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PubMed1986

Bacterial lipopolysaccharides, phorbol myristate acetate, and zymosan induce the myristoylation of specific macrophage proteins.

We demonstrate stimulus-dependent incorporation of exogenously added [3H]myristic acid into specific macrophage proteins. In control unstimulated cells an 18-kDa protein is the major acylated species. In cells incubated with bacterial lipopolysaccharide (LPS), or its monoacyl glucosamine phosphate derivative, fatty acid is incorporated into proteins with molecular mass of 68 kDa and a doublet of approximately 42-45 kDa. Phorbol 12-myristate 13-acetate (PMA) or a phagocytic stimulus (zymosan) promotes the acylation of a similar array of proteins. However, PMA and zymosan also promote the myristoylation of unique proteins of 92 and 50 kDa. The fatty acid associated with each of the acylated proteins is myristic acid. The myristate is probably linked to the proteins through amide bonds, since it is not released by treatment with hydroxylamine. Palmitate and arachidonate are not incorporated into proteins in the same manner. Temporal analysis revealed that LPS-induced proteins are myristoylated by 30 min, while the 50-kDa protein myristoylated in response to PMA is labeled later. Most myristoylated proteins appear to be associated with the membrane fraction. Macrophages from C3H/HeJ mice, which do not respond to LPS, do not show any LPS-dependent protein acylation. Interestingly, zymosan and PMA induce the myristoylation of the 50-kDa protein in C3H/HeJ macrophages, but not the acylation of the 68-kDa and 42-kDa doublet species. We suggest that myristoylation of specific proteins is an intermediary in the capacity of LPS, PMA, and zymosan to alter macrophage functions such as arachidonic acid metabolism.

Animals↗
PubMed2005

Glycerylprostaglandin synthesis by resident peritoneal macrophages in response to a zymosan stimulus.

Cyclooxygenase (COX)-2 oxygenates arachidonic acid (AA) and 2-arachidonylglycerol (2-AG) to endoperoxides, which are subsequently transformed to prostaglandins (PGs) and glycerylprostaglandins (PG-Gs). PG-G formation has not been demonstrated in intact cells treated with a physiological agonist. Resident peritoneal macrophages, which express COX-1, were pretreated with lipopolysaccharide to induce COX-2. Addition of zymosan caused release of 2-AG and production of the glyceryl esters of PGE2 and PGI2 over 60 min. The total quantity of PG-Gs (16 +/- 6 pmol/10(7) cells) was much lower than that of the corresponding PGs produced from AA (21,000 +/- 7,000 pmol/10(7) cells). The differences in PG-G and PG production were partially explained by differences in the amounts of 2-AG and AA released in response to zymosan. The selective COX-2 inhibitor, SC236, reduced PG-G and PG production by 49 and 17%, respectively, indicating a significant role for COX-1 in PG-G and especially PG synthesis. Time course studies indicated that COX-2-dependent oxygenation rapidly declined 20 min after zymosan addition. When exogenous 2-AG was added to macrophages, a substantial portion was hydrolyzed to AA and converted to PGs; 1 microm 2-AG yielded 820 +/- 200 pmol of PGs/10(7) cells and 78 +/- 41 pmol of PG-Gs/10(7) cells. SC236 reduced PG-G and PG production from exogenous 2-AG by 88 and 76%, respectively, indicating a more significant role for COX-2 in the utilization of exogenous substrate. In conclusion, lipopolysaccharide-pretreated macrophages produce PG-Gs from endogenous 2-AG during zymosan phagocytosis, but PG-G formation is limited by substrate hydrolysis and inactivation of COX-2.

Animals↗
PubMed1998

Alterations in the functions of the reticuloendothelial and protease-antiprotease systems after intraperitoneal injection of zymosan in rats.

OBJECTIVE: To evaluate alterations in the function of the reticuloendothelial system (RES) and potential protective effects of pretreatment with the antioxidants: N-acetyl-L-cysteine (NAC) or dimethyl sulphoxide (DMSO), after intraperitoneal injection of zymosan (0.50 mg/g body weight) in rats. DESIGN: Experimental study. SETTING: University hospital, Sweden. ANIMALS: 81 male Sprague-Dawley rats. INTERVENTION: Intraperitoneal injection of either 4 ml saline or zymosan suspension (0.50 mg/g body weight). One hour before the intraperitoneal injection, 1 ml of saline, or a solution of NAC (150 mg/kg) or DMSO (80 mg/kg) were given intravenously. MAIN OUTCOME MEASURES: Systemic arterial pressure, packed cell volume, concentrations of plasma proteins and plasma protease inhibitors, uptake of 125I-labelled Escherichia coli in organs, blood clearance and body uptake rate of radiolabelled E. coli, and blood flow in organs at 3, 6, and 12 hours after injection. RESULTS: The uptake of radiolabelled E. coli in the liver, spleen and lungs decreased significantly from 3 hours onwards after zymosan challenge (p <(0.05). Blood clearance and body uptake rate also decreased significantly from 3 hours onwards (p < 0.05), but this did not correlate with the reduction in organ blood flow. Significant falls in plasma concentrations of prekallikrein (p < 0.01) and protease inhibitors (p <0.05) suggested possible contact-phase activation and activation of the kallikrein-kinin and fibrinolytic system. Pretreatment with NAC, and to a less extent DMSO, significantly prevented these alterations in RES function. CONCLUSION: Zymosan induced an impairment in RES function that was not initially associated with a reduction in blood flow. Plasma proteolytic activity seems to be involved in the impaired RES function. Pretreatment with NAC or DMSO effectively improved RES function.

Acetylcysteine↗
PubMed1999

Potential mechanisms responsible for zymosan-associated endothelial injury in rats.

OBJECTIVE: To assess alterations in endothelial barrier integrity and potential factors involved in zymosan-associated endothelial injury. DESIGN: Experimental study. SETTING: University hospital, Sweden. ANIMALS: 42 adult male Sprague-Dawley rats. INTERVENTIONS: One hour before an intraperitoneal injection of paraffin or zymosan (0.25 mg/g body weight), 1.0 ml of a solution of saline, N-acetyl-L-cysteine, dimethyl sulphoxide, indomethacin, verapamil, or allopurinol was given intravenously. MAIN OUTCOME MEASURES: Measurement of tissue water content, tissue intravascular plasma volume, interstitial fluid volume, and extravascular 125I-labelled human serum albumin distribution as well as plasma concentrations of albumin, alpha1-macroglobulin, alpha2-antiplasmin, and antithrombin III, 24 hours after the intraperitoneal injection. RESULTS: Endothelial permeability significantly increased in abdominal organs and the gastrointestinal tract, and plasma antiplasmin concentrations decreased. Pretreatment with N-acetyl-L-cysteine, dimethyl sulphoxide, or indomethacin protected against zymosan-induced endothelial barrier injury and the decline in protease inhibitors in plasma to varying degrees, while pretreatment with verapamil or allopurinol had a limited effect. CONCLUSION: Oxygen free radicals, prostaglandin, and proteases may have roles in the pathogenesis of zymosan-induced endothelial barrier injuries, implying that several mediators probably are interacting.

Animals↗
PubMed1974

Modification of zymosan-induced release of lysosomal enzymes from human polymorphonuclear leukocytes by cytochalasin B.

During the process of phagocytosis, polymorphonuclear leukocytes (PMN) release lysosomal enzymes into the extracellular medium. When the antibiotic cytochalasin B (CB) is present in the incubation medium along with phagocytable particles, enhanced recovery of enzyme activities from the incubation medium has been observed. These findings have led to the interpretation that CB enhances lysosomal enzyme release. Our results contradict this interpretation. The lysosomal enzymes acid phosphatase and beta-galactosidase are unstable after they are released from cells. During the first 5-15 min of phagocytosis, significant amounts of both acid phosphatase and beta-galactosidase can be recovered from the extracellular medium. After this, the recovery of enzyme from the medium declines, presumably because the rate of loss of lysosomal enzyme activity exceeds the rate of release at later time periods. In the presence of CB, the appearance of lysosomal enzymes in the extracellular medium of cells exposed to zymosan is retarded for 5-10 min, after which it begins and then continues for approximately 20 min. At the end of a 30-min incubation period, therefore, in the absence of CB, extracellular levels of lysosomal enzymes (especially those which are unstable) are declining toward low levels while, in the presence of CB, extracellular enzyme levels are continuing to rise. We also measured the lysosomal enzyme remaining within cells after exposure to zymosan. CB retarded the disappearance of enzyme from cells and resulted in significantly less total cell enzyme loss. Thus, in the presence of CB, a greater proportion of the lysosomal enzyme lost from cells is recovered in the extracellular medium. In contrast to the previous conclusions that CB enhances lysosomal enzyme release, our results indicate that CB delays and decreases the zymosan-stimulated release of lysosomal enzymes from PMN. Since CB inhibits phagocytosis by PMN, our results indicate that the antibiotic modifies the mechanism of release of lysosomal enzymes, resulting in zymosan stimulation of their release independently of phagocytosis.

Acid Phosphatase↗
PubMed1984

Local opsonization by secreted macrophage complement components. Role of receptors for complement in uptake of zymosan.

We have examined the role of macrophage (M phi plasma membrane receptors for the cleaved third complement component (iC3b; CR3) and mannosyl, fucosyl terminated glycoproteins (MFR) in uptake of unopsonized zymosan. Monoclonal antibodies against CR3, M1/70 (Mac-1) and MO1, each inhibited approximately 50% of uptake of 125I-zymosan by murine and human M phi, respectively. Yeast mannan inhibited 0-50% of zymosan uptake in various M phi, in parallel with their expression of MFR. We demonstrated that M phi were the source of C3 in our assay and that the activity of other components of the complement system, namely a C3 convertase, factor I, and a factor I cofactor were also present in serum-free cultures of human monocytes. Macrophage C3 was deposited rapidly, within 10 min, on the zymosan particles and mediated binding, ingestion, and stimulation of superoxide release in BCG-activated and thioglycollate-elicited peritoneal M phi via CR3. Local secretion of complement proteins by M phi themselves can therefore opsonize pathogens and cells able to activate the alternative pathway and effect their destruction.

Animals↗
PubMed1995

A role for MARCKS, the alpha isozyme of protein kinase C and myosin I in zymosan phagocytosis by macrophages.

Myristoylated, alanine-rich C-kinase substrate (MARCKS) is a lipopolysaccharide-induced protein kinase C (PKC) substrate that has been proposed to regulate actin-membrane interactions, as well as actin structure at the membrane. We studied the distribution of MARCKS, the alpha isozyme of PKC (PKC alpha), and myosin I in lipopolysaccharide-treated peritoneal macrophages ingesting zymosan particles. MARCKS, PKC alpha, and myosin I colocalized with F-actin and talin in the cortical cytoplasm adjacent to forming phagocytic cups. After particle ingestion was completed, myosin I, F-actin, and talin were no longer enriched in the vicinity of the phagosome. By contrast, MARCKS and PKC alpha remained associated with the phagosome membrane until after acquisition of the lysosomal marker Lamp-1. Vinculin was not detected on phagosomes at any time point examined. Phagocytosis of zymosan was accompanied by rapid and sustained phosphorylation of MARCKS. Inhibitors of PKC reduced zymosan binding to the macrophage surface and blocked the focal accumulation of F-actin, talin, phosphotyrosine-containing proteins, MARCKS, and PKC alpha beneath attached particles. We propose that PKC-dependent phosphorylation is an early signal required for zymosan phagocytosis and that MARCKS and PKC alpha have a role in phagosome maturation. The colocalization of F-actin and MARCKS at the cytoplasmic face of the nascent phagosome reinforces the hypothesis that MARCKS regulates actin structure at the membrane. Our data also suggest that myosin I functions as a mechanical motor during particle uptake.

Actins↗
PubMed2002

Organ damage in zymosan-induced multiple organ dysfunction syndrome in mice is not mediated by inducible nitric oxide synthase.

OBJECTIVE: To examine the role of inducible nitric oxide synthase (iNOS) in the development of the multiple organ dysfunction syndrome (MODS) in a murine model by using either a selective iNOS inhibitor or iNOS knockout mice. DESIGN: Prospective randomized laboratory study. SETTING: Central animal laboratory and experimental laboratory. SUBJECTS: Fifty inbred C57BL/6 mice, 39 iNOS knockout (-/-) mice, and 30 wild-type (+/+) mice, 7-9 wks old, weighing 20-25 g. INTERVENTIONS: Mice received an aseptic intraperitoneal injection of 40 microg of lipopolysaccharide followed by zymosan at a dose of 1 mg/g of body weight 6 days later (day 0). In experiment 1, C57BL/6 mice additionally received intraperitoneal injections with 5 mg of aminoguanidine or saline every 12 hrs, from 4 days after the injection of zymosan onward. In experiment 2, both iNOS-/- mice and corresponding wild-type (iNOS+/+) mice were treated with lipopolysaccharide and zymosan. MEASUREMENTS AND MAIN RESULTS: In all animals, the injection of zymosan induced an acute peritonitis, followed by an apparent recovery. From approximately day 6 onward, animals entered the third-MODS-like-phase, indicated by weight loss, a decrease in body temperature, and significant mortality rates. Quantitative reverse transcriptase polymerase chain reaction and immunochemistry revealed a strongly increased expression of iNOS messenger RNA and iNOS protein in livers of mice in the last phase. However, neither the in vivo administration of aminoguanidine to C57BL/6 mice nor the complete absence of iNOS enzyme (iNOS-/- mice) had a beneficial effect on survival rate, body temperature, or body weight. In addition, relative lung, liver, and spleen weights and lung scores were not different between experimental groups. CONCLUSIONS: The current results strongly argue against an essential and causative role of iNOS in the development of organ damage in our murine model of MODS.

Animals↗
PubMed1997

Gradual development of organ damage in the murine zymosan-induced multiple organ dysfunction syndrome.

A well defined animal model is a prerequisite to test intervention strategies aimed at preventing the development of the multiple organ dysfunction syndrome. This study compares changes in clinical parameters to histopathologic changes in tissues, observed over a 12 day period after a single intraperitoneal injection of zymosan in C57BL/6 mice. Administration of zymosan induced gradual and progressive changes in wet and dry organ weight of the liver, kidneys, and particularly, lungs and spleen that correlated with increasing histopathology. From 6 days after zymosan injection onwards, hemorrhagic spots were found in the lungs evolving into massive hemorrhages at 12 days, when thickened interstitial walls and loss of the honey comb-like structures were observed. The liver displayed progressive accumulation of macrophage-like and mononuclear cells. After 12 days, numerous granuloma-like structures were disseminated throughout the liver parenchyma. The spleen displayed great changes in red and white pulp with increasing numbers of megakaryocytes and plasma-like cells. In the kidneys, necrosis of the tubular epithelium adjacent to granulomas on the ventral (peritoneal) side was found. In mice, a single intraperitoneal challenge with zymosan leads to progressive multiple organ damage, which becomes apparent at some time after the insult. This animal model displays a number of features encountered in human multiple organ dysfunction syndrome and appears suitable to conduct intervention studies.

Animals↗
PubMed1999

Protective effect of N-acetylcysteine on cellular energy depletion in a non-septic shock model induced by zymosan in the rat.

Recently, it was proposed that zymosan, a nonbacterial agent, causes cellular injury by inducing the production of peroxynitrite and consequent poly-(ADP-ribose) synthetase (PARS activation). Here we investigated whether in vivo N-acetylcysteine treatment inhibits cellular injury in macrophages collected from rats subjected to zymosan-induced shock. Macrophages harvested from the peritoneal cavity exhibited a significant production of peroxynitrite, as measured by the oxidation of the fluorescent dye dihydrorhodamine 123, and by nitrotyrosine. Furthermore, zymosan-induced shock caused a suppression of macrophage mitochondrial respiration, DNA strand breakage, and reduction of cellular levels of NAD+. In vivo treatment with N-acetylcysteine (40, 20, and 10 mg/kg, intraperitoneally, 1 and 6 h after zymosan) 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+. Our study supports the view that the antioxidant and anti-inflammatory effect of N-acetylcysteine is also correlated with the inhibition of peroxynitrite production. In conclusion, N-acetylcysteine may be a novel pharmacological approach to prevent cell injury in inflammation.

Acetylcysteine↗
PubMed2001

The involvement of multiple protease-antiprotease systems and gut origin sepsis in zymosan-associated endothelial barrier injury and multiple organ dysfunction in rats.

Multiple organ dysfunction syndrome is a dominant cause of mortality in the intensive care unit. Experimentally, a condition similar to the multiple organ dysfunction syndrome can be induced by the intraperitoneal injection of sterile zymosan. In the present study we investigate potential alterations in multiple organ functions, endothelial permeability, and antiproteinases after intraperitoneal injection of zymosan at various doses. Zymosan-induced generalized inflammation lead to endothelial barrier injury in multiple organs/tissues, a decrease in systemic arterial pressure, impaired organ function and gut defence function, and consumption of protease inhibitors, particularly the consumption of alpha2 antiplasmin. Endothelial barrier injury appears to present a dose- and organ-dependent pattern in multiple organs/tissues, and the increase in endothelial barrier permeability occurred prior to organ dysfunction. Zymosan induced the development of multiple organ dysfunction syndrome, probably initiating multiple protease-antiprotease systems, particularly the fibrinolytic system, leading to endothelial barrier injury, tissue edema, parenchymal cell damage, and eventual organ dysfunction, potentially augmented by a secondary bacterial infection.

Animals↗
PubMed2002

Improved survival of TNF-deficient mice during the zymosan-induced multiple organ dysfunction syndrome.

The purpose of the study was to investigate the course of the zymosan-induced multiple organ dysfunction syndrome (MODS) in the absence of tumor necrosis factor (TNF) in a murine model. Tumor Necrosis Factor-alpha-lymphotoxin-a knockout (TNF/LT-/-) mice (n = 36) and wild-type (TNF/LT+/+) mice (n = 36) received 40 microg of lipopolysaccharide (LPS) intraperitoneally followed by zymosan at a dose of 1 mg/g body weight 6 days later (day 0). Animals were monitored daily for body weight and temperature and clinical symptoms. At day 22, most of the surviving mice were killed to examine organ weight and histology. A small number of animals were followed until day 48. In all animals, zymosan induced an acute sterile peritonitis phase followed by an apparent recovery. From day 8 onwards the TNF/LT+/+ mice entered a third-MODS-like-phase, characterized by loss of body weight, decreased body temperature, and significant mortality. At day 22, survival in the TNF/LT-/- mice (92%) was significantly (P = 0.01) higher than in the TNF/LT+/+ mice (60%). In addition, average body temperature and average relative (vs. weight at day 0) body weight were higher in the TNF/LT-/- mice than in the TNF/LT+/+ mice (35.9 degrees C and 100% vs. 33.3 degrees C and 84%, respectively). However, at this time point, surviving animals from both groups showed similar and significant organ damage, indicated by an increase in absolute and relative (vs body weight) weight of lung, spleen, and liver (liver only in the TNF/LT-/- mice). Moreover, histopathological examination of organs from the surviving animals showed a similar degree of microscopic damage in both groups. Interestingly, besides mononuclear cells, inflammatory infiltrates in lungs and livers of TNF/LT+/+ but not of TNF-/- mice contained neutrophils. In conclusion, TNF-deficient mice exhibit significantly improved morbidity and mortality during zymosan-induced MODS. However, the absence of TNF does not completely protect against MODS in this murine model.

Animals↗
PubMed1987

The role of prostaglandins in the nociceptive response induced by intraperitoneal injection of zymosan in mice.

Intraperitoneal injection of zymosan (1 mg in 0.5 ml saline) in mice induces a transient writhing response accompanied by the synthesis of small amounts of prostaglandin E2(PGE2, less than 2 ng) and larger amounts of PGI2 (200 ng per mouse), measured as its non-enzymatic breakdown product, 6-keto-PGF1 alpha. Although both centrally-acting analgesics (morphine, clonidine) and prostaglandin biosynthesis inhibitors (aspirin, indomethacin, ibuprofen) blocked the writhing response to intraperitoneal injection of zymosan, only the latter reduced prostaglandin levels in the peritoneal cavity. The writhing response correlated equally well with PGE2 levels and 6-keto-PGF1 alpha levels when data from mice treated with centrally-acting analgesics were excluded. However, intraperitoneal injection of PGI2, but not PGE2, reversed the analgesia induced by indomethacin in zymosan-injected mice. Centrally-acting agents, but not ibuprofen, blocked the ability of PGI2 to reverse the analgesic activity of indomethacin. PGI2 (2 micrograms per mouse), injected intraperitoneally in otherwise untreated mice, induced writhing. These data indicate that PGI2 is the prostaglandin involved in mediation of the writhing response to zymosan and that prostaglandin biosynthesis inhibitors, but not centrally-acting analgesics, exert their analgesic activity by reducing the peritoneal level of PGI2. It is possible that PGI2 may have the ability to stimulate pain receptors directly in the mouse peritoneal cavity, in addition to its previously recognized ability to sensitize pain receptors to other pain-producing stimuli.

Animals↗
PubMed1990

The antinociceptive activity of paracetamol in zymosan-induced peritonitis in mice: the role of prostacyclin and reactive oxygen species.

1. Oral administration of high doses of paracetamol (600 mg kg-1 or more) resulted in inhibition of the writhing and reduced the levels of prostacyclin (PGI2, measured as 6-keto-PGF1 alpha) induced by intraperitoneal administration of zymosan in mice. The high oral doses of paracetamol required were accompanied by behavioural toxicity which may have contributed to the inhibition of writhing. 2. The number of writhes per mouse and the proportion of mice writhing at least once correlated significantly with the levels of 6-keto-PGF1 alpha. However, inhibition of writhing by paracetamol occurred at higher levels of 6-keto-PGF1 alpha than was previously observed with acidic non-steroidal anti-inflammatory agents. 3. When injected i.p., PGI2, carbacyclin and iloprost (agonists at the PGI2 receptor) induced writhing. Intraperitoneal injection of PGI2 reversed the inhibition of writhing induced by indomethacin (1 mg kg-1, p.o.) but not that induced by oral administration of paracetamol. 4. Paracetamol at 800 mg kg-1, p.o., inhibited carbacyclin-induced writhing but indomethacin at 1 mg kg-1 p.o. did not. Paracetamol administered i.p. at 100 mg kg-1 reduced the peritoneal levels of 6-keto-PGF1 alpha and inhibited zymosan-induced but not carbacyclin-induced writhing and did not produce behavioural toxicity. 5. The in vitro potency of paracetamol as a prostaglandin synthesis inhibitor is known to be reduced by the presence of lipid peroxides. However, no lipid peroxides, measured as thiobarbituric acid reactive material, were detected in the peritoneal lavage fluid of zymosan-injected mice. 6. Intraperitoneal administration of a mixture of superoxide dismutase and catalase reduced detectable superoxide anion by 98% without inhibiting the writhing response to zymosan or the antinociceptive potency of paracetamol. 7. The data are consistent with the suggestion that inhibition of PGI2 synthesis in the peritoneal cavity by paracetamol is responsible for only a part of its antinociceptive activity in this test. However, extremely high oral doses of paracetamol were required which produced behavioural toxicity which clearly contributed to the inhibition of writhing. The low potency of paracetamol in this model cannot be attributed to the generation of lipid peroxides via the oxidative burst.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Exocytosis of zymosan particles by human phagocytes.

The kinetics of human leucocyte phagocytosis and exocytosis of fluorescein-isothiocyanate (FITC)-labelled zymosan particles were studied by flow cytometry (FCM). The leucocytes rapidly associated with zymosan particles, and internalization was confirmed by a fluorescence quenching technique. For incubation periods longer than about 60 min, exocytosis of ingested particles was observed. All human phagocytes ejected zymosan particles. The rate of exocytosis was about 1 particle per phagocyte per h, and was independent of the number of internalized particles. Exocytosis was dependent on temperature and glucose, but did not require Ca++ and Mg++ ions. Phagocytosis and exocytosis occurred concurrently, and phagocytosis accelerated ejection of previously internalized particles. The exocytosed particles were partially degraded by the phagocytes, and rephagocytosis of ejected zymosan particles was slower than the uptake of control particles. Phagocytes undergoing exocytosis remained intact during the 210 min examined. The findings indicate a heretofore neglected vector in the interaction of prey and phagocytosing cells.

Exocytosis↗
PubMed1993

Modulation of the expression of galactose-specific receptors on Kupffer cells after partial hepatectomy and zymosan stimulation.

Partial hepatectomy (PH) and a single intravenous injection of zymosan were used to provoke expansion of the Kupffer cell population in rat liver. The number of Kupffer cells per unit of area of liver increased after both stimulations. During these growth phases the number of binding sites for galactose-exposing ligands was studied on Kupffer cell plasma membranes. Both partial hepatectomy and zymosan stimulation affected the binding of lactosylated bovine serum albumin conjugated to gold particles (LacBSA-Au5). The reduction observed depended on the time after the PH or zymosan injection studied. Low levels of binding sites were found at 24 h from PH and 5 days after zymosan stimulation and represented only 1/4 or 1/10 of the binding sites expressed on the cell surface of Kupffer cells from normal adult rats. In addition, in both experimental situations we observed that the clustered distribution of gold particles typical of adult Kupffer cell was changed.

Animals↗
PubMed1998

Protective effect of melatonin on cellular energy depletion mediated by peroxynitrite and poly (ADP-ribose) synthetase activation in a non-septic shock model induced by zymosan in the rat.

DNA single-strand breakage and activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS) triggers an energy-consuming, inefficient repair cycle, which contributes to peroxynitrite-induced cellular injury. Recently it was proposed that zymosan, a non-bacterial agent, causes cellular injury by inducing the production of peroxynitrite and consequent PARS activation. Here we investigated whether in vivo melatonin treatment inhibits cellular injury induced by peroxynitrite production and PARS activation in macrophages collected from rats subjected to zymosan-induced shock. Macrophages harvested from the peritoneal cavity exhibited a significant production of peroxynitrite, as measured by the oxidation of the fluorescent dye dihydrorhodamine 123. Furthermore, zymosan-induced shock caused a suppression of macrophage mitochondrial respiration, DNA strand breakage, activation of PARS and reduction of cellular levels of NAD+. In vivo treatment with melatonin (25 and 50 mg/kg, intraperitoneally, 1 hr after zymosan injection) significantly reduced in dose-dependent manner peroxynitrite formation and prevented the appearance of DNA damage, the decrease in mitochondrial respiration, the loss of cellular levels of NAD+, and the PARS activation. Our study supports the view that the antioxidant and antiinflammatory effect of melatonin is also correlated with the inhibition of peroxynitrite production and PARS activation. In conclusion, melatonin may be a novel pharmacological approach to prevent cell injury in inflammation.

Animals↗
PubMed2003

Antinociceptive effects of interleukin-4, -10, and -13 on the writhing response in mice and zymosan-induced knee joint incapacitation in rats.

The antinociceptive effects of interleukin (IL)-4, -10, and -13 were investigated in two different experimental pain models. Our results showed that pretreatment (30 min) with IL-4 (1-5 ng/animal), IL-10 (0.4-10 ng/animal), or IL-13 (0.4-2.5 ng/animal) inhibited the writhing response induced by the i.p. administration of acetic acid (53-89%) or zymosan (63-74%) in mice, and the knee joint incapacitation induced by i.a. injection of zymosan (49-66%) in rats. Neither of the cytokines affected the pain elicited in mice using the hot-plate test. This analgesic effect of IL-4, -10, and -13 was not reversed by the combined pretreatment with the opioid receptor antagonist naloxone. IL-4, -10, or -13 significantly inhibited the release of both tumor necrosis factor (TNF)-alpha (60, 53, and 100%, respectively) and IL-1beta (80, 100, and 100%, respectively) by mice peritoneal macrophages obtained after local (i.p.) injection of zymosan. Antisera against IL-4, -10, and -13 potentiated both the zymosan-induced writhing response and the articular incapacitation. Our results demonstrate that IL-4, -10, and -13 display analgesic activity that is probably not due to endogenous opioid release. This analgesic effect could be related to a peripheral mechanism, probably via the inhibition of the release of the pro-inflammatory cytokines TNF-alpha and IL-1beta by resident peritoneal macrophages.

Acetic Acid↗