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PubMed1985

Reactive-oxygen formation and its relationship to prostaglandin and cyclic AMP production by zymosan-treated rat peritoneal macrophages.

Addition of zymosan (20 particles/cell) to suspensions of resident rat peritoneal macrophages caused an increase in the concns of prostaglandins and cyclic AMP. Preincubation of the cells with inhibitors of arachidonate metabolism led to inhibition of prostaglandin, but not of cyclic AMP, formation, which suggested that the two processes may occur independently of each other in phagocytosing cells. The luminol-dependent chemiluminescence associated with the addition of zymosan to the cells consisted of a minor, Ca2+-dependent, glucose-independent component and a major, glucose-dependent, Ca2+-independent component. Only the minor, Ca2+-dependent component appeared to be related to the lipoxygenation of arachidonic acid. Close examination of the production of prostaglandins and cyclic AMP and of chemiluminescence after zymosan addition, indicated that the expanded pool of endogenous cyclic AMP was probably not a negative modulator of the other two processes, although they remained susceptible to inhibition by exogenously-added cyclic AMP analogues or PGE2. The events induced by zymosan may be relevant to the physiological roles of prostaglandins during the inflammatory response.

Animals↗
PubMedDate not supplied

Heparin and derivatized heparin inhibit zymosan and cobra venom factor activation of complement in serum.

Heparin has been shown to inhibit activity of the alternative, classical and terminal pathways of complement by regulating C1, C1 inhibitor, C4 binding protein, C3b, factor H and S-protein. In vivo, heparin inhibits cobra venom factor activation of complement in a dose-related manner in guinea pigs. However, the ability of heparin and of modified heparin to inhibit complement activation in serum has not been examined systematically. The present study compared commercial heparin with a modified heparin that has reduced anticoagulant activity (N-desulfated, N-acetylated heparin) for ability to inhibit cobra venom factor and zymosan-induced complement activation in guinea pig and human serum. Both heparins inhibited cobra venom factor and zymosan-induced consumption of C3 activity in both human and guinea pig serum. In both serum types, commercial heparin was about twice as active as modified heparin on a weight basis for ability to inhibit cobra venom factor-induced complement activation. Both heparins also inhibited zymosan-induced complement activation in human serum. About four times more heparin was required to inhibit cobra venom factor-induced complement activation in guinea pig serum than in human serum while heparin was more than ten times more active in human serum than in guinea pig serum when zymosan was used as the activator of complement. This study suggests that heparin is considerably more effective in regulating complement activity in humans than in guinea pigs, an animal model in which heparin clearly has in vivo capacity to regulate complement activity. These observations represent an important step in the development of new clinically relevant oligosaccharide-derived pharmacologic agents to regulate complement activity.

Animals↗
PubMed1983

Correlation between chemiluminescence response and rate of zymosan uptake by rat alveolar macrophages. Scanning electron microscope observations.

The rate of particle uptake by rat alveolar macrophages (AM) exposed to zymosan (mean number of zymosan particles becoming bound to 100 cells at a fixed time interval) was determined with the aid of the scanning electron microscope (SEM). The intensity of the chemiluminescence (CL) emitted by the AM on addition of zymosan, was measured concomitantly. During the whole course of CL emission, all the particles were found to be either attached or engulfed, but not ingested by the AM. A good correlation was obtained between the time dependence of CL intensity and that of the rate of particle uptake, both reaching a peak value at about 5 min after exposure. It is therefore assumed that the CL emitted by AM exposed to zymosan reflects the attachment and engulfment stages of phagocytosis.

Animals↗
PubMed1996

Role of kinases and G-proteins on arachidonate release induced by zymosan in mouse peritoneal macrophages.

The present study investigated the role of kinases and G-proteins in arachidonic acid (AA) mobilization by resident mouse peritoneal macrophages in response to phagocytosis of opsonized zymosan. Stimulation of resident murine peritoneal macrophages with opsonized zymosan caused an increase in [3H] arachidonic acid release. This increase was dose-dependent and was not accompanied by de novo synthesis of proteins. Neither staurosporine, a protein kinase C inhibitor, nor genistein, a tyrosine kinase inhibitor, had any effect on [3H] AA mobilization, although trifluoperazine significantly inhibited AA release. The involvement of G proteins and phospholipase C (PLC) in the regulation of arachidonic acid release induced by opsonized zymosan was also examined in mouse peritoneal macrophages. Prior treatment of cells with pertussis toxin induced a partial decrease in AA mobilization. However, neomycin or aspirin, at doses that inhibit inositol phosphate formation (PLC activity), did not [3H] AA mobilization by PLA2. We proposed that the AA release by peritoneal macrophages in response to opsonized zymosan phagocytosis could be due to the participation of enzymes other than PLC and PKC, or proteins other than G proteins.

Analysis of Variance↗
PubMed2006

Gelatinase B/matrix metalloproteinase-9 contributes to cellular infiltration in a murine model of zymosan peritonitis.

Murine zymosan-induced peritonitis represents a well-defined model of acute inflammation. However, the molecular mechanisms by which leukocytes degrade basement membranes during extravasation into the peritoneum are not clear. Gelatinase B (MMP-9) is thought to participate in cellular migration, yet its role in leukocyte transmigration through endothelia during inflammation remains controversial. The aim of the present study was to evaluate the role of MMP-9 in the cell influx during zymosan-induced experimental peritonitis. In zymosan-treated Balb/c mice MMP-9 and its natural inhibitor (tissue inhibitor of metalloproteinase 1 - TIMP-1) were present in the peritoneal fluid and plasma at the time of peritoneal neutrophil (polymorphonuclear leukocyte - PMN) infiltration and persisted there until the time of monocytes/macrophages influx. To probe the function of gelatinases, gelatinase B-deficient mice (MMP-9(-/-)) were used as well as Balb/c mice treated with cyclic CTTHWGFTLC (INH), a specific peptide inhibitor of gelatinases. The studies revealed that in either group of mice deprived of MMP-9 activity, PMN infiltration was impaired at the time of their maximal extravasation (6h) while tumor necrosis factor alpha (TNF-alpha), cytokine-induced neutrophil chemoattractant (KC) and interleukin 10 (IL-10) levels were not changed. At later stages (24 h post-zymosan) a significant increase in PMNs was observed in MMP-9(-/-) mice, but not in the inhibitor-treated mice, in comparison to their respective controls. Moreover, intraperitoneal (i.p.) injection of recombinant mouse pro-MMP-9 induced leukocyte accumulation in peritoneum. Collectively, the findings indicate that gelatinase B participates in leukocyte transmigration; however, its function can be compensated by other mechanisms.

Animals↗
PubMed2005

Morphine-induced changes in the activity of proopiomelanocortin and prodynorphin systems in zymosan-induced peritonitis in mice.

We have shown that supplementation of proinflammatory agent with a high dose of morphine not only abolishes inflammation-related pain symptoms but also inhibits influx of leukocytes to the inflamed peritoneal cavity. Present investigations focused on effects of morphine on proopiomelanocortin and prodynorphin systems during zymosan-induced peritonitis. Males of SWISS mice were ip injected with zymosan (Z, 40 mg/kg) or zymosan with morphine (ZM, 20 mg/kg). At time 0 (controls) and 4 and 24h after stimulation, peritoneal leukocytes (PTLs) were counted, PTL levels of opioid peptides (beta-endorphin and dynorphin) measured by radioimmunoassays, while mRNAs coding their respective precursors (POMC and PDYN) and receptors (MOR and KOR) determined by QRT-PCR. Influx of inflammatory PTLs, mainly PMNs, was significantly delayed by morphine co-injection. Total levels of beta-endorphin and dynorphin corresponded with PTL numbers, while levels per cell were similar in all groups except of beta-endorphin, decreased in ZM at 4h. Levels of both peptides in peritoneal fluid were increased in Z and ZM groups at 4h, while at 24h only in case of beta-endorphin in Z group. POMC was increased only in ZM group at 4h of peritonitis, while PDYN in both Z and ZM groups at the same time. MOR mRNA was increased 24h after injection in Z and ZM groups, while KOR mRNA was similar in all groups except of decrease in Z at 24h. In conclusion, endogenous opioids and their receptors are involved in zymosan-induced peritonitis and affected in various ways by morphine co-injection.

Animals↗
PubMed2005

Altered chemokine response in an animal model of multiple organ dysfunction syndrome induced by zymosan.

PURPOSE: The aim of this study was to determine the monocyte chemoattractant protein-1 (MCP-1) response over time in an animal model of multiple organ dysfunction syndrome (MODS). METHODS: On day 0, rats were randomized to receive an intraperitoneal injection of zymosan at a dose of 1 mg/g of body weight (n = 36) or vehicle (n = 9). Serum, peritoneal lavage (PL) fluid, and bronchoalveolar lavage (BAL) fluid were collected from 3 rats in the control group and 6 to 7 rats in the zymosan group at days 1, 5, and 12. Monocyte chemoattractant protein-1 concentrations were determined by enzyme-linked immunosorbent assay. RESULTS: The authors observed a 47% mortality in the zymosan-treated rats. Monocyte chemoattractant protein-1 levels were unchanged in the serum, PL, and BAL of control animals. Both serum and PL MCP-1 were significantly higher in zymosan-treated rats on days 1 (P < .01) and 5 (P < .05) when compared with controls. By day 12, no difference between the 2 groups was observed. No significant difference was noted in BAL MCP-1. CONCLUSIONS: Chemokines are increased systemically and locally during MODS. The fact that MCP-1 is significantly higher early in the course of MODS may suggest that this chemokine is important in the early inflammatory changes that lead to MODS later in the course of this illness.

Animals↗
PubMed2006

The macrophage beta-glucan receptor mediates arachidonate release induced by zymosan: essential role for Src family kinases.

Yeast-derived zymosan beads are among the classical agents used to induce sterile inflammatory responses in experimental animals and macrophage activation in cell culture. In macrophages the cytosolic phospholipase A2 becomes activated, leading to mobilization of arachidonate and the generation of prostaglandins and leukotrienes. Although zymosan can interact with several receptors it has not been unequivocally demonstrated which interaction is required for induction of the eicosanoid response. We have compared arachidonate release induced in primary mouse macrophages by zymosan and particulate beta-glucan and found striking similarities. The similarities include the effects of dectin-1 antagonists (soluble beta-glucan and laminarin) and of inhibitors of Src family kinases, the Tec kinase Btk, phosphatidylinositol 3-kinase and the Map kinases ERK and p38. Furthermore, particulate beta-glucan was equally effective as zymosan in causing phosphorylation of phospholipase Cgamma2, arguing that both agents act via the beta-glucan receptor dectin-1 and that the above signal components are engaged down-stream of that receptor. Suggestive evidence for a role of the scaffold adaptor Gab2 is also presented.

Animals↗
PubMed1995

Alpha-tocopherol attenuates lung edema and lipid peroxidation caused by acute zymosan-induced peritonitis.

BACKGROUND: Inflammation-induced disease as seen with trauma and infection can lead to increased lung oxidant activity resulting in cell membrane lipid peroxidation. Acute zymosan-induced peritonitis in rats produces lung inflammation, edema, and lipid peroxidation. We determined whether administered alpha-tocopherol (vitamin E), the key antioxidant protection against cell membrane lipid peroxidation, would improve this process. METHODS: Male Wistar rats were given 0.75 mg/kg of intraperitoneal zymosan, volume resuscitated, monitored, and killed at 4 or 24 hours. Lung histologic changes and levels of conjugated dienes, a marker of lipid peroxidation, were used to monitor injury. The levels of vitamin E, vitamin C, and catalase were used to monitor antioxidant defenses. The effect of administering alpha-tocopherol (50 mg/kg) by gavage immediately after zymosan on the degree of the lung injury was then determined. RESULTS: Twenty-four hours after zymosan was administered, the vitamin E levels in plasma were significantly decreased, but lung tissue vitamin E levels were maintained, whereas tissue catalase and vitamin E levels decreased. Lung tissue-conjugated diene levels, alveolar edema, and neutrophil count were significantly increased. alpha-Tocopherol treatment increased the postzymosan plasma vitamin E levels by 50%. Lung tissue vitamin E levels did not increase; however, the degree of lung injury and lipid peroxidation was significantly attenuated. Tissue catalase levels were also maintained. CONCLUSIONS: We conclude that alpha-tocopherol given at the onset of a progressing inflammatory injury can protect the lung from oxidant damage and attenuate the degree of lung injury.

Acute Disease↗
PubMed1981

Activation of bone marrow-derived macrophages by repeated zymosan phagocytosis leads to enhanced prostaglandin synthesis.

Bone marrow-derived macrophages were stimulated by the addition of zymosan. Phagocytic activity and prostaglandin release were taken as a measure of the activation state of the macrophages. Repeated stimulation with zymosan of macrophages which had been freed from extracellular zymosan led to further phagocytosis and prostaglandin formation. Very low amounts of prostaglandins were synthesized after the second phagocytic stimulus if the time interval between the first and second stimulation was one or two hours. In contrast, however, if the second phagocytic stimulation occurred 9 hours after the first stimulation there was a doubling of the number of phagocytosed zymosan particles and a fifteen fold increase in prostaglandin synthesis. These findings are explained as the consequences of internalized membrane material which provides additional substrates for the generation of prostaglandins.

Animals↗
PubMed1989

Studies on the accumulation of serum proteins in zymosan-induced inflammation in mouse peritoneum.

Inflammatory responses were induced in mice by intraperitoneal (i.p.) injection of zymosan. This resulted in a rapid accumulation of protein in the peritoneum that was dependent on the time of the injection and concentration of zymosan used. Though other stimuli, e.g., phorbol myristate acetate, lipopolysaccharide, carrageenan and latex beads, caused the accumulation of proteins, the maximum response was obtained only with zymosan. Injection of free fatty acids were unable to induce protein accumulation in peritoneum. Factors which decreased leukotriene production in mouse peritoneum, i.e., dietary n-3 fatty acids essential fatty acid deficient diets, did not affect protein accumulation. Direct injection of leukotrienes also failed to induce protein accumulation. Analyses revealed that the proteins were similar to serum proteins, indicating that zymosan causes the leakage of serum proteins into peritoneum.

Animals↗
PubMed1999

Activation of arachidonate release and cytosolic phospholipase A2 via extracellular signal-regulated kinase and p38 mitogen-activated protein kinase in macrophages stimulated by bacteria or zymosan.

The mitogen-activated protein kinases (MAP kinases), extracellular signal-regulated kinase (ERK) and p38, can both contribute to the activation of cytosolic phospholipase A2 (cPLA2). We have investigated the hypothesis that ERK and p38 together or independent of one another play roles in the regulation of cPLA2 in macrophages responding to the oral bacterium Prevotella intermedia or zymosan. Stimulation with bacteria or zymosan beads caused arachidonate release and enhanced in vitro cPLA2 activity of cell lysate by 1.5- and 1.7-fold, respectively, as well as activation of ERK and p38. The specific inhibitor of MAP kinase kinase, PD 98059, and the inhibitor of p38, SB 203580, both partially inhibited cPLA2 activation and arachidonate release induced by bacteria and zymosan. Together, the two inhibitors had additive effects and completely blocked cPLA2 activation and arachidonate release. The present results demonstrate that ERK and p38 both have important roles in the regulation of cPLA2 and together account for its activation in P. intermedia and zymosan-stimulated mouse macrophages.

Animals↗
PubMed2003

HUVEC take up opsonized zymosan particles and secrete cytokines IL-6 and IL-8 in vitro.

Uptake of zymosan A particles by human umbilical vein endothelial cells (HUVEC) and its effect on cellular cytokine and oxygen radical production was examined. HUVEC took up more serum-opsonized than -unopsonized zymosan as demonstrated by flow cytometry with fluorescence-labeled particles. The former uptake was inhibited in the presence of anti-C3c antibodies and thus complement-mediated. It probably occurred via CR1 (CD35), although participation of other receptors cannot be ruled out. Scanning electron microscopy indicated that HUVEC with fully internalized zymosan particles were damaged. Prolonged incubation of both serum-opsonized and -unopsonized zymosan particles with HUVEC induced increased secretion of the proinflammatory cytokines IL-6 and IL-8 to the cell culture supernatants, but had no effect on production of oxygen radicals. The results confirm previous reports that EC can internalize yeast and other pathogens and points to complement as a mechanism of uptake, but illustrates that the cells may be damaged in the process. Moreover, EC may participate in the anti-infection defense effort by secreting proinflammatory and chemotactic cytokines in response to the contact with pathogens.

CD11b Antigen↗
PubMed1999

IL-13 induces serine phosphorylation of cPLA2 in mouse peritoneal macrophages leading to arachidonic acid and PGE2 production and blocks the zymosan-induced serine phosphorylation of cPLA2 and eicosanoid production.

In a recent investigation, we demonstrated that long-term treatment of macrophages with IL-13 enhances cPLA2 expression and modulates zymosan-stimulated AA mobilization. In the present study, we examine the ability of IL-13 to modify the cPLA2 activity and the AA mobilization of macrophages after a short-period of treatment. We demonstrate that in resting macrophages, IL-13 induces, through a MAP kinase-dependent process, (1) an increase of free AA release within 15 min, followed by increased PGE2 production and (2) a time-dependent serine phosphorylation of cPLA2. Conversely, in macrophages stimulated by zymosan, IL-13 added 30 min before zymosan inhibited the AA release and the serine phosphorylation of cPLA2 induced by the phagocytic agonist. In conclusion, these findings show for the first time that a Th2-type cytokine can upregulate cPLA2 activity and downregulate zymosan-induced AA metabolism. Thus, establishment of the connection between these two events may help to understand the complex regulatory role of IL-13 on the macrophage AA metabolism.

Animals↗
PubMed1999

Beneficial effects of Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), a superoxide dismutase mimetic, in zymosan-induced shock.

1 The therapeutic efficacy of Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), a novel superoxide dismutase mimetic which scavenges peroxynitrite, was investigated in rats subjected to shock induced by peritoneal injection of zymosan. 2 Our data show that MnTBAP (given at 1, 3 and 10 mg kg-1 intraperitoneally, 1 and 6 h after zymosan injection) significantly reduce in dose dependent manner the development of peritonitis (peritoneal exudation, high nitrate/nitrite and peroxynitrite plasma levels, leukocyte infiltration and histological examination). 3 Furthermore, our data suggest that there is a reduction in the lung, small intestine and liver myeloperoxidase (MPO) activity and lipid peroxidation activity from MnTBAP-treated rats. 4 MnTBAP also reduced the appearance of nitrotyrosine immunoreactivity in the inflamed tissues. 5 Furthermore, a significant reduction of suppression of mitochondrial respiration, DNA strand breakage and reduction of cellular levels of NAD+ was observed in ex vivo macrophages harvested from the peritoneal cavity of zymosan-treated rat. 6 In vivo treatment with MnTBAP significantly reduced in a dose-dependent manner peroxynitrite formation and prevented the appearance of DNA damage, the decrease in mitochondrial respiration and the loss of cellular levels of NAD+. 7 In conclusion our results showed that MnTBAP was effective in preventing the development of zymosan-induced shock.

Alanine Transaminase↗
PubMed2001

Modulation of haem oxygenase-1 expression by nitric oxide and leukotrienes in zymosan-activated macrophages.

Phagocytosis of unopsonized zymosan by RAW 264.7 macrophages upregulated protein expression of haem oxygenase-1 (HO-1), inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2) in a time- and concentration-dependent manner. In the presence of zymosan, exogenous prostaglandin E(2) (PGE(2)) did not exert significant effects on the expression of these three enzymes. In contrast, exogenous leukotriene B(4) (LTB(4)) and LTC(4) in the nanomolar range inhibited HO-1 and iNOS expression, as well as nitrite accumulation. The COX inhibitors indomethacin and NS398 weakly inhibited HO-1 expression but had no effect on iNOS and COX-2 expression or nitrite. In contrast, the 5-lipoxygenase (5-LO) inhibitor ZM 230,487 significantly decreased HO-1, iNOS and nitrite, which were not affected by zileuton. Dexamethasone showed an inhibitory effect on HO-1 expression induced by zymosan. ZM 230,487 but not zileuton, inhibited the shift due to nuclear factor-kappaB (NF-kappaB), whereas they did not modify activator protein-1 (AP-1) binding. Our results suggest that inhibition of NF-kappaB binding could mediate the effects of ZM 230,487 on the modulation of HO-1 and iNOS protein expression. NOS inhibition by L-N(G)-nitroarginine methyl ester (L-NAME) or 1400 W abolished nitrite production and strongly reduced HO-1 expression. These results show an induction of HO-1 protein expression by zymosan phagocytosis in macrophages, with a positive modulatory role for endogenous NO and a negative regulation by exogenous LTs, likely dependent on the reduction of iNOS expression and NO production.

Amidines↗
PubMed1981

The binding of human complement proteins C5, factor B, beta 1H and properdin to complement fragment C3b on zymosan.

The covalent binding of complement fragment C3b to zymosan by the action of the alternative-pathway C3 convertase and the reversible binding of several complement proteins (component C5, factor B, beta 1H and properdin) to C3b on zymosan have been investigated. When C3b is deposited on zymosan after activation by a surface-bound C3 convertase, the C3b molecules are deposited in foci around the C3 convertase site, with an average of 30 C3b molecules per site. The association constants of C5, factor B, beta 1H, and properdin for C3b bound to zymosan have been determined. The association constants ranged from 6.5 x 10(-5) M-1 for factor B to 2.9 x 10(7) M-1 for properdin. An approximate stoichiometry of 1 : 1 for C5, factor B, and properdin binding to C3b has been observed. Curvilinear Scatchard plots were observed for beta 1H binding to C3b, with the maximal extrapolated ratio of beta 1H to C3b of 0.32. Physiological amounts of properdin increase by 7-fold the affinity constant for factor B binding to C3b with no alteration in the stoichiometry. Similarly, physiological amounts of factor B increase the affinity constant of properdin to C3b about 4-fold with only a small measured difference in stoichiometry. Competition binding studies and protein modification suggest that C5, factor B, beta 1H, and properdin each bind to a distinct region on C3b.

Binding, Competitive↗
PubMed1995

Glucan receptor and zymosan-induced lysosomal enzyme secretion in macrophages.

A receptor for beta-glucan was in the present study shown to mediate binding of zymosan particles to resident mouse peritoneal macrophages. Lysosomal enzyme secretion in response to zymosan was maximal at a low particle/cell ratio, continuous for at least 3 h after particle/cell contact and inhibitable by soluble glucan. Latex particles of various size caused no selective secretory response, but at high particle/cell ratios were toxic. By use of a fluorescent ligand, the macrophage beta-glucan receptor was shown to be trypsin-sensitive, Ca2+/Mg(2+)-independent, recirculating and also present in an intracellular mobilizable pool. Binding of ligand to the beta-glucan receptor and inhibition of the lysosomal secretory response to zymosan were both more efficient with glucans of larger size, indicating that clustering of glucan receptors at the cell surface occurs. Such clustering could stabilize ligand binding by multiple interactions and possibly trigger intracellular signaling events on binding of zymosan particles.

Acetylglucosaminidase↗