Dynamics of Blood Components and Peritoneal Fluid during Treatment of Murine E. coli Sepsis with β‐1,3‐D‐polyglucose Derivatives

Abstract

The influences of pretreatment with beta-1,3-D-polyglucose derivatives on levels of cytokines and arachidonic acid metabolites in body fluids in experimental peritonitis in mice are reported. Peritonitis was induced by an intraperitoneal injection of 10(8) live Escherichia coli. Pretreated animals survived the infection, untreated animals died about 12 h after inoculation with E. coli. Levels of IL-1 in plasma and peritoneal fluid, measured by cytotoxicity assay of the HT-2 cell line, increased significantly during the first 48 h after intraperitoneal treatment with beta-1,3-D-polyglucose-derivatized microbeads (GDM) or soluble, aminated beta-1,3-D-polyglucose (AG). After subsequent challenge with E. coli, the levels of IL-1 were significantly lower than in untreated animals. There was no increase in levels of TNF after treatment with GDM or AG, measured by cytotoxicity assay of the WEHI clone 13 cell line. After challenge with E. coli, TNF in plasma and peritoneal fluid was significantly lower compared with untreated animals. Both PGE2 and LTB4, measured by radioimmunoassay kits, were increased in peritoneal fluid after treatment with GDM and AG. After challenge with E. coli, PGE2 and LTB4 in peritoneal fluid increased to about half the concentration of infected control animals. Intraperitoneal injection of indomethacin to pretreated animals resulted in increased levels of IL-1 and TNF and decreased levels of PGE2 following challenge with E. coli. The levels of IL-1 and TNF remained elevated until the animals died after about 12 h. These studies demonstrate that the raised levels of arachidonic acid metabolites after pretreatment with GDM or AG seem to inhibit the otherwise lethal elevation of IL-1 and TNF in body fluids which is seen in untreated animals.

Biological Effects of the Immunomodulator β1‐3d Polyglucose are Strongly Potentiated by Conjugation to Biodegradable Microbeads

“…About 2 mg of glucan coupled to plastic microbeads were able to protect against an otherwise lethal E. coli sepsis in mice [3,4,6,12]. This is three orders of magnitude less than is needed with soluble aminated b1-3 glucan E. coli sepsis following pretreatment with PBS: b1-3 glucan derivatized plastic microbeads (GDP) equivalent to 4 mg of polysaccharide; aminated b1-3 glucan (AG) 10 mg or 2 mg; b1-3 glucan derivatized bovine serum albumin microbeads (GBM) equivalent to 10 mg of polysaccharide; underivatized bovine serum albumin microbeads (BM).…”

“…We have previously reported the striking biological effects of aminated b1-3D polyglucose as: (1) protection against otherwise lethal bacterial infection [1]; (2) complete regression of syngeneic mouse tumours [2]; and (3) strong stimulation of cytokine and arachidonic acid metabolite production [3]. We have also reported that the effects, notably the protection against infection, are potentiated by at least three orders of magnitude when the polysaccharide is linked to polystyrene microbeads [4].…”

Activation of rat macrophages by Betafectin PGG-glucan requires cross-linking of membrane receptors distinct from complement receptor three (CR3)

“…Immobilized and cross-linked ligands have been shown to directly induce a respiratory burst in phagocytic cells [56,57] and the cross-linking of receptors has been shown to stimulate the secretion of cytokines [49,50,58]. Furthermore, ␤-glucans conjugated to plastic or conjugated to biodegradable microbeads have been shown to induce the production of IL-1 and arachidonic acid metabolites by macrophages [20,59,[60][61][62] and PGG-glucan passively adsorbed to a plastic surface has been shown to induce the secretion of IL-1Ra by human peripheral blood mononuclear cells (PBMCs) [30]. Our results with immobilized PGG-glucan provide an additional example of a non-stimulating soluble ligand that, when immobilized, triggers phagocytic cell activation.…”

“…␤-Glucans nonspecifically enhance the innate immune system and are pharmacologically classified as biological response modifiers [3][4][5][6]. In numerous animal models, (1,3)-␤-glucans were shown to have broad anti-infective and anti-tumor activities, with the predominant immunopharmacological effects being the activation of neutrophils and macrophages (i.e., leukocytes) and the stimulation of pro-inflammatory mediators (i.e., cytokines, eicosanoids, and enzymes) [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”

β-Glucans, History, and the Present: Immunomodulatory Aspects and Mechanisms of Action

“…The protective effect of β-glucans was shown in experimental infection with Leishmania major (Al Tuwaiji et al, 1987) and L. donovani (Cook and Holbrook, 1984), C. albicans (Bacon and Farmer, 1968), Toxoplasma gondii (Bousquet et al, 1988), Streptococcus suis (Dritz (Kumar and Ahmad, 1985), Staphylococcus aureus (Liang et al, 1998), Escherichia coli (Rasmussen and Seljelid, 1990), Mesocestoides corti (White et al, 1988), Trypanosoma cruzi (Williams et al, 1989), Eimeria vermiformis (Yun et al, 1998), and anthrax infection (Vetvicka et al, 2002).…”