Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “ZYMOSAN”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 847 records · Page 47Linked to original sources
PubMed1989

Independence of neutrophil respiratory burst oxidant generation from the early cytosolic calcium response after stimulation with unopsonized Candida albicans hyphae.

We previously noted differences between neutrophil responses to unopsonized Candida albicans hyphae and responses to other particulate stimuli such as opsonized hyphae or zymosan; these differences include delayed rises in cytosolic calcium [( Ca2+]i), 1,4,5-inositol trisphosphate, and superoxide release and the total absence of early membrane depolarization. Respiratory burst stimulation is required for killing of C. albicans hyphae. Since an early rise in [Ca2+]i may act as a second messenger for burst activation by most agonists, we chelated (Ca2+)i and extracellular Ca2+ [( Ca2+)e] to compare requirements for superoxide responses to hyphae and other stimuli. Intracellular chelation, which ablated early [Ca2+]i rises, eliminated the fMet-Leu-Phe-induced respiratory burst and profoundly reduced that response to opsonized zymosan (by 96.7%), but chelation of both (Ca2+)i and (Ca2+)e only partially inhibited responses to opsonized and unopsonized hyphae (60.5 and 23.3%, respectively; the latter exceeded absolute responses evoked by opsonized zymosan, a 12-fold-more-potent stimulus for unchelated cells). Simultaneous (Ca2+)i and (Ca2+)e chelation further decreased superoxide responses to opsonized zymosan and hyphae (99.4 and 90.4%, respectively) but not to unopsonized hyphae (26.7% inhibition). Though both ingestible (zymosan) and uningestible (hyphae) opsonized particulate stimuli elicited reduced but significant respiratory bursts without early [Ca2+]i rises, the greater superoxide responses and sensitivity to chelation with opsonized zymosan suggest important differences in initiation and/or regulation of responses to these particulate stimuli. In contrast, the respiratory burst elicited by unopsonized hyphae appeared largely Ca2+ independent. If different events mediate neutrophil activation by opsonized and unopsonized hyphae, candidacidal activity in vivo may vary under divergent conditions with specific localized sites of infection.

Calcium↗
PubMed1992

Contribution of antibody in normal human serum to early deposition of C3 onto encapsulated and nonencapsulated Cryptococcus neoformans.

Encapsulated and nonencapsulated cryptococci differ in their activation of the complement system. Incubation of nonencapsulated cryptococci in normal human serum (NHS) initiates both the classical and alternative pathways. This activation is characterized by an immediate, synchronous activation and binding of C3 to the yeast cells. Encapsulated cryptococci activate only the alternative pathway. This activation is characterized by a delayed (4 to 5 min), asynchronous activation and binding of C3. We examined the properties of antibodies in NHS that mediate immediate, synchronous binding of C3 to nonencapsulated cryptococci and zymosan. Adsorption of NHS with nonencapsulated cryptococci or zymosan produced a 4- to 6-min delay in the kinetics for activation and binding of C3 from the adsorbed serum to each respective yeast cell. This delay was similar to the delay observed when nonencapsulated cryptococci or zymosan was incubated in NHS in which the classical pathway was blocked by chelation of Ca2+. Proteins bound to serum-treated nonencapsulated cryptococci or zymosan were eluted and found to be predominantly immunoglobulin G (IgG), with lesser amounts of IgM. The eluted IgG could restore to adsorbed serum the rapid early kinetics for activation and binding of C3 characteristic of classical pathway initiation. Cross-adsorption showed that there was considerable cross-reactivity between the antibodies which restored rapid, early activation kinetics to NHS adsorbed with zymosan or nonencapsulated cryptococci. Encapsulated cryptococci were unable to adsorb the antibodies from NHS that mediated the rapid, early activation and binding of C3 to zymosan and nonencapsulated cryptococci. The latter results show that occlusion of antigenic sites at the cryptococcal cell wall is a newly recognized property that can be added to the repertoire of biological activities of the cryptococcal capsule.

Adsorption↗
PubMed1998

Platelet-activating factor plays a pivotal role in the induction of experimental lung injury.

We have previously described a model of acute lung injury in the mouse in which intravenous administration of lipopolysaccharide (LPS) results in a marked sequestration of neutrophils in the pulmonary microvasculature, although this by itself was not sufficient to induce injury. If the sequestered neutrophils were exposed to zymosan, then a striking increase in pulmonary vascular permeability to albumin was found, suggesting that sequestered neutrophils may produce one or more mediators capable of acting directly on the capillary endothelium. Because activated neutrophils are known to release platelet-activating factor (PAF), we hypothesized that PAF produced locally within the pulmonary capillaries may be the mediator involved. Treatment of mice with the PAF antagonist UK-74,505 prior to administration of zymosan alone or combined LPS and zymosan resulted in a substantial attenuation of lung injury, as measured by the accumulation of extravascular 125I-labeled human serum albumin. UK-74,505 had no effect on neutrophil sequestration as measured by myeloperoxidase activity in whole lung tissue and as assessed by light microscopy. Administration of UK-74,505 after LPS, but before zymosan, was also effective at inhibiting lung injury but again, neutrophil sequestration was unaffected. In contrast, UK-74,505 had no effect on cobra venom factor-induced lung injury and neutrophil sequestration. These data suggest that PAF production is involved in the increases in pulmonary vascular permeability, but not in the sequestration of neutrophils, induced by zymosan alone or by combined LPS and zymosan treatment. Early treatment with PAF antagonists may be beneficial in preventing the development of acute lung injury in humans.

Animals↗
PubMed2006

Protein-tyrosine kinase Syk is required for pathogen engulfment in complement-mediated phagocytosis.

The protein tyrosine kinase Syk plays a central role in Fcgamma receptor-mediated phagocytosis in the adaptive immune system. We show here that Syk also plays an essential role in complement-mediated phagocytosis in innate immunity. Macrophage-like differentiated HL60 cells and C3bi-opsonized zymosan comprised the pathogen-phagocyte system. C3bi-opsonized zymosan particles promptly attached to the cells and were subsequently engulfed via complement receptor 3. During this process, Syk became tyrosine phosphorylated and accumulated around the nascent phagosomes. The transfer of Syk-siRNA or dominant-negative Syk (DN-Syk) into HL60 cells resulted in impaired phagocytosis. Quenching assays using fluorescent zymosan revealed that most of the attached zymosan particles were located inside parental HL60 cells, whereas few were ingested by the mutant cells. These data indicated that Syk is required for the engulfment of C3bi-opsonized zymosan. During C3bi-zymosan-induced phagocytosis, actin accumulation occurred around phagosomes and was followed by depolymerization, and further RhoA was activated together with tyrosine phosphorylation of Vav. These responses including the actin remodeling were suppressed in Syk-siRNA- or DN-Syk-expressing cells. Our results demonstrated that Syk plays an indispensable role in complement-mediated phagocytosis by regulating both actin dynamics and the RhoA activation pathway and that these functions of Syk lead to phagosome formation and pathogen engulfment.

Actins↗
PubMed1981

Iprindole-induced phospholipidosis in rat alveolar macrophages: alterations in oxygen consumption and release of oxidants.

Rats chronically treated with the cationic amphipilic drug iprindole developed a phospholipid storage disorder in their pulmonary alveolar macrophages (AMs). AMs from these iprindole-treated rats (IP-AMs) were compared to AMs from control rats (C-AMs) regarding oxygen consumption and the release of two reactive oxygen species, superoxide anion and hydrogen peroxide. Responses of C-AMs and IP-AMs were compared at rest and when stimulated by unopsonized or opsonized zymosan. Opsonization was not necessary in order to induce respiratory burst-associated phenomena in either cell type; in fact in all cases, for given cell type responses to unopsonized zymosan were virtually identical to those of opsonized zymosan. When at rest, IP-AMs consumed oxygen at a rate nearly identical to that of C-AMs. When stimulated with zymosan particles, IP-AMs consumed more oxygen than controls. However, when superoxide anion and hydrogen peroxide, two products of the respiratory burst were measured, IP-AMs released less of these species than C-AMs when at rest and when particle stimulated. Despite the lower total release of these species by the IP-AMs, the zymosan-induced release (stimulated minus resting levels) was greater for these cells than C-AMs. Therefore, the IP-AMs were found to be more responsive to the zymosan particle than C-AMs. The results indicate marked changes in the release of reactive oxygen species from the AMs following induction of phospholipidosis.

Animals↗
PubMed2003

Effects of activated complements on platelets.

AIM: To observe the effects of activation of complements on platelets and subsequently on vascular endothelial cells (VEC) and vascular smooth muscle cells (VSMC). METHODS: Zymosan A-induced morphological change of platelets was determined with an aggregometer, and prothrombinase expression was quantified using chromogenic substrate. Supernatant of zymosan A-treated platelet rich plasma (PRP) was added to the cultured VEC or VSMC for the observation of cell growth, DNA content, and the membrane microviscosity. RESULTS: Zymosan A induced marked metamorphosis, increased membrane microviscosity, and increased prothrombinase expression of platelets in PRP, but platelet metamorphosis induced by zymosan A was not found in washed platelets and fresh platelet suspended in platelet poor plasma (PPP) which had been pretreated with cobra venom factor (CVF). The effect of zymosan A on platelets was prevented by egtazic acid 5 mmol/L, Mn2+ 10 mmol/L, tetrodotoxin 40 micromol/L or indomethacin 100 micromol/L. The supernatant of zymosan A-treated PRP inhibited the growth of VEC, but accelerated the growth of VSMC and made most VSMC enter G2- and M- phase. The endoplasmic reticulum with rough surface and free ribosome in VSMC and vacuoles appeared in VEC mitochondria. CONCLUSION: Activated complements induced significant shape change of platelets, stimulated platelets to release some factors and subsequently injured VEC, but accelerated the growth of VSMC, which may contribute to the development of blood coagulation and to the chronic inflammation.

Animals↗
PubMed1987

Desensitization of macrophage oxygen metabolism on immobilized ligands: different effect of immunoglobulin G and complement.

During adhesion and spreading to immobilized immune complexes, casein-elicited mouse peritoneal macrophages produced superoxide anion. This production was time-dependent, ceased after a couple of hours, and was due to interaction with immunoglobulins G (IgG) because neither immobilized antigen alone nor immunoglobulins M with or without complement-derived fragments were efficient stimuli. Cultivation of macrophages on immobilized IgG for 24 hr caused desensitization of the response to an unrelated stimulus like zymosan. Desensitization was due neither to inhibition of binding and uptake of zymosan nor to alterations of NADPH oxidase. In fact, macrophages cultivated on immobilized IgG bound and internalized zymosan and responded to PMA with production of superoxide anion normally. Desensitization was not specific for casein-elicited macrophages because both resident peritoneal and Corynebacterium parvum-activated macrophages underwent desensitization if cultivated for 24 hr on immobilized immune complexes. Desensitization on immobilized IgG was maximal after 24 hr, lasted up to 3 days in culture, and was reversed by detaching macrophages from the IgG surface and further cultivating them in normal tissue culture plastic. Scavengers of products of the oxygen metabolism such as superoxide dismutase and catalase and inhibitors of arachidonic acid metabolism such as indomethacin and nordihydroguaiaretic acid did not prevent desensitization. In addition, the zymosan-stimulated release of arachidonic acid was suppressed after cultivation on immobilized IgG for 24 hr; also in this case, the response to PMA was conserved. Contrary to cultivation on immobilized IgG, cultivation of macrophages on fragments derived from C3 was not accompanied by desensitization of the response to zymosan. These results indicate that although the interaction of Fc receptors with their ligands does not impair binding and uptake of zymosan, alterations in the sequence of signals which leads to the activation of the oxygen metabolism can occur, causing a complete dissociation between phagocytosis and stimulation of the oxygen metabolism.

Animals↗
PubMed1986

Effect of cations on leukotriene release: requirements for the metabolism of peptido-leukotrienes (leukotrienes C4, D4) by human polymorphonuclear granulocytes.

Stimulation of human polymorphonuclear granulocytes with opsonized zymosan leads to a time-dependent release of the leukotrienes LTB4, 6-trans-LTB4, 12-epi-6-trans-LTB4 and LTC4 measured by HPLC analysis and LTC4 radioimmunoassay. The amounts of leukotrienes released on stimulation with opsonized zymosan are lower than those obtained with the calcium ionophore A23187. Opsonized zymosan as stimulus required higher calcium concentrations to obtain optimal leukotriene release as compared with the calcium ionophore. Magnesium in the presence of calcium increased the leukotriene formation with opsonized zymosan. Addition of the peptido-leukotrienes LTC4, LTD4 to the unseparated, opsonized zymosan-prestimulated cell suspension leads to the generation of 6-trans-LTB4, 12-epi-6-trans-LTB4 and a metabolite which is more polar than LTC4. The rate of LTC4 metabolism is strongly dependent on the time of prestimulation as well as on the stimuli used for cell triggering, e.g. opsonized zymosan, phorbol-12-myristate-13-acetate, calcium ionophore A23187 or formyl-methionyl-leucyl-phenylalanine. Inhibitors of the oxidative burst decreased LTC4 metabolism. Thus, the peptido-leukotriene LTC4 is metabolized by two pathways: the enzymes gamma-glutamyl-transpeptidase and dipeptidase transform LTC4 into LTD4 and LTE4; these enzymes are present within the supernatants of stimulated cells; transformation of LTC4 into LTB4-isomers occurs in the presence of stimulated cells.

Calcium↗
PubMed1994

Protein kinase C-dependent and -independent pathways of mitogen-activated protein kinase activation in macrophages by stimuli that activate phospholipase A2.

The activation of mitogen-activated protein kinase (MAP kinase) in macrophages and the involvement of protein kinase C (PKC) in MAP kinase activation was investigated in macrophages exposed to agents that have previously been shown to activate the 85-kDa cytosolic phospholipase A2 (PLA2) and induce arachidonic acid release. Phorbol 12-myristate 13-acetate (PMA) and zymosan maximally stimulated MAP kinase activity by 5 and 15 min, respectively, whereas the response to okadaic acid was maximal by 60-90 min. MAP kinase activation correlated with tyrosine phosphorylation of p44 MAP kinase in PMA-stimulated cells and p44 and p42 MAP kinases in zymosan- and okadaic acid-stimulated cells. MAP kinase activity was not elevated in A23187-stimulated macrophages. Inhibition of PKC with the inhibitor, bisindolylmaleimide (GF109203X), or by prolonged exposure to PMA suppressed both arachidonic acid release and MAP kinase activation in PMA- and zymosan-stimulated macrophages but not in okadaic acid or A23187-treated cells. However, prolonged exposure to PMA did not suppress the increased cytosolic PLA2 activity in agonist-treated macrophages. This approach was complicated since initial exposure to PMA to down-regulate PKC increased cytosolic PLA2 activity which remained elevated for 16 h. In contrast, GF109203X treatment suppressed the increase in cytosolic PLA2 activity in response to zymosan and PMA but not to okadaic acid or A23187. The results demonstrate that PMA and zymosan trigger PKC activation that leads to the activation of MAP kinase and PLA2, whereas these responses are PKC independent in okadaic acid-treated cells. In addition, the results are consistent with a role for MAP kinase activation in regulating the activation of the 85-kDa PLA2 and arachidonic acid release in PMA-, zymosan-, and okadaic acid-stimulated cells, whereas these responses in A23187-treated cells are MAP kinase-and PKC-independent.

Animals↗
PubMedDate not supplied

Suppression of chemiluminescence of eastern oyster (Crassostrea virginica) hemocytes by the protozoan parasite Perkinsus marinus.

Experiments were conducted to determine the ability of the protistan parasite, Perkinsus marinus, to inhibit chemiluminescence of hemocytes from the eastern oyster, Crassostrea virginica. Luminol-enhanced chemiluminescence (CL) was used to measure the production of reactive oxygen intermediates (ROI) generated by oyster hemocytes using zymosan as a stimulant. To determine whether P. marinus suppresses ROI evoked from zymosan-stimulated hemocytes, live or heat killed P. marinus in filtered estuarine water (YRW) (salinity = 20 ppt) were added to (1) zymosan-stimulated hemocytes after CL reached its peak, or (2) hemocytes at the same time as zymosan, and reduction of CL responses were recorded. In both tests, controls received only estuarine water. Live P. marinus meronts significantly suppressed ROI production by zymosan-stimulated hemocytes. The suppression of ROI production was dose dependent. Suppression of ROI production from zymosan-stimulated hemocytes by heat killed P. marinus was significantly less than by live P. marinus. Similarly, CL of hemocytes was reduced, though not significantly when hemocytes were exposed to YRW preincubated with P. marinus. When P. marinus meronts were used as a stimulant, no CL response was elicited. Results of this study suggest that P. marinus cells are able to suppress ROI release from oyster hemocytes, thus evading this component of the host's defense.

Animals↗
PubMed1993

Histoplasma capsulatum modulates the acidification of phagolysosomes.

The phagolysosome is perhaps the most effective antimicrobial site within macrophages due both to its acidity and to its variety of hydrolytic enzymes. Few species of pathogens survive and multiply in these vesicles. However, one strategy for microbial survival would be to induce a higher pH within these organelles, thus interfering with the activity of many lysosomal enzymes. Altering the intravesicular milieu might also profoundly influence antigen processing, antimicrobial drug delivery, and drug activity. Here we report the first example of an organism proliferating within phagolysosomes that maintain a relatively neutral pH for a sustained period of time. We inoculated P388D1 macrophages with fluorescein isothiocyanate (FITC)-labeled Histoplasma capsulatum or zymosan. Using the ratio of fluorescence excitations at 495 and 450 nm, we determined that vesicles containing either virulent or avirulent FITC-labeled H. capsulatum yeasts had a pH one to two units higher than vesicles containing either zymosan or methanol-killed H. capsulatum. The difference in pH remained stable for at least 5.5 h postinoculation. Longer-term studies using cells preincubated with acridine orange indicated that phagolysosomes containing live Histoplasma continued to maintain a relatively neutral pH for at least 30 h. Many agents raise the pH of multiple vesicles within the same cell. In contrast, H. capsulatum affects only the phagolysosome in which it is located; during coinoculation of cells with unlabeled Histoplasma and labeled zymosan, organelles containing zymosan still acidified normally. Similarly, unlabeled zymosan had no influence on the elevated pH of vesicles housing labeled Histoplasma. Thus, zymosan and Histoplasma were segregated into separate phagolysosomes that responded independently to their phagocytized contents. This localized effect might reflect an intrinsic difference between phagosomes housing the two particle types, active buffering by the microbe, or altered ion transport across the phagolysosomal membrane such that acidification is inhibited.

Animals↗
PubMed1981

Transmembrane potential changes during phagocytosis in rat alveolar macrophages.

Studies were carried out to measure changes in the transmembrane potential of rat alveolar macrophages during exposure of the cells to zymosan particles or to the membrane perturbant, phorbol-12-myristate-13-acetate (PMA), and to determine if changes in membrane potential are related to superoxide anion release. Exposure of the cells to either zymosan or PMA leads to membrane depolarization, which precedes superoxide anion release. Furthermore, the magnitude of the depolarization is dependent upon the concentration of either zymosan or PMA. During exposure of the alveolar macrophages to increasing levels of zymosan, there is an increase in the amount of superoxide released as well as an increase in the magnitude of the depolarization. Incubation of the cells in medium containing 150 mM K+, a medium which causes membrane depolarization, leads to superoxide release from resting cells and a decrease in the amount of superoxide released from cells exposed to zymosan. These results indicate that release of superoxide anion from rat alveolar macrophages is related to membrane depolarization and suggest that the transmembrane potential change may act as a signal to initiate the phagocytotic responses of the cells.

Animals↗
PubMed1994

Human neutrophils are selectively activated by independent ligation of the subunits of the CD11b/CD18 integrin.

The yeast cell wall preparation zymosan is a particulate stimulus for human neutrophils (PMNs). Unopsonised zymosan particles bind to the PMN CD11b/CD18 integrin and are phagocytosed, leading to activation of the 5-lipoxygenase pathway and release of the lipid chemotaxin leukotriene B4 (LTB4). Specific monoclonal antibodies (mAbs) to CD11b and to CD18 were used in the present study to evaluate the contribution of each chain to these processes. All four anti-CD18 mAbs but none of five anti-CD11b mAbs dose-dependently blocked PMN phagocytosis of zymosan. Nevertheless, all anti-CD11b mAbs and all anti-CD18 mAbs significantly inhibited zymosan-stimulated LTB4 release in a dose-dependent manner. In addition, there was a dose-dependent stimulation of LTB4 release resulting from the specific ligation and cross-linking of either chain of the integrin heterodimer. Thus zymosan-stimulated LTB4 release is initiated by signals from both chains of the CD11b/CD18 integrin, whereas only CD18 is essential for phagocytosis.

Antibodies, Monoclonal↗
PubMed1994

Evidence for involvement of beta-glucan-binding cell surface lectins in human natural killer cell function.

We have studied the effects of yeast cell wall derivatives (zymosan and particulate beta-glucan), on the cytolytic effector function of human natural killer cells. Both zymosan and particulate beta-glucan were found to inhibit the NK-cell-mediated killing of K562, Molt-4, U937, and HL60 tumor cells. Zymosan also inhibited the IL-2-dependent proliferation of NK cells, suggesting that some component of the yeast cell wall delivers a down-modulatory signal affecting multiple NK cell functions. NK cell surface molecules capable of binding both zymosan and Sepharose-immobilized pustulan (linear 1,6-beta-D-glucan, a carbohydrate component of zymosan and particulate beta-glucan) were identified in detergent lysates prepared from surface iodinated NK cells. Our results suggest that NK cells express cell surface beta-glucan-binding lectins that may contribute to NK-cell-mediated natural cytotoxicity.

Cell Wall↗
PubMed2000

Opsonophagocytosis versus lectinophagocytosis in human milk macrophages.

Some important immunoprotective effects of human breast milk have been attributed to the presence of macrophages. We investigated the generation of superoxide anion (O2-) by monocytes and human milk macrophages after stimulation with opsonized and unopsonized zymosan in the absence and presence of mannose as an inhibitor to investigate lectinophagocytic and opsonophagocytic properties. Peripheral blood monocytes generated more O2- than human milk macrophages (417,4 + 79,1 nmol O2-/mg protein vs. 216,1 +/-15,1 nmol O2-/mg protein, p<0,05) after stimulation with opsonized zymosan. When unopsonized zymosan was used as a serum-independent stimulus monocytes generated slightly less O2- in comparison to human milk macrophages (150,8 +/- 34,5 nmol/mg protein vs. 176,1 +/- 18 nmol O2-/mg protein, p<0,05). These findings demonstrate that the proportion of opsonin-independent phagocytosis in human milk macrophages is higher than in monocytes (82% vs. 36%). When mannose was used as an inhibitor a significantly higher reduction of O2- generation occurred in human milk macrophages compared to monocytes stimulated with opsonized zymosan, whereas no difference was found when unopsonized zymosan was used. These results indicate that human milk macrophages are stimulated to a greater extent by opsonin-independent mechanisms than blood borne monocytes. As the colostrum and the intestinal environment of the neonate offers only a little amount of opsonins like complement and immunoglobulin G, such a differentiation to lectinophagocytic properties could bear a great advantage for protective functions of human milk macrophages.

Adjuvants, Immunologic↗
PubMed1984

Phagocyte C3-mediated attachment and internalization: flow cytometric studies using a fluorescence quenching technique.

The dynamics of phagocyte C3-mediated attachment and internalization of fluorescein-isothiocyanate (FITC)-labelled zymosan particles was studied by a flow cytometric (FCM) fluorescence quenching technique, using trypan blue as quenching agent. Trypan blue effectively quenched the fluorescence of extracellular, i.e. free and phagocyte-attached, zymosan particles, but did not influence on the fluorescence of particles internalized by phagocytes. During phagocytosis, an average of 2 C3-coated zymosan particles were simultaneously attached to the phagocyte surface, and the number of attached particles could not be increased by increasing the zymosan to leukocyte ratio, the concentration of C3, the incubation time, or by inhibiting internalization by Cytochalasin B. Phagocyte C3-mediated internalization of zymosan particles was dependent on the concentration of complement, and in the presence of sufficient amounts of C3, internalization continued until saturation was reached at 11 particles per phagocyte.

Complement C3↗
PubMed1985

Stimulation of neutrophil oxidative metabolism by indomethacin.

Human neutrophils exposed to indomethacin demonstrate an enhanced capacity for superoxide ion (O2-) generation when stimulated with opsonized zymosan. Enhancement is not seen with indomethacin-treated cells exposed to soluble oxidative stimuli. To further investigate this phenomenon, O2- generation, chemiluminescence, and phagocytosis were assessed in human neutrophils preincubated with indomethacin. Zymosan-stimulated O2- release was increased from 150 to 300% of controls in neutrophils exposed to 400 micrograms/ml indomethacin. Enhancement was not reversed by removal of indomethacin from the medium prior to addition of the stimulus and was dose-dependent at drug concentrations of 5 to 400 micrograms/ml. Neutrophils exposed to methacin alone also generated more O2- than control cells, although this increment was not sufficient to account for the degree of enhancement seen when indomethacin-treated cells were exposed to zymosan. Neutrophil chemiluminescence induced by zymosan was also increased by exposure to indomethacin, and at a drug concentration of 400 micrograms/ml (1.1 mM) enhancement ranged from 253 to 333% of controls. As was observed with O2- generation, chemiluminescence of neutrophils was increased in the presence of indomethacin alone, although, to a degree far less than was seen when drug-treated cells were stimulated with zymosan. Phagocytosis of radiolabeled S. aureus by neutrophils incubated with indomethacin was increased 13 +/- 5% over controls (P less than 0.01, n = 5), but was unaltered by incubation of cells with the buffer used to solubilize the drug. The modest degree of enhancement of phagocytosis suggests that increased particle uptake is not the sole mechanism of oxidative enhancement.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug Synergism↗
PubMedDate not supplied

Thalidomide reduces lipopolysaccharide/zymosan-induced acute lung injury in rats.

Pharmacological therapies targeting fulminant lung inflammation in acute lung injury (ALI) need to be improved. We evaluated the effect of thalidomide, a chemical modulating both acute and chronic inflammation, on ALI induced by intravenous administration of lipopolysaccharide (LPS) and zymosan in male Sprague-Dawley rats. Injection of LPS and zymosan induced significant lung inflammation, as evidenced by increased neutrophil sequestration in lung tissue as well as enhanced nitric oxide metabolite (NO(x)(-)) production in the serum and bronchoalveolar lavage (BAL) fluid. Lactate dehydrogenase (LDH) activity and protein concentration in BAL fluid were significantly increased after administration of LPS and zymosan. Pulmonary microvascular permeability was determined using the Evans blue retention method, which showed a significant increase in microvascular permeability after LPS and zymosan administration, indicating the development of ALI. Animals that received thalidomide (100 mg/kg) 2 h prior to LPS injection had significantly reduced pulmonary NO(x)(-) production, pulmonary microvascular permeability, and LDH activity and protein concentration in BAL fluid. We therefore conclude that thalidomide ameliorates lung inflammation and reduces ALI induced by combined LPS and zymosan administration in rats.

Acute Disease↗