, although the greatest amount was in the liver and spleen.

Relationship of complement to experimental arthritis induced in rats with streptococcal cell walls.

Experimental arthritis developed in rats injected intraperitoneally with aqueous suspensions of peptidoglycan-polysaccharide complexes (PG-APS) isolated from group A streptococcal cell walls. Reduction of serum complement by pretreatment with cobra venom factor (COV) reduced acute joint inflammation over the first 3 days following injection of PG-APs. Thereafter, the course of the disease was not different in the COV-treated rats.

Arthropathic properties related to the molecular weight of peptidoglycan-polysaccharide polymers of streptococcal cell walls.

The covalently bound polymers of peptidoglycan and group-specific polysaccharide (PG-APS) were isolated from the cell walls of group A streptococci. Arthritis was induced in rats with a single intraperitoneal injection of an aqueous suspension of PG-APS fragments derived by sonication. The joint lesions induced with this polydisperse suspension followed a bimodal pattern consisting of an acute phase, which reached a peak 5 days after injection and then receded, followed by a chronic, remittent, erosive arthritis lasting several months.

Cell-mediated immune response during experimental arthritis induced in rats with streptococcal cell walls.

Chronic, remittent, erosive arthritis was produced in rats by a single intraperitoneal injection of an aqueous suspension of cell wall fragments isolated from group A streptococci. Arthritis could be induced in rats which had been immunologically compromised by neonatal thymectomy. Delayed hypersensitivity to cell wall peptidoglycan could not be elicited in these rats, although progressive joint disease was obvious by clinical and radiological measurements.

The relation of experimental arthritis to the distribution of streptococcal cell wall fragments.

The intraperitoneal injection of peptidoglycan-carbohydrate fragments from Group A streptococci produces a chronic, polyarticular, erosive synovitis in rats. The cell wall material accumulates rapidly in the liver, spleen, and lymph nodes, where it causes little injury. At the same time, selective localization and persistence of the material in the synovial and periarticular tissues occurs.

Modulation of the susceptibility of inbred and outbred rats to arthritis induced by cell walls of group A streptococci.

Inbred Buffalo rats were resistant to the induction of experimental arthritis induced by systemic injection of cell wall fragments in a crude whole-cell sonic extract of group A streptococci. This was in contrast to the susceptibility of outbred Sprague-Dawley and certain other inbred strains. Preliminary breeding studies indicated that genetic control of resistance of susceptibility is multigenic.

Arthritis in rats after systemic injection of streptococcal cells or cell walls.

Further investigation of the biological properties of streptococcal cells and their components has produced a model of erosive synovitis in rats. A single intraperitoneal injection of an aqueous suspension of whole cell sonicate of group A streptococci into Sprague-Dawley rats induced an acute arthritis which evolved into a prolonged inflammatory process characterized by several complete or partial remissions, joint deformity, and ankylosis. The toxic moiety is a peptidoglycan-polysaccharide fragment of the cell wall which persists in tissue.

Relation of rheumatic-like cardiac lesions of the mouse to localization of group A streptococcal cell walls.

Mice injected intraperitoneally with isolated cell wall fragments of Group A streptococci develop a carditis similar to that previously observed in mice injected with crude extracts of this organism. Neither the soluble cytoplasmic components of Group A streptococcal cells nor the nonfragmented cell walls produced carditis in this experimental model. Fluorescein and (125)I-labeled antibodies specific for Group A streptococcal cell wall antigens were used to demonstrate that, for 5 wk after injection, cell wall material is localized around the sites of active lesions in the heart.

Association of experimental chronic arthritis with the persistence of group A streptococcal cell walls in the articular tissue.

A single injection of isolated fragments of group A streptococcal cell walls into the joints of rabbits stimulated an initial acute reaction which was followed by a prolonged inflammatory process. The chronic process was characterized by hyperplasia of the synovial cells, diffuse infiltration of the villi by macrophages, and focal collections of lymphocytes in the stroma of the villi. These histological changes were similar to those seen in the early stages of rheumatoid arthritis.