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PubMed1992

A wave of elevated intracellular free calcium spreads through human neutrophils during phagocytosis of zymosan.

The cytosolic concentration of free calcium ([Ca2+]i) plays an important role in the control of many neutrophil functions. In this study, we characterize the early rapid subcellular changes in [Ca2+]i that occur in adherent neutrophils during phagocytosis of zymosan particles, using both dual- and single-excitation wavelength Fura-2 ratio imaging. We observed a wave of elevated cytosolic calcium that began shortly after zymosan contact and propagated from the region of neutrophil contact with the zymosan throughout the cell at a rate of approximately 17 microns/s at 31 degrees C. The wave was initiated by both opsonized and unopsonized zymosan and occurred independently of extracellular calcium. Multiple characteristics of the [Ca2+]i signal (including the absolute and regional [Ca2+]i and wave properties such as amplitude, frequency, duration, and topography) may be responsible for the differential regulation of cellular functions in the neutrophil.

Calcium↗
PubMed1996

Resident joint tissues, rather than infiltrating neutrophils and monocytes, are the predominant sources of TNF-alpha in zymosan-induced arthritis.

Intraarticular injection of zymosan (1 mg) into the knee joints of male Wistar rats led to infiltration of neutrophils and monocytes, joint swelling and elevation of tumour necrosis factor (TNF-alpha) in joint lavage fluids. Neutrophil infiltration was maximal at 5 h after induction of arthritis but had declined by 24 h post injection. Monocyte infiltration was maximal around the same time as that of the neutrophil infiltration but was sustained through 24 h. Joint swelling was apparent at 1 h but was not maximal until 6 h after induction of zymosan-induced arthritis. The maximum levels of TNF-alpha (150-200 pg of mouse equivalents per joint) in joint fluid preceded the infiltration of neutrophils and monocytes and was maximal at 1-2 h after injection of zymosan but had declined to below 100 pg per joint at 5 h (the time of maximal leukocyte infiltration) and was below the lower limit of detection at 24 h after induction of arthritis. Depletion of neutrophils and monocytes with a rabbit anti-rat leukocyte antibody reduced leukocyte infiltration and the later phase of joint swelling but did not reduce the levels of TNF-alpha in joint fluid. These data indicate that in zymosan-induced arthritis TNF-alpha is produced from the resident joint tissues such as the synovial lining cells rather than infiltrating neutrophils or monocytes.

Animals↗
PubMed1999

Immune complexes, but not streptococcal cell walls or zymosan, cause chronic arthritis in mouse strains susceptible for collagen type II auto-immune arthritis.

In this study we investigated mechanisms involved in the chronic character of experimental collagen type II induced arthritis (CIA). We compared the knee joints of mouse strains which are prone to develop this autoimmune disease (DBA/1,B10RIII) with other nonsusceptible mouse strains (C57Bl/6,BALB/c) in their reaction to different stimuli: immune complexes (IC), zymosan and streptococcal cell walls (SCW). Inflammation was evaluated by(99m)Tc uptake measurements and in haematoxylin- and eosin-stained knee-joint sections. Passively induced immune complex mediated arthritis (ICA) in knee joints of C57Bl/6 and BALB/c mice, showed moderate cell influx at day 3, whereas at day 7 only minor amounts of inflammatory cells were observed. In contrast, in arthritic DBA/1 and, to a lesser extent, in B10.RIII joints, a tremendous cell influx was observed at day 3 and even at day 14 there was still significant synovitis. In contrast, if arthritis was elicited by intra-articular injection of zymosan or SCW in C57Bl/6 and DBA/1, the course of inflammation was similar in both strains and no chronic inflammation developed. In line with severe arthritis, chemotactic factor production was dramatically enhanced in ICA in DBA/1 mice, and a prolonged production of IL-1 was evident. When IL-1 was neutralized before or during the ICA using specific anti-IL-1alpha,beta antibodies, inflammation could be blocked completely. Single or multiple injection of IL-1 in the knee joint of C57Bl/6 or DBA/1 showed comparable inflammation, indicating that the chemotactic response per se is comparable in both strains. No prolonged production of IL-1 was found during zymosan or SCW arthritis. Selective removal of macrophages from the synovial intima prior to ICA induction (using clodronate-containing liposomes) prevented the onset of inflammation in C57Bl/6 and DBA/1 mice. It can be concluded that immune complexes, but not zymosan or SCW, cause a more severe and chronic arthritis in mouse strains which are susceptible for collagen type II autoimmune arthritis. This is due to higher and prolonged expression of IL-1 and chemotactic factors, caused by stimulation with immune complexes. The interaction of IC with lining macrophages probably plays a dominant role in development of chronicity.

Animals↗
PubMed1990

Cellular and extracellular phospholipase A2 activity in zymosan pleurisy in rat.

The pleural exudate from rats treated intrapleurally with zymosan contains phospholipase A2 (PLA2) activity which is Ca2(+)-independent and optimally active at a neutral pH. This PLA2 activity was found in approximately equal amounts in both the cellular and extracellular fractions of the exudate. The Ca2(+)-independency of the PLA2's in the pleural exudate distinguishes them from plasma PLA2's and this suggests that the source of the exudate PLA2's is not plasma. The appearance of PLA2 activity in zymosan-induced pleural exudate correlates temporally with increases in exudate volume and pleural cell number. In all cases, the maximum response was seen 24 hr after zymosan challenge. All parameters of pleurisy and PLA2 activity are similarly sensitive to the steroid dexamethasone which has been hypothesized to act, in part, through the synthesis of PLA2 inhibitory peptides. In its entirety, this information suggests that there is a relationship between pleural PLA2 activity and the appearance of pleural inflammation (exudate volume and cells) and that PLA2 may play an important role in the initiation and propagation of this inflammatory process in rats. Furthermore, the zymosan-induced pleurisy model may serve as a useful model for the identification of PLA2 inhibitors with antiinflammatory activity.

Animals↗
PubMed1983

Biochemical and morphologic changes in rabbit lung following endotracheal instillation of zymosan particles.

In order to establish a model of lung disease in which the usefulness of potential antiinflammatory compounds can be evaluated, we have analyzed the biochemical and cellular responses of rabbits to zymosan deposition in their lungs. A suspension of zymosan particles was instilled into the lungs of rabbits using an intratracheal catheter. Because the influx of leukocytes and the transudation of plasma into affected lungs was expected to contribute to the total cellular enzyme and protein levels, lungs were homogenized and assayed after various time intervals for six cellular enzymes and for protein content. After one day, alkaline phosphatase and neutral protease levels were elevated by 90% and 50%, respectively, above normal values. After two and three days, all of the pulmonary enzymes assayed displayed maximal two- to fourfold increases in their levels of activity. After seven days, only the alkaline phosphatase and neutral protease levels remained slightly elevated by 50% and 30%, respectively. Histologic analysis revealed focal and diffuse intraalveolar, interstitial, peribronchiolar, and perivascular accumulations of macrophages, granulocytes, and lymphocytes. Severe pulmonary edema, evident microscopically after one to three days, correlated well with 100% increases in both the wet weight and protein content of the lungs. In control experiments, the intratracheal infusion of saline solution minus zymosan particles resulted in a variety of enzymatic changes in the lungs after three days, which could be distinguished both enzymatically and histologically from those following zymosan deposition; histopathologic analysis revealed a pattern of intravascular congestion with erythrocytes, edematous thickening of alveolar septa, and focal intraalveolar hemorrhages, but with no inflammatory infiltration. In summary, this study demonstrates the time course of an experimental model for acute and chronic lung inflammation, the extent of which may be quantitatively evaluated using cellular enzymatic markers.

Animals↗
PubMed1987

Effect of selected antiinflammatory agents and other drugs on zymosan, arachidonic acid, PAF and carrageenan induced paw edema in the mouse.

Zymosan, carrageenan, arachidonic acid and platelet activating factor (PAF) were used to induce inflammation (edema) in the paws of mice. Antiinflammatory drugs (e.g., BW 755C and indomethacin) as well as cyproheptadine (mediator antagonist), theophylline (phosphodiesterase inhibitor) and guanabenz (alpha adrenoceptor agonist) showed the greatest efficacy in the carrageenan and zymosan models. Nonsteroidal antiinflammatory (NSAIDs) agents showed greater activity in the arachidonic acid (AA) paw edema model than the dual 5-lipoxygenase (LO)/cyclooxygenase (CO) inhibitors. The PAF model was insensitive to NSAIDs but showed some activity with drugs possessing inhibitory 5-LO activity (e.g., phenidone, BW 755C) and the mediator antagonist, cyproheptadine. Suramin, a complement inhibitor, as expected, was active only against zymosan-induced edema. In conclusion, the inhibitory activities of dual 5-LO/CO inhibitors and NSAIDs were not different in the zymosan, carrageenan and AA edema models in the mouse; however, some selectivity for 5-LO inhibitors was observed in the PAF model.

Animals↗
PubMed1989

Extracellular phospholipase A2 activity in cell free peritoneal lavage fluid from mice with zymosan peritonitis.

The kinetics and appearance of extracellular phospholipase A2 (PLA2) activity and its relationship to the appearance of arachidonic acid (AA) metabolites in the peritoneal cavity of mice injected with zymosan is described. AA metabolites levels including leukotriene C4 (LTC4) were maximum 15-30 min after zymosan. Peak PLA2 activity was also found 15-30 min after zymosan and was significantly increased above levels found in saline control exudates (3.83 +/- 0.89 and 0.35 +/- 0.11, respectively, p less than or equal to 0.05). Results show that an extracellular PLA2 is present in zymosan peritonitis.

Animals↗
PubMed1993

A new assay for antiphlogistic activity: zymosan-induced mouse ear inflammation.

A new model of local inflammation has been developed: intradermal zymosan-induced mouse ear edema. The symptoms of inflammation induced by injecting zymosan into one of the ears were followed up for 72 h. The ear edema and the local accumulation of polymorphonuclear leukocytes' (PMN) marker enzyme, myeloperoxidase (MPO), were determined. Edema peaked at 4-6 h, while MPO activity peaked at 24 h after zymosan application. The correlation between inflammatory response and concentration of zymosan was also tested. Of the various concentrations tested, 1% suspension has been found optimal. Anti-inflammatory drugs and mediator antagonists were examined in order to establish the selectivity and sensitivity of the assay. A glucocorticoid (dexamethasone), two cyclooxygenase inhibitors (indomethacin, piroxicam) and an interleukin-1 (IL-1) release inhibitor (IX 207-887, Sandoz) all reduced edema and MPO activity as well. However, a lipoxygenase inhibitor (phenidone), a serotonin receptor antagonist (methysergide) and H1 and H2 receptor antagonists (clemastine and cimetidine, respectively) all failed to inhibit the reaction.

Animals↗
PubMed2006

Cytokine production profile of splenocytes derived from zymosan A-treated SKG mice developing arthritis.

OBJECTIVE: SKG mice have a point mutation of the zeta-associated protein of 70 kD (ZAP-70) and spontaneously develop a severe polyarthritis in the conventional condition, whereas they are healthy under the specific pathogen free (SPF) condition. The purpose of this study was to investigate the cytokine production from splenocytes in SKG mice developing arthritis under the SPF condition. MATERIAL: SKG and BALB/c mice were intraperitoneally injected with zymosan A under the SPF condition. Spleen was isolated 1, 2 or 8 weeks after the intraperitoneal injection of saline or zymosan A. Splenocytes were cultured with concanavalin A. Cytokine production and proliferation were measured 48 and 72 h after the culture. RESULTS: An intraperitoneal injection of zymosan A induced severe polyarthritis with increased levels of rheumatoid factor and interleukin 6 (IL-6) only in SKG mice. Splenocytes from SKG mice did not proliferate well maybe because of less productivity of IL-2. The IL-4 production from splenocytes of SKG mice was higher, while interferon-gamma production was lower than those of BALB/c mice. An injection of zymosan A reduced the IL-4 production only in SKG mice. CONCLUSIONS: SKG mice do not develop arthritis under the SPF condition possibly because of a low proliferative activity of T cells and Th2-predominance.

Animals↗
PubMed2006

Fluoro-Jade B staining following zymosan microinjection into the spinal cord white matter.

1. The fluorescein derivate Fluoro-Jade B (FJB), which primarily labels dead or dying neurons, was used to study the acute focal inflammation in the spinal cord white matter. Inflammation was induced by microinjection of the yeast particulate zymosan to evaluate the biological effects of intraspinal macrophages activation without the confounding effects of physical trauma. 2. A single bolus of zymosan (Sigma, 75 nL) was stereotaxically injected at the thoracic level into the lateral white matter of rat spinal cord. A standard Fluoro-Jade B staining protocol was applied to spinal cord sections at 6, 12, 24 h and 2, 4 days postinjection. Neutral Red, NADPH-diaphorase, Iba1-IR, and DAPI staining protocols accomplished examination of the cells participating in the acute inflammatory response. 3. Zymosan caused formation of clearly delineated inflammation lesions localized in the lateral white matter of the spinal cord. Fluoro-Jade B stained cells in the area of inflammation were not observed at 12 h postinjection while mild FJB staining appeared at 24 h and intense staining was observed at 2 and 4 days postinjection. 4. This study shows that the acute response to zymosan-induced inflammation in the rat spinal cord white matter causes a gradual appearance of phagocytic microglia/macrophages and delayed FJB staining of the inflammatory cells. 5. FJB, a reliable marker of dying neurons, is a more universal agent than formerly believed. One possible explanation for the gradual appearance of FJB-stained cells in the area of inflammation is that specific time is required for sufficient levels of proteins and/or myelin debris of axonal origin to appear in the cytoplasm of phagocytic microglia/macrophages.

Animals↗
PubMed1989

Characterization of a monoclonal antibody to guinea pig peritoneal macrophages that inhibits phagocytosis of unopsonized zymosan: structural and functional similarities of the antigen to human and mouse CR3.

A monoclonal antibody, anti-Z-1, was established by fusion of spleen cells from mice immunized with guinea pig thioglycollate-induced peritoneal macrophages (TGC-M phi s) with mouse myeloma cells, P3-X63-Ag8-6.5.3. The Fab' fragments of anti-Z-1 bound to almost all of the TGC-M phi s with a high association constant (6.0 +/- 0.8) X 10(8) M-1, and effectively inhibited phagocytic activities of the cells for unopsonized zymosan and serum-treated zymosan. On the contrary, neither the phagocytic activity for rabbit IgG antibody-sensitized sheep erythrocytes nor that for periodate-treated sheep erythrocytes was inhibited by anti-Z-1. Immunoprecipitation analysis revealed that the antigen recognized by anti-Z-1, which was named Z-1 antigen, consists of a polypeptide chain with a molecular weight of 140,000 (alpha chain) noncovalently associated with a polypeptide chain of 95,000 (beta chain). The epitope with which anti-Z-1 reacts was found to be on the alpha chain by Western blotting. Furthermore, it was found that Z-1 antigen solubilized from the cells with nonionic detergent was capable of binding to unopsonized zymosan, suggesting that Z-1 antigen may function as a receptor for zymosan. These findings show the structural and functional similarities of Z-1 molecules on guinea pig peritoneal macrophages to the third complement receptor on human and mouse leukocytes.

Animals↗
PubMed1990

Differential dependence on protein kinase C of arachidonic acid metabolism stimulated by hydrogen peroxide and by zymosan in the alveolar macrophage.

The dependence on protein kinase C (PKC) of arachidonic acid (AA) metabolism stimulated by the biologically important oxidant H2O2, as compared to zymosan particles, was investigated in the rat alveolar macrophage. The PKC inhibitor staurosporine markedly reduced AA release and eicosanoid synthesis stimulated by zymosan, but only slightly inhibited AA release and metabolism induced by H2O2. Furthermore, in macrophages depleted of PKC by extended exposure to phorbol 12-myristate 13-acetate, AA release in response to zymosan was greatly inhibited, whereas that stimulated by H2O2 was attenuated to a significantly lesser degree. Thus, zymosan-stimulated AA metabolism requires active PKC, whereas H2O2-induced metabolism is largely PKC-independent. This provides direct evidence for the existence of two pathways of agonist-stimulated AA metabolism, which differ in their dependence on PKC, in the alveolar macrophage.

Alkaloids↗
PubMed1983

Does the induction of macrophage lysosomal enzyme secretion by zymosan involve the mannose receptor?

Secretion of the lysosomal enzyme hexosaminidase induced by zymosan is inhibited by mannose and by high concentrations of mannose-6-phosphate and 2-deoxy-glucose but not by mannan. Secretion of hexosaminidase from cells storing previously endocytosed zymosan is unaffected by mannose. Exposure of the cells to mannose does not affect secretion caused by subsequent exposure to zymosan. These findings suggest a role for the mannose-glycoprotein receptor in initiation of lysosomal enzyme secretion by zymosan.

Animals↗
PubMed1987

The effect of six prostaglandins, prostacyclin and iloprost on generation of superoxide anions by human polymorphonuclear leukocytes stimulated by zymosan or formyl-methionyl-leucyl-phenylalanine.

Prostaglandins (PG) E2,E1,6-keto-E1 and D2 at concentrations of 0.15-0.80 microM inhibited by 25% the generation of superoxide anions (O2-) in human polymorphonuclear leukocytes (PMNs) stimulated with formyl-methionyl-leucyl-phenylalanine (FMLP). The potency of that inhibition by either PGD2 or PGE1 was the same when zymosan was used as a stimulator whereas PGE2 and 6-keto-PGE1 were by 13 and 21 times less potent inhibitors of O2-) in zymosan-stimulated as compared to FMLP-activated PMNs. PGF2 alpha inhibited the generation of O2- by activated PMNs only when used at the highest concentration studied (30 microM). Prostacyclin, 6-keto-PGF1 alpha and Iloprost (a carbacyclin analogue of prostacyclin) at concentrations up to 30 microM showed no significant inhibition of O2- in human PMNs stimulated either with FMLP or with zymosan. It is concluded that PGD2 and PGEs use a common basic mechanism for inhibition of the generation of O2- by PMNs activated with FMLP or zymosan. PGD2 is most generously furnished with these properties. In addition to this basic mechanism PGE2 and 6-keto-PGE1 abrogate the FMLP-induced response by occupation of formyl peptide receptor of PMNs. It is hypothesised that inhibition of the generation of O2- in PMNs and, possibly, in other cells by PGD2, PGE2 and by products of prostacyclin biotransformation might be responsible for their cytoprotective action in myocardial infarction, stroke, liver damage and peripheral vascular disease.

Epoprostenol↗
PubMed1986

Mast cell amines and the oedema induced by zymosan and carrageenans in rats.

Cimetidine and metiamide suppressed the paw swelling induced in rats by low doses of histamine while these H2 antagonists had little effect on the oedema induced by 100 micrograms of histamine and inhibited by mepyramine. When administered 0.5 h before the inflammagens, H2 antagonists reduced the oedema induced by zymosan and iota carrageenan; they had a slight effect on the oedema induced by lambda and kappa carrageenans and no effect on the oedema induced by compound 48/80. When administered 18 h before the inflammagens, cimetidine greatly increased zymosan oedema and slightly increased lambda carrageenan oedema. Mepyramine, methysergide or depletion of the 5-hydroxytryptamine stores in mast cells by pretreatment with reserpine inhibited the oedema induced by compound 48/80 and zymosan but did not affect the oedema induced by lambda and kappa carrageenans. Histamine may play a dual role in inflammatory reactions. Mast cell amines take a part in the development of zymosan oedema though they play a minor role in the oedema induced by the carrageenans.

Amines↗
PubMed1985

Exclusive leukotriene C4 synthesis by purified human eosinophils induced by opsonized zymosan.

Purified human eosinophils were challenged with N-formyl-methionyl-leucyl-phenylalanine, leukotriene B4, platelet-activating-factor, valyl-glycyl-seryl-glutamic acid, phorbol myristate acetate, zymosan, opsonized zymosan and the calcium ionophore A23187 to induce leukotriene synthesis. Reversed-phase high performance liquid chromatography analysis demonstrated the almost exclusive synthesis of leukotriene C4 by eosinophils of 11 healthy donors after challenge with opsonized zymosan [(22 +/- 4) X 10(6) molecules LTC4/cell, mean +/- SE] or the calcium ionophore A23187 [(54 +/- 7) X 10(6) molecules LTC4/cell, mean +/- SE]. The other agents were not capable of inducing leukotriene formation. When in addition to opsonized zymosan N-formyl-methionyl-leucyl-phenylalanine or platelet-activating factor were added a significant increase of the leukotriene C4 synthesis by eosinophils was observed. These results suggest that eosinophils might be triggered to produce considerable amounts of the spasmogenic leukotriene C4 in vivo by C3b- and/or IgG-mediated mechanisms e.g. phagocytosis.

Calcimycin↗
PubMed1990

Comparison of the generation of platelet-activating factor and leukotriene C4 in human eosinophils stimulated by unopsonized zymosan and by the calcium ionophore A23187: the effects of nedocromil sodium.

The generation of platelet-activating factor (PAF) and leukotriene C4 (LTC4) from normodense human eosinophils (EOSs), stimulated with unopsonized zymosan or calcium ionophore A23187, has been studied. There was a zymosan time- and dose-dependent increase in both PAF and LTC4 production. A plateau of 0.11 +/- 0.04 ng of PAF per 10(6) EOSs (mean +/- SEM; n = 7) and of 1.38 +/- 0.58 ng of LTC4 per 10(6) EOSs (n = 5) was reached at 5 x 10(8) zymosan particles at 37 degrees C for 30 minutes. Under optimal conditions, 91 +/- 1% of the PAF and 66 +/- 13% of the LTC4 remained cell associated. Calcium ionophore A23187 induced a time- and dose-dependent increase in the quantities of PAF and of LTC4 generated by EOSs. A plateau of 31 +/- 13 ng of LTC4 per 10(6) EOSs (n = 5) was reached at 1 mumol/L of calcium ionophore A23187 at 37 degrees C for 15 minutes. The dose response for PAF generation reached 4.2 +/- 0.8 ng/10(6) EOSs (n = 8) at 10 mumols/L of calcium ionophore A23187 at 37 degrees C for 15 minutes and had not plateaued; 90 +/- 5% of the generated PAF was cell associated. In vitro preincubation of EOSs with 10(-8) to 10(-4) mol/L of nedocromil sodium for 15 minutes did not change the subsequent generation or cellular distribution of PAF or LTC4 in EOSs optimally stimulated with either zymosan or calcium ionophore A23187.

Anti-Inflammatory Agents, Non-Steroidal↗