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PubMed2002

The tyrosine kinase inhibitor tyrphostin AG 126 reduces the multiple organ failure induced by zymosan in the rat.

OBJECTIVE: To investigate the effects of tyrphostin AG 126, a tyrosine kinase inhibitor, on the multiple organ failure (MOF) caused by zymosan in the rat. DESIGN: Zymosan (500 mg/kg, suspended in saline solution, i.p.) causes an enhanced formation of reactive oxygen species, which contribute to the pathophysiology of MOF. After zymosan or saline administration, animals were monitored for 12 days. MEASUREMENTS AND RESULTS: Treatment of rats with tyrphostin AG 126 (10 mg/kg, 3 mg/kg or 1 mg/kg intraperitoneally, 1 h and 6 h after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan in a dose-dependent fashion. Tyrphostin AG 126 also attenuated the lung, liver, and intestinal injury (histology) as well as the increase in the levels of myeloperoxidase and malondialdehyde caused by zymosan in the lung, liver, and intestine. Immunohistochemical analysis for nitrotyrosine, poly (ADP-ribose) polymerase (PAR), iNOS, and COX-2 revealed a positive staining in lung, liver and intestine from zymosan-treated rats. The degree of staining for nitrotyrosine, PAR, iNOS, and COX-2 were markedly reduced in tissue sections obtained from zymosan-treated rats which had received tyrphostin AG 126. Furthermore, treatment of rats with tyrphostin AG 126 significantly reduced the production of peroxynitrite and of pro-inflammatory cytokines TNF-alpha and IL-1beta. CONCLUSIONS: This study provides the first evidence that the protein kinase inhibitor tyrphostin AG 126 attenuates the degree of MOF associated with zymosan-induced peritonitis in the rat.

Animals↗
PubMed2003

Pyrrolidine dithiocarbamate attenuates the development of organ failure induced by zymosan in mice.

OBJECTIVE: Nuclear factor (NF) kappaB is a transcription factor which plays a pivotal role in the induction of genes involved in physiological processes as well as in the response to injury and inflammation. Dithiocarbamates are anti-oxidants which are potent inhibitors of NF-kappaB. We postulated that pyrrolidine dithiocarbamate (PDTC) would attenuate multiple-organ failure (MOF). DESIGN AND SETTING: Rats in a university research laboratory. INTERVENTIONS AND MEASUREMENTS: We investigated the effects of PDTC (10 mg/kg) on the MOF caused by zymosan (500 mg/kg, administered i.p. as a suspension in saline) in mice. MOF in mice was assessed 18 h after administration of zymosan and/or PDTC and monitored for 7 days (for loss of body weight and mortality). RESULTS: Treatment of mice with PDTC (10 mg/kg i.p., 1 and 6 h after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan. PDTC also attenuated the lung, liver and pancreatic injury and renal dysfunction caused by zymosan as well as the increase in myeloperoxidase activity and malondialdehyde levels caused by zymosan in the lung, liver and intestine. Immunohistochemical analysis for inducible nitric oxide synthase, nitrotyrosine and poly(ADP-ribose) revealed positive staining in lung, liver and intestine tissues obtained from zymosan-treated mice. The degree of staining for nitrotyrosine and poly(ADP-ribose) were markedly reduced in tissue sections obtained from zymosan-treated mice which received PDTC. Furthermore, treatment of mice with PDTC significantly reduced the expression of nitric oxide synthase in lung, liver and intestine. CONCLUSIONS: This study provides the first evidence that PDTC attenuates the degree of zymosan-induced MOF in mice.

Animals↗
PubMed2002

Dual effect of nitric oxide in articular inflammatory pain in zymosan-induced arthritis in rats.

The contribution of nitric oxide (NO) to articular pain in arthritis induced by zymosan (1 mg, intra articular) in rats was assessed by measuring articular incapacitation (AI). Systemic treatment with the non-selective NO synthase (NOS) inhibitor L-NAME (10 - 100 mg kg(-1) i.p.) or with the selective iNOS inhibitors aminoguanidine (AG; 10 - 100 mg kg(-1) i.p.) or 1400W (0.5 - 1 mg kg(-1) s.c.) inhibited the AI induced by injection of zymosan 30 min later. Local (intra articular) treatment with the NOS inhibitors (L-NAME or AG, 0.1 - 1 micromol; 1400W, 0.01 (micromol) 30 min before zymosan also inhibited the AI. Systemic or local treatment with the NOS inhibitors (L-NAME; AG, 100 mg kg(-1) i.p. or 0.1 micromol joint(-1); 1400W, 1 mg kg(-1) s.c. or 0.01 micromol joint(-1)), 2 h after zymosan did not affect the subsequent AI. Local treatment with the NO donors SNP or SIN-1, 2 h after zymosan did inhibit AI. L-NAME and AG, given i.p. inhibited nitrite but not prostaglandin E(2) (PGE(2)) levels in the joints. L-NAME (100 mg kg(-1)) but not AG (100 mg kg(-1)) increased mean arterial blood pressure. Neither L-NAME, AG nor the NO donor SIN-1 altered articular oedema induced by zymosan. In conclusion, inhibitors of iNOS decrease pain in zymosan arthritis only when given before the zymosan. This was not due to inhibition of articular PGE(2) release or oedema. NO donors also promoted antinociception in zymosan arthritis without affecting oedema.

Amidines↗
PubMed2002

Effects of calpain inhibitor I on multiple organ failure induced by zymosan in the rat.

OBJECTIVE: Zymosan enhances the formation of reactive oxygen species, which contributes to the pathophysiology of multiple organ failure. We investigated the effects of calpain inhibitor I (5, 10, or 20 mg/kg) on the multiple organ failure caused by zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) in rats. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats.INTERVENTIONS Multiple organ failure in rats was assessed 18 hrs after administration of zymosan and/or calpain inhibitor I and was monitored for 12 days (for loss of body weight and mortality rate). MEASUREMENT AND MAIN RESULTS: Treatment of rats with calpain inhibitor I (5, 10, or 20 mg/kg intraperitoneally, 1 and 6 hrs after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan in a dose-dependent fashion. Calpain inhibitor I also attenuated the lung, liver, and intestinal injury (histology) as well as the increase in myeloperoxidase activity and malondialdehyde concentrations caused by zymosan in the lung, liver, and intestine. Immunohistochemical analysis for nitrotyrosine and for poly(adenosine-disphosphate-ribose) revealed positive staining in lung, liver, and intestine from zymosan-treated rats. The degree of staining for nitrotyrosine and poly(adenosine-disphosphate-ribose) was reduced markedly in tissue sections obtained from zymosan-treated rats administered calpain inhibitor I (20 mg/kg intraperitoneally). Furthermore, treatment of rats with calpain inhibitor I significantly reduced the expression of inducible nitric oxide synthase and cyclooxygenase-2 in lung, liver, and intestine. CONCLUSION: This study provides the first evidence that calpain inhibitor I attenuates the degree of zymosan-induced multiple organ failure in the rat.

Animals↗
PubMed1997

Role of nitric oxide in a nonseptic shock model induced by zymosan in the rat.

Nitric oxide (NO) is a short-lived mediator, the synthesis of which is induced by various cytokines during inflammatory processes. Recently, it has been proposed that zymosan, a nonbacterial agent, causes inflammation by inducing the production of various cytokines and proinflammatory mediators. In the present study we investigated the role of NO in a nonseptic shock model induced by zymosan administration in the rat. Administration of zymosan (500 mg/kg, intraperitoneally) in the rat induced acute peritonitis, as assessed by a marked increase in the leukocytes count in the exudate, as well as by an increase in the exudate nitrate/nitrite concentration. Zymosan-treated rats developed a severe hypotension and showed signs of systemic illness, significant loss of body weight, and a high mortality rate (53% of animals died within 72 h). Elevated plasma levels of nitrite and nitrate were also observed in zymosan-treated rats compared with control rats (67 +/- 4 microM and 23 +/- 2 microM, respectively; p < .01). In ex vivo experiments, vascular reactivity was studied in thoracic aorta rings of zymosan-treated rats. The contractile responses to norepinephrine (100 nM) and endothelin-1 (5 nM) were significantly reduced. An impairment of the endothelial-dependent relaxation in response to acetylcholine was also observed. Pretreatment of zymosan-shocked rats with NG-nitro-L-arginine methyl ester (L-NAME) or NG-monomethyl-L-arginine (L-NMA), (10 mg/kg, subcutaneously, 15 min before zymosan) decreased mortality, prevented the development of peritonitis, improved ex vivo vascular reactivity, and significantly reduced hypotension. Our data suggest that overproduction of NO plays a role in the zymosan-induced peritonitis and cardiovascular derangements in the rats.

Acute Disease↗
PubMed2004

Treatment with a novel poly(ADP-ribose) glycohydrolase inhibitor reduces development of septic shock-like syndrome induced by zymosan in mice.

OBJECTIVE: Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide by poly(ADP-ribose) polymerase (PARP) and degraded by poly(ADP-ribose) glycohydrolase (PARG). The activation of the PARP/PARG pathway has been found in a variety of animal models of diseases, including septic shock-like syndrome. We have previously demonstrated that PARP inhibition by 3-ami-nobenzamide or GPI 6150 ameliorates multiple organ dysfunctions induced by zymosan. In the present study, we investigated whether similar effect could be achieved through PARG inhibition to break the cycle of poly(ADP-ribose) turnaround. DESIGN: Experimental study. SETTING: University laboratory. SUBJECTS: Male CD mice (20-22 g). INTERVENTIONS: We tested the effects of GPI 18214 (40 mg/kg intraperitoneally bolus), a novel and potent PARG inhibitor, at 1 and 6 hr after zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) on the development of septic shock-like syndrome in mice. Organ failure and systemic inflammation in mice were assessed 18 hrs after administration of zymosan and/or GPI 18214 and monitored for 12 days (for loss of body weight and mortality). MEASUREMENTS AND MAIN RESULTS: At 18 hrs after zymosan administration, we found a significant increase of peritoneal exudates, leukocyte infiltration in peritoneal cavity as well as an infiltration of neutrophils in lung and ileum tissues and subsequent lipid peroxidation, and increased production of plasma tumor necrosis factor-alpha and interleukin-1 beta. Furthermore, zymosan administration induced significant liver, lung, pancreas, intestine, and kidney dysfunction as well as a systemic toxicity and significant loss of body weight. At the end of observation period (12 days), 90% of zymosan-treated mice were dead. GPI 18214 (40 mg/kg intraperitoneally, 1 and 6 hrs after zymosan) treatment significantly reduced peritoneal exudates, inflammatory cell infiltration, and organ injury and mortality rate in zymosan-treated mice. CONCLUSIONS: This study supports early studies that show efficacy from blocking the poly(ADP-ribose) pathway in septic shock-like syndrome model. It provides evidence that GPI 18214, a PARG inhibitor, attenuates the degree of zymosan-induced nonseptic shock in mice, suggesting that PARG may be an alternative therapeutic target for shock treatment.

Acute Disease↗
PubMed2006

Lipopolysaccharide-induced tumor necrosis factor alpha production and not monocyte human leukocyte antigen-DR expression is correlated with survival in septic trauma patients.

Multiple trauma patients have an impaired immune system and thus frequently develop life-threatening septic complications. Because there is an ongoing debate on which are the most predictive immunologic parameters of clinical outcome, we prospectively studied 19 multiple trauma patients with sepsis (mean age, 38.7 +/- 15.8 years; mean Injury Severity Score, 40.6 +/- 11.6) over a period of 14 days. The following parameters were measured daily after admission to the intensive care unit: ex vivo lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) production, monocyte human leukocyte antigen (HLA)-DR expression, constitutive interleukin (IL) 6 secretion, white blood cell count, and C-reactive protein. In addition, procalcitonin, neopterin, LPS-binding protein, and constitutive TNF-alpha secretion were measured every third day. Immediately after trauma, all patients had significantly lower levels of HLA-DR and ex vivo LPS-stimulated TNF-alpha secretion than healthy controls (n = 7; P < 0.001). On the day after clinical diagnosis of sepsis, before any other parameter differed between survivors (n = 13) and nonsurvivors (n = 6), ex vivo LPS-induced TNF-alpha secretion was significantly lower (P < 0.05) in nonsurvivors than in survivors. We conclude that ex vivo LPS-induced TNF-alpha production is an earlier predictor of clinical outcome in multiple trauma patients with sepsis than monocyte HLA-DR expression, constitutive IL-6 secretion, or any other parameter assessed.

Adolescent↗
PubMed2007

Glycogen synthase kinase 3beta inhibition reduces the development of nonseptic shock induced by zymosan in mice.

Glycogen synthase kinase 3 has recently been identified as a ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and plays an important role in the pathophysiology of a number of diseases. In the present study, we have investigated the effects of 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), a glycogen synthase kinase 3beta inhibitor, on the development of nonseptic shock caused by zymosan (dose, 500 mg/kg i.p. suspension in saline) in mice. Organ failure and systemic inflammation in mice was assessed 18 h after administration of zymosan and/or TDZD-8; another group of mice was monitored for 12 days (for clinical score and mortality). Treatment of mice with TDZD-8 (dose, 10 mg/kg i.p., 1 and 6 h after zymosan administration) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan. TDZD-8 also attenuated the lung, liver, and pancreatic injury, the renal dysfunction caused by zymosan, and the increase in myeloperoxidase activity caused by zymosan in the lung and in the intestine. Immunohistochemical analysis for inducible nitric oxide synthase, nitrotyrosine, poly(ADP-ribose), CD30, CD30 ligand, and Fas ligand revealed positive staining in lung and intestinal tissues obtained from zymosan-injected mice. The degree of staining for inducible nitric oxide synthase, nitrotyrosine, poly(ADP-ribose), CD30, CD30 ligand, and Fas ligand were markedly reduced in tissue sections obtained from zymosan-injected mice that had received TDZD-8. This study provides the first evidence that TDZD-8 attenuates the degree of zymosan-induced, nonseptic shock in mice.

Animals↗
PubMed1987

Possible involvement of eicosanoids in the zymosan and arachidonic-acid-induced oxygen uptake, glycogenolysis and Ca2+ mobilization in the perfused rat liver.

Exposure of perfused rat livers to zymosan, arachidonic acid and phenylephrine, but not to latex particles, induces pronounced oxygen uptake, glycogenolysis and Ca2+ mobilization. The oxygen uptake induced by arachidonic acid and by zymosan remains elevated even after the agents have been removed. NaN3 was found to be much more effective in inhibiting the oxygen uptake induced by phenylephrine than that induced by zymosan or arachidonic acid. Glucose release induced by zymosan and by arachidonic acid reaches a maximum after about 2 min and then declines very rapidly even while the agents are still being infused. In contrast, glucose release induced by phenylephrine remains elevated for the duration of the infusion. Ca2+ fluxes induced by arachidonic acid are similar to those induced by phenylephrine in that efflux occurs when the agent is administered and influx occurs only when the agent is removed. This contrasts to the Ca2+ flux changes induced by zymosan where both Ca2+ efflux and Ca2+ influx occur even while zymosan is still being infused. Glucose release induced by zymosan is inhibited by bromophenacylbromide and nordihydroguaiaretic acid, but not by indomethacin. Indomethacin, however inhibits the arachidonic-acid-induced glucose release which is also inhibited by nordihydroguaiaretic acid but not by bromophenacylbromide. Indomethacin inhibits also the arachidonic-acid-induced Ca2+ flux changes whereas the zymosan- and the phenylephrine-induced Ca2+ flux changes are not inhibited by the cyclooxygenase inhibitor. The data presented in this paper suggest that in the perfused rat liver the zymosan-induced glycogenolysis, as well as the Ca2+ flux changes and glycogenolysis induced by arachidonic acid, are mediated by eicosanoids.

Animals↗
PubMed1990

Apolipoprotein E expression by human-monocyte-derived macrophages. Modulation by opsonised zymosan and cholesterol.

The effects of opsonised zymosan and of acetylated low-density lipoprotein (AcLDL) on the synthesis and secretion of apolipoprotein E (apoE), and of apoE mRNA abundance, have been studied in human-monocyte-derived macrophages (MDM). Stimulation by opsonised zymosan led to a concentration-dependent increase in apoE secretion; non-opsonised zymosan was without effect. Incubation with AcLDL led to a concentration-dependent elevation in apoE synthesis which paralleled the increase in cellular cholesterol content. The opsonised-zymosan-induced stimulation of apoE production was additive to that resulting from cholesterol loading with AcLDL. Opsonised zymosan alone did not affect the cholesterol content of MDM. Cholesterol-loaded MDM remained responsive to opsonised zymosan stimulation, displaying a 3.5-fold elevation in apoE secretion as compared to their non-stimulated counterparts. Cell-associated apoE remained at trace levels under all conditions of cell treatment. Studies involving [35S]methionine incorporation showed de novo synthesis of apoE to be enhanced in both cholesterol-loaded and opsonised-zymosan-stimulated macrophages. Estimation of apoE mRNA in opsonised-zymosan-stimulated and control MDM by dot-blot analysis revealed similar message abundance; by contrast, elevation in cellular cholesterol content following incubation with modified LDL led to a significant increase in apoE mRNA levels. We conclude that the opsonised-zymosan-induced stimulation of apoE synthesis and secretion in human MDM may occur by a mechanism(s) independent of cellular cholesterol content.

Apolipoproteins E↗
PubMed1998

Protective effect of melatonin in a non-septic shock model induced by zymosan in the rat.

In vitro studies have demonstrated that melatonin is a scavenger of oxyradicals and peroxynitrite and an inhibitor of nitric oxide (NO) production. Recently, it has been proposed that zymosan, a non-bacterial agent, causes inflammation by inducing the production of various cytokines and pro-inflammatory mediators. In the present study we evaluated the effect of melatonin treatment in a non-septic shock model induced by zymosan in the rat. Administration of zymosan (500 mg/kg intraperitoneally) in the rat induced acute peritonitis, as assessed by a marked increase in the leukocyte count in the exudate, as well as by an increase in the exudate nitrate/nitrite concentration. This inflammatory process coincided with the damage of lung, small intestine, and liver, as assessed by histological examination and by increase of myeloperoxidase activity, indicative of neutrophil infiltration. Peritoneal administration of zymosan in the rat induced also an significant increase in the plasma levels of nitrite and nitrate, stable metabolites of nitric oxide (NO), and in the levels of peroxynitrite, as measured by the oxidation of the fluorescent dye dihydrorhodamine 123, at 18 hr after zymosan challenge. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, a specific "footprint" of peroxynitrite, in the lung of zymosan-shocked rats. Pretreatment of zymosan-shocked rats with melatonin (25 and 50 mg/kg, intraperitoneally, 5 min before zymosan) prevented in a dose dependent manner the development of peritonitis and reduced peroxynitrite formation. In addition, melatonin (50 mg/kg, intraperitoneally, 5 min before zymosan) was effective in preventing the development of organ failure since tissue injury and neutrophil infiltration, by myeloperoxidase evaluation, was reduced in lung, small intestine, and liver. Taken together, the present results demonstrate that melatonin exerts potent antiinflammatory effects.

Acute Disease↗
PubMed1985

Interaction of human monocytes, macrophages, and polymorphonuclear leukocytes with zymosan in vitro. Role of type 3 complement receptors and macrophage-derived complement.

Macrophages take up zymosan in the absence of exogenous complement via receptors for iC3b (type 3 complement receptors) acting with or without lectin-like receptors for mannosyl-fucosyl-terminated glycoconjugates. We previously provided evidence that macrophages themselves secrete complement-alternative pathway components able to opsonize zymosan locally (Ezekowitz et al., J. Exp. Med. 1984. 159:244-260). We show here that covalently bound C3 cleavage products C3b and iC3b can be eluted from zymosan particles cultivated with 36-h adherent human monocytes in the absence of serum. The ligand binding site of type 3 complement receptors is involved in macrophage-zymosan interactions as shown by inhibition studies of zymosan binding and uptake with Fab fragments of anti-C3 antibodies and monoclonal antireceptor antibodies M01 and OKM10. In contrast, antibody IB4, which binds to a receptor epitope distinct from the binding site, does not inhibit zymosan uptake. Selective modulation of macrophage receptors onto anticomplement receptor antibody and mannose-rich yeast mannan, respectively, confirms that the complement and lectin-like receptors are distinct. Human polymorphonuclear leukocytes, which express receptors for complement, but are not known to secrete complement proteins, bind and ingest only exogenously opsonized zymosan. Unopsonized zymosan is a poor trigger of respiratory burst activity in neutrophils or 7-d adherent human macrophages, but induces cell aggregation and secretion of large amounts of superoxide anion when these cells are co-cultivated in serum-free medium and challenged with zymosan. Our studies indicate that complement and/or other products synthesized by macrophages at extravascular sites could play an important role in opsonization and lysis of pathogens able to activate the alternative pathway and mediate macrophage-neutrophil collaboration in first-line host defence.

Animals↗
PubMed2006

Differential effects of selective cyclooxygenase (COX)-1 and COX-2 inhibitors on anorexic response and prostaglandin generation in various tissues induced by zymosan.

We have shown that anorexic response is induced by intraperitoneal injection of zymosan in mice, although the role of prostaglandins in this response is relatively unknown as compared with lipopolysaccharide (LPS)-induced anorexic response. Indomethacin (0.5 and 2.0 mg/kg), a non-selective cyclooxygenase (COX) inhibitor, as well as meloxicam (0.5 mg/kg), a selective COX-2 inhibitor, but not FR122047 (2.0 mg/kg), a selective COX-1 inhibitor, attenuated zymosan-induced anorexia. Zymosan injection elevated COX-2 expression in brain and liver but not in small intestine and colon. Meloxicam (0.5 mg/kg) and FR122047 treatment (2.0 mg/kg) similarly suppressed the generation of brain prostaglandin E(2) (PGE(2)) and peritoneal prostacyclin (PGI(2)) upon zymosan injection. PGE(2) generation in liver upon zymosan injection was suppressed by meloxicam (0.5 mg/kg) but not by FR122047 treatment (2.0 mg/kg). Our observations suggest that COX-2 plays an important role in zymosan-induced anorexia, which is a similar feature in LPS-induced anorexic response. However, non-selective inhibition by selective COX-1 and COX-2 inhibitors of brain PGE(2) generation upon zymosan injection does not support the role of COX-2 expressed in brain in zymosan-induced anorexic response. PGE(2) generation in liver may account for peripheral role of COX-2 in zymosan-induced anorexic response.

Animals↗
PubMed1986

Activation of human polymorphonuclear leucocytes by particulate zymosan is related to both its major carbohydrate components: glucan and mannan.

Unopsonized particulate zymosan and its major carbohydrate component glucan were phagocytosed under serum-free conditions by adherent polymorphonuclear leucocytes (PMN) in a dose- and time-dependent manner. Preincubation of PMN monolayers with mannan did not cause a reduction in the phagocytosis of either particle. The phagocytic response was inhibited by preincubation of the cells with trypsin at a concentration that did not inhibit the phagocytosis of sheep erythrocytes coated with IgG or of latex particles. Homology of the recognition mechanisms for glucan and zymosan was confirmed when cells cultured on fixed glucan or on fixed zymosan failed to ingest either particle to more than 40% of control phagocytosis. Similarly, zymosan and glucan activated PMN in suspension, in a dose- and time-dependent manner, to generate reactive oxygen species which were measured as luminol-dependent chemiluminescence (CL). There was, however, a four-fold greater CL response to zymosan. Preincubation of PMN with mannan resulted in a significantly decreased CL response to zymosan, while the response to glucan was unaffected. The CL response was also sensitive to a range of concentrations of trypsin. In contrast, two other complex polysaccharide particles (barley-derived beta-glucan and algae-derived laminarin) were not phagocytosed by PMN, nor did they cause the generation of CL, despite the fact that they possessed the capacity, in common with zymosan and glucan, to activate the alternative pathway of complement. The identification of a trypsin-sensitive recognition mechanism on the surface of human PMN for unopsonized zymosan and glucan represents a response not hitherto characterized. Furthermore, our data indicate that the phagocytosis of unopsonized zymosan by human PMN is dependent primarily on its glucan content, but that its capacity to activate the respiratory burst may involve mannan and the recruitment of a second cell surface recognition mechanism.

Complement Activation↗
PubMed1993

Zymosan-induced tyrosine phosphorylations in human monocytes. Role of protein kinase C.

Protein tyrosine phosphorylations are involved in the proliferation and secretory responses of immune cells, but their role in phagocytes is poorly understood. The ability of unopsonized zymosan to induce protein tyrosine phosphorylations was investigated in human monocytes. The addition of zymosan to monocytes resulted in an increase in tyrosine phosphorylation of several endogenous proteins including 28-, 33-, 38-, 42-, 47-, 55- to 60-, 62-, 68-, 90-, 105-, 116-, and 120-kDa proteins; 55- to 60-kDa proteins were the predominant phosphoproteins. Moreover, we studied the effects of tyrphostin 23, a specific tyrosine kinase inhibitor, on stimulated tyrosine phosphorylations and early secretory responses of monocytes, i.e., arachidonic acid release and oxidative metabolism. We showed that tyrphostin inhibited zymosan-stimulated tyrosine phosphorylations and arachidonic acid release, but that it did not affect superoxide generation induced by zymosan. Zymosan binds mainly to CR3 receptor on human monocytes, and CR3 is devoid of intrinsic tyrosine kinase activity. It was predictable that zymosan stimulated a tyrosine kinase distal to the receptor or associated with it. We observed that PMA mimicked zymosan-induced tyrosine phosphorylations, thus suggesting that both agonists used a common transductional pathway implicating the serine/threonine kinase, protein kinase C. The antagonists of protein kinase C, sphingosine and calphostin C, inhibited zymosan-stimulated tyrosine phosphorylations. We suggest that, in human monocytes, zymosan-induced tyrosine phosphorylations are involved in cell responses such as the release of arachidonic acid, and that they require the sequential activation of protein kinase C and cellular protein tyrosine kinases.

Catechols↗
PubMed1998

The cytochrome P450 suicide inhibitor, 1-aminobenzotriazole, sensitizes rats to zymosan-induced toxicity.

Reduction in whole body cytochrome P450 (CYP 450) activity is evident in humans who develop trauma and sepsis-induced multiple organ failure (MOF). It is not known whether this has any deleterious or protective effect. Intraperitoneal injection of zymosan, the cell wall of Saccharomycoses A, induces dose-dependent inflammation with concomitant MOF in rats. High dose intraperitoneal zymosan (100 mg/100 g body weight) causes mortality and organomegaly in rats; low dose zymosan (20 mg/100 g body weight) does not. To study a role for CYP 450 in zymosan-induced toxicity, we examined the effect of the non-specific CYP 450 suicide inhibitor 1-aminobenzotriazole (1-ABT)(80 mg/kg/d), on rats treated with low dose zymosan. The 90% reduction in CYP 450 content achieved by this dose of 1-ABT was associated with 58% mortality in rats treated with low dose zymosan, in contrast to no mortality in rats treated with low dose zymosan alone (p < 0.01). In survivors, liver and lung organomegaly (p < 0.01), and polymorphonuclear leukocyte accumulation in the liver (p < 0.01) were increased after zymosan administration in rats treated with 1-ABT compared to those without 1-ABT. There was no effect of treatment with 1-ABT on the increased urinary excretion of nitric oxide byproducts observed after zymosan administration. These observations are consistent with the hypothesis that the CYP 450 enzyme system is an endogenous protectant in this experimental model of inflammation-induced MOF.

Animals↗
PubMed2004

Increased expression of matrix metalloproteinases in the murine zymosan-induced multiple organ dysfunction syndrome.

Matrix metalloproteinases (MMPs) have been implicated as mediators of tissue damage in several inflammatory diseases. Since the multiple organ dysfunction syndrome (MODS) is thought to result from systemic inflammation, overactivation of MMPs could contribute to the organ damage observed. The expression and activity of several MMPs were studied in a murine model for MODS. Sixty mice were given an aseptic intraperitoneal injection of lipopolysaccharide, followed, after 6 days, by zymosan. At days 2, 5, 8, 12, and 16 after the injection of zymosan, the liver, lungs, spleen, and kidneys were collected from groups of mice for either RNA extraction, gelatinase zymography and collagenase (MMP-1 and -13) assays (six mice per time point), or immunohistochemistry (three mice per time point). A group of nine mice did not receive zymosan and acted as controls. The expression of MMP-2 mRNA in zymosan-treated mice was strongly up-regulated in liver tissue only. For MMP-9, this was the case in all organs examined. Quantitative gelatin zymography demonstrated the near complete absence of any gelatinase activity in tissues from control mice. However, in the liver, lungs, and especially the spleen of zymosan-treated animals, significantly increased activity of proform and active MMP-2 and -9 was observed with time. Overall, MMP-1 and -13 activities were very low in all samples from the liver and lungs. In the spleen, however, high levels of MMP-1 and -13 were observed in zymosan-treated animals. Immunohistochemical staining for MMP-2 was detected in the liver and spleen, but not in lung and kidney tissue of zymosan-treated animals. Staining for MMP-9 could be detected in liver, lung, and spleen tissues of zymosan-treated mice. For both MMPs, staining appeared to be limited to phagocytes. In conclusion, the data suggest a role for MMPs, especially MMP-9, in the pathogenesis of MODS.

Animals↗
PubMed1995

Influence of zymosan (a non-specific macrophage stimulator) and of indomethacin on liver tumours--an experimental study in rats.

Zymosan--a non-specific macrophage-stimulating agent--reduces tumour take in the liver. The mechanism for this effect is not clear, but it may be mediated via the Kupffer cells and prostaglandins. On the other hand, the Prostaglandin-synthesis inhibitor, indomethacin, inhibits tumour growth. Pretreatment with zymosan (3 mg 100 g-1) for 3 days of two different strains of rats, inoculated in the liver with a hepatoma or an adenocarcinoma cell suspension respectively, reduced tumour take and also initial tumour growth. The effect on tumour take and initial growth was inhibited by concomitant administration of indomethacin (0.2 mg 100 g-1). When zymosan was administered after tumour cell inoculation the growth rate of the hepatoma was retarded, but this effect was not abrogated by indomethacin. Pretreatment with indomethacin had no significant effect on tumour take or initial growth. When given after the tumour was established in the liver, indomethacin reduced the growth rate of the hepatoma, but not of the adenocarcinoma. These results suggest that there are different mechanisms for the effects of zymosan on tumour take and on growth of an established tumour. In immunoincompetent nude mice the effect on the hepatoma was similar to the effect in the rat. In vitro both tumours were insensitive to zymosan and indomethacin. This study confirms that pretreatment with a non-specific macrophage stimulator (zymosan) diminishes tumour take and growth in the liver, that the effect of zymosan on tumour take in the liver is abrogated by indomethacin and that the zymosan effect on tumour take in the liver is at least partly mediated by the Kupffer cells and prostaglandins.

Adenocarcinoma↗