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PubMed1995

Pharmacological antagonism of lipoprivic feeding induced by sodium mercaptoacetate.

Drugs, such as sodium mercaptoacetate and methylpalmoxirate, which block fatty acid oxidation at different levels in the metabolic pathway, stimulate feeding. It is well known that selective centrally induced stimulation of dopamine, serotonin (5-hydroxytryptamine, 5-HT) and beta-adrenoceptors, or inhibition of the opiatergic system substantially decrease food intake in rats trained to eat 4 h a day. The results of the present study show that centrally acting dopaminergic and serotoninergic anorectic drugs, the opiate receptor antagonist naloxone, the alpha-adrenoceptor blocking drug phentolamine, and peripherally administered 5-HT counteract the overeating induced by mercaptoacetate. Comparing these effects to those described in 2-deoxy-D-glucose- and insulin-induced feeding, our data support the proposition that distinct neural circuits are involved in the hyperphagic responses to diverse metabolic stimuli.

Animals↗

PubMed2004

Spectroscopic, redox and biological activities of transition metal complexes with ons donor macrocyclic ligand derived from semicarbazide and thiodiglycolic acid.

A novel macrocyclic Schiff base ligand (2,5,9,12,14,18-hexaoxo-7,16-dithia-1,3,4,10,11,13-hexaazacycloocta-decane (H6L) with N4S2 coordinating sites was prepared by the reaction of the semicarbazide and thiodiglycolic acid. The transition metal complexes with macrocyclic ligand were synthesized and characterized by elemental analyses, magnetic susceptibility measurements, molar conductance, IR, electronic, and EPR spectral studies. Mass, 1H NMR and IR spectral techniques suggest the structural features of macrocyclic ligand. Magnetic and electronic spectral studies suggest an octahedral geometry of complexes. Electrochemical behaviour of cobalt, nickel and copper complexes were determined by cyclic voltammetry. The cyclic voltammogram of the copper complex at room temperature shows a quasi-reversible peaks for Cu(III)-->Cu(II) and Cu(II)-->Cu(I) couples. The macrocyclic ligand and its complexes show growth inhibitory activity against pathogenic bacteria and plant pathogenic fungi A. niger, A. alternata and P. variotii. Most of the complexes have higher activities than that of free ligand.

Anti-Bacterial Agents↗

PubMed1983

Neocarzinostatin chromophore. Assignment of spectral properties and structural requirements for binding to DNA.

The site responsible for the mercaptan (or borohydride)-stimulated DNA scission activity of neocarzinostatin chromophore (NCS-Chrom) is located in the central C12-subunit of the molecule. This has been determined by studies of the characteristic spectral properties of the chromophore and its reduction products and of the spectral changes induced by their interaction with its apoprotein (apo-NCS) and DNA. The UV-visible absorption, fluorescence, CD, and MCD spectral properties of the major nonprotein chromophoric component of neocarzinostatin (NCS-Chrom A) are assigned to its component substructures, the 2-hydroxy-5-methoxy-7-methyl-1-naphthoate, the five-membered cyclic carbonate ring (1,3-dioxolan-2-one), the 2,6-dideoxy-2-methylaminogalactose, and the incompletely defined C12-subunit which links the other three residues. Although the major source of its UV-visible absorption is the naphthoic acid residue (HNA-NCS), a significant absorption from approximately 260 to 330 nm is due to the presence of the highly unsaturated C12-subunit. The presence of the C12-subunit and, to a lesser extent, the cyclic carbonate reduces the intensity of the fluorescence emission of the fluorophore of NCS-Chrom A, the HAN-NCS subunit. The CD activity of NCS-Chrom A is also due to the presence of the C12-subunit. The MCD activity of NCS-Chrom A, however, is completely accounted accounted for by the naphthoic acid residue. A role for the C12-subunit in the binding of NCS-Chrom to DNA or apo-NCS is indicated by the resultant absorption hypochromicity in the region assigned to the C12-moiety. Limited modification of the C12-subunit (by mercaptan or borohydride) inactivates the chromophore for DNA strand scission, although both products still bind DNA. The naphthoic acid residue alone is not sufficient for binding to DNA. Therefore, the intercalation of the naphthoate residue between DNA base pairs requires the binding of NCS-Chrom to DNA probably via electrostatic interaction between the positively charged 2-methylamino group of the galactose residue and the negatively charged oxygens of the phosphate in the DNA backbone. The C12-unit is viewed as forming a short-lived reduction-activated species that, in the presence of oxygen, causes single-strand breaks in DNA. The cyclic carbonate residue is not required for in vitro DNA strand scission activity but affects its stability with respect to hydrolysis and reactivity with mercaptan. If DNA is absent the activated species decompose to inactive products, including a mercaptan (or hydrogen) addition product of the C12-subunit.

Animals↗

PubMed1989

Capsaicin abolishes lipoprivic but not glucoprivic feeding in rats.

To assess the contribution of visceral sensory neurons to feeding induced by blockade of glucose and fatty acid metabolism, adult rats were anesthetized and treated systemically with capsaicin, a toxin that destroys fine-diameter unmyelinated primary sensory neurons, including many visceral sensory neurons. Rats were maintained on a fat-supplemented diet throughout experimentation. For feeding tests, intake of this diet was measured hourly for 6 h after systemic blockade of fatty acid or glucose utilization with mercaptoacetate (MA) or 2-deoxy-D-glucose (2-DG), respectively, after simultaneous administration of MA and 2-DG and after saline injection. 2-DG stimulated a dose-related feeding response that was similar in magnitude in both capsaicin and vehicle-treated rats. MA also stimulated a dose-related feeding response in vehicle-treated rats. However, capsaicin-treated rats did not eat in response to MA. In addition, 2-DG and MA were additive in their stimulation of feeding in vehicle-treated controls, but capsaicin-treated rats ate the same amount after 2-DG plus MA as they did in response to 2-DG alone. Thus glucoprivation and lipoprivation activate anatomically and chemically distinct receptors for the metabolic control of feeding.

Animals↗

PubMed1992

Induction of two K+ currents by complement component C5a in mouse macrophages.

Puff application of complement component C5a (5 x 10(-8) M) onto peritoneal macrophages from thioglycollate-stimulated mice induced two kinds of outward current at a holding potential of -68 mV, a slowly-rising sustained outward current and a spike-like transient outward current. Quinidine (2 x 10(-4) M) and tetraethylammonium (10(-2) M) partially suppressed both types of outward current. Charybdotoxin (2 x 10(-6) M) markedly suppressed the spike-like outward current. Reversal potentials in bath solutions of different external K+ concentrations were dependent only on K+ concentrations. The transient current was not suppressed in Ca(2+)-free EGTA-containing solution, but was completely abolished in BAPTA-containing solution. One kind of single channel responding to C5a, which has a single-channel conductance of 29 pS, was recorded from cell-attached patches. These results suggest that C5a activates a Ca(2+)-dependent and another type of K+ current.

Animals↗

PubMed1993

Thyrotropin-releasing hormone enhances the superoxide anion production of rabbit peritoneal macrophages stimulated with N-formyl-methionyl-leucyl-phenylalanine and opsonized zymosan.

Effects of thyrotropin-releasing hormone (TRH) on the superoxide anion (O2-) production, which is essential for effective microbicidal and cytotoxic activity in macrophages (M phi s), were investigated. TRH by itself failed to induce the O2- production of rabbit peritoneal M phi s elicited with thioglycollate medium. However, M phi s preincubated with TRH showed the significant enhancements of O2- production following stimulation with the chemotactic peptide, N-formyl-methionyl-leucyl-phenylalanine (FMLP), at TRH concentrations from 10(-7) to 10(-4) M with a peak enhancement at 10(-5) M. O2- generations of M phi s stimulated with opsonized zymosan (OZ) were also enhanced at TRH concentrations from 10(-10) to 10(-5) M with a peak enhancement at 10(-7) M. Maximal enhancements of O2- production were obtained with 10 min preincubation with TRH both for FMLP and OZ stimulations. TRH had no effect on O2- production when stimulated with phorbol 12-myristate 13-acetate. Thyrotropin did not augment the O2- production induced with either FMLP or OZ. These results indicate that TRH has the priming effect on FMLP- and OZ-induced O2- production of rabbit peritoneal M phi s, although the mechanism remains to be clarified.

Amino Acid Sequence↗

PubMed1995

Mercaptoacetate-induced feeding is impaired by central nucleus of the amygdala lesions.

Systemic administration of mercaptoacetate (MA) blocks beta oxidation of fatty acids and stimulates food intake. The present experiment examined MA-induced feeding in rats with bilateral lesions of the central nucleus of the amygdala (CNA) and sham-operated controls. Food intake was measured for 6 h immediately following i.p. injection of 400, 600, or 800 mumol/kg of MA or saline. Feeding was also measured in these rats in response to 2-deoxy-D-glucose (2DG) (100, 200, and 300 mg/kg, SC), a glucose analogue that competitively inhibits glucose utilization. We found that CNA lesions blocked feeding in response to all three doses of MA. Feeding in response to 2DG was significantly reduced, but not abolished, by the lesion. These findings suggest that the CNA is a crucial component of the neural pathway for feeding in response to MA and may also participate in 2DG-induced feeding.

Amygdala↗

PubMed2002

Inhibitors of ATP-binding cassette transporters suppress interleukin-12 p40 production and major histocompatibility complex II up-regulation in macrophages.

ATP-binding cassette (ABC) transporters are a large family of proteins whose role is to translocate various substances across biological membranes. They include the Tangier disease protein ABC1, sulfonylurea receptors (SUR), multidrug resistance protein (MDR), and cystic fibrosis transmembrane regulator (CFTR). In the current study, we investigated the involvement of ABC transporters in the regulation of lipopolysaccharide (LPS) and/or interferon (IFN)-gamma-induced interleukin (IL)-12 p40 and tumor necrosis factor (TNF)-alpha production, nitric oxide formation, as well as major histocompatibility complex II up-regulation in macrophages. The general ABC transporter inhibitor glibenclamide suppressed both IL-12 p40 and nitric oxide production. However, glibenclamide failed to affect the production of TNF-alpha. The selective ABC1 inhibitors 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid and sulfobromophthalein mimicked the suppressive effect of glibenclamide on IL-12 p40 production. On the other hand, both the MDR inhibitor verapamil and CFTR blocker 2,2'-iminodibenzoic acid failed to suppress the production of IL-12 p40. Furthermore, selective inhibitors and activators of SURs were without effect. In agreement with the pharmacological data, macrophages expressed mRNA for ABC1, but not SURs or CFTR. Intracellular levels of IL-12 p40 were decreased by glibenclamide, suggesting that glibenclamide does not affect IL-12 p40 secretion. The effect of glibenclamide did not involve an interference with the activation of the p38 and p42/44 mitogen-activated protein kinases or c-Jun kinase. Glibenclamide also suppressed IFN-gamma-induced up-regulation of major histocompatibility complex II. Taken together, our results indicate that ABC proteins regulate LPS and/or IFN-gamma-induced macrophage activation.

ATP-Binding Cassette Transporters↗

PubMed1998

S-methyl derivatives from thiol compounds by the pyrolytic reaction with trimethylsulfonium hydroxide.

Base-catalyzed transesterification of acyl lipids with methanol in the presence of trimethylsulfonium hydroxide (TMSH) is an easy and convenient method for the preparation of fatty acid methyl esters for gas chromatography (GC) analyses. Free fatty acids are converted to fatty acid methyl esters by the pyrolytic reaction with TMSH as well. We have found that lipids and other compounds containing thiol groups are also converted easily to the corresponding methyl sulfides (methyl thioethers) by the pyrolytic reaction with TMSH occurring in the injector of the gas chromatograph. For example, alkane thiols such as dodecane thiol and octadecane thiol are converted to the corresponding alkyl methyl sulfides, whereas bis(methylthio) derivatives are formed from alpha,omega-alkane dithiols, e.g., 1,8-octanedithiol, and from 2,3-dimercaptopropan-1-ol (dimercaprol). Furthermore, 3beta-mercaptocholest-5-ene (thiocholesterol) is converted to 3-methylthiocholest-5-ene by the same reaction. The S-methylation reactions which finally lead to the corresponding methylthio derivatives of lipids and other compounds with thiol groups may be of diagnostic value for the structural analysis of such compounds by GC and GC/mass spectrometry.

Biochemistry↗

PubMed1993

Optimisation of small-scale coupling of A5B7 monoclonal antibody to carboxypeptidase G2.

Conjugates of F(ab')2 fragment of the monoclonal antibody A5B7 coupled to carboxypeptidase G2 (CPG2) have been produced using the heterobifunctional reagents 2-mercapto-[S-acetyl]acetic acid, N-hydroxysuccinimide ester (SATA) and m-maleimidobenzoyl-N-hydroxysuccinimide ester (SMPB). The effect of various levels of modifying reagent on enzyme activity and antigen binding activity were determined, and it was shown that whilst CPG2 is relatively sensitive to modification, insertion of three maleimide groups per CPG2 resulted in the loss of 30% of enzyme activity; A5B7 F(ab')2 was insensitive to modification, little or no activity being lost. The coupling efficiency of the reaction was shown to be fairly constant over a wide range of substitution levels. There was thus no advantage to be gained in using high substitution levels, which may result in loss of enzyme activity. The formation of undesired high molecular weight aggregates could be controlled by adjustment of the protein concentration during the final coupling step.

Antibodies, Monoclonal↗

PubMed2006

Protein oxidation and lipid peroxidation after renal ischemia-reperfusion injury: protective effects of erdosteine and N-acetylcysteine.

Oxygen radicals have roles in the renal ischemia-reperfusion (IR) injury usually encountered in several conditions such as renal transplantation. The aim of this study was to investigate the effects of erdosteine and N-acetylcysteine (NAC) on the oxidant/antioxidant status and microscopy of renal tissues after IR injury. Male Sprague-Dawley rats were randomly assigned to four groups: control untreated rats, IR (30 min ischemia and 120 min reperfusion), IR + NAC (i.p.; 180 mg/kg) and IR + erdosteine (oral; 50 mg/kg/day for 2 days before experiments) groups. After unilateral renal IR, the right kidney was rapidly excised and sectioned vertically into two pieces for microscopic examination and biochemical analysis. Erdosteine and NAC treatment did not cause any significant change in the activity of superoxide dismutase (SOD) in comparison with the IR group, even if the SOD activity increased in IR groups than in the control group. Catalase (CAT) activity was decreased in the IR group in comparison with control and IR + erdosteine groups (P<0.05), whereas it was higher in the IR + erdosteine group than in the IR + NAC group (P<0.05). Xanthine oxidase (XO) activity was higher in all the IR-performed groups than in the control group (P<0.05). Thiobarbituric acid-reactive substances (TBARS) level and protein carbonyl (PC) content were increased after IR injury (P<0.05). Erdosteine or NAC treatments ameliorated these increased TBARS and PC contents in comparison with the IR group (P<0.05). Light microscopy of the IR group showed tubular dilatation, tubular necrosis and vacuole formation in epithelial cells. Erdosteine but not NAC apparently reduced the renal tissue damage. The pathological damage score after IR was significantly reduced after erdosteine treatment (P<0.05), but not after NAC treatment. In conclusion, renal IR resulted in oxidative damage as seen in biochemical lipid peroxidation and protein oxidation results with aggravated tubular necrosis. Erdosteine and NAC treatments improved the biochemical results of IR injury. However, on microscopic evaluations, animals receiving erdosteine showed a great reduction in renal damage when compared with the NAC group.

Acetylcysteine↗

PubMed1969

Inactivation of the bactericidal activity of human serum by liquoid (sodium polyanetholsulfonate).

Four serum-sensitive strains of Escherichia coli were exposed to 10, 20, and 50% fresh, heat-inactivated, and fresh human serum to which had been added Liquoid at a final concentration of 0.05, 0.025, 0.0125 and 0.006%. It was found that 50% fresh serum (in nutrient, Mueller-Hinton, thioglycolate, or Trypticase Soy Broth) killed more than 10(4) organisms/ml within 3 min, whereas 20 and 10% fresh serum required up to 20 and 40 min, respectively, to kill a comparable number of organisms. To neutralize the activity of 50% fresh serum, 0.0125% Liquoid had to be added, whereas an 0.006% final concentration of Liquoid was sufficient to antagonize the activity of 10 and 20% serum. However, when exposing extremely small bacterial inocula to fresh serum, at least 0.025% Liquoid was necessary to abolish the serum-bactericidal activity of 20 and 50% fresh serum. Liquoid had to be added to 50% fresh serum within seconds to prevent the killing of the majority of test organisms derived from small inocula. It is recommended that blood samples drawn from septicemic or bacteremic patients be aseptically added to a suitable broth which contains at least 0.025% Liquoid in order to improve the chances of isolating pathogens present in small numbers.

Bacteriological Techniques↗

PubMed1986

C3 activation by a new factor B-dependent enzyme detected in culture supernatant from guinea-pig peritoneal macrophages.

Culture supernatants (c.s.) collected from thioglycollate-elicited macrophages were concentrated and incubated with purified C3. In this reaction mixture loss of haemolytic C3 according to classical enzyme kinetics was observed. As revealed by SDS-PAGE, c.s.-catalysed fragmentation of the C3 alpha-chain occurred. The cleavage products were identified by size and function as C3a and C3b. The apparent molecular weight of this C3-activating enzyme in c.s. was approximately 220,000 according to ultracentrifugation studies. This large enzyme showed the following characteristics: it had no activity against C5; it was inhibited by EDTA; Mg2+ was required for its optimal function; its half-life at 37 degrees was approximately 35 min; it was completely inhibited by anti-B IgG. Thus, we were able to detect a C3-activating enzyme in c.s. containing B but differing otherwise from a preformed C3 convertase of the alternative pathway. The exact component composition of this new enzyme is under further investigation.

Animals↗

PubMed2006

Plasma interleukin (IL)-18 (interferon-gamma-inducing factor) and other inflammatory cytokines in patients with gouty arthritis and monosodium urate monohydrate crystal-induced secretion of IL-18.

To determine whether levels of interleukin (IL)-18, together with those of IL-1beta, tumor necrosis factor-alpha, IL-6, and IL-8, are elevated in the plasma of patients with gouty arthritis, the plasma concentrations of those cytokines were measured in 31 males with gouty arthritis. Further, CD14+ cells were obtained from human blood and thioglycolate medium-induced peritoneal cells obtained from caspase 1-deficient mice, and then separately cultured in the presence of monosodium urate monohydrate (MSU) crystals. In addition, in an animal in vivo experiment, MSU crystals were injected into subcutaneous air pouches of IL-18-deficient mice. The plasma concentrations of IL-18, IL-6, and IL-8 were elevated in the presence of gouty arthritis in the gout patients. In the in vitro study, the presence of MSU crystals stimulated CD14+ cells (monocytes) to secrete IL-18 and increased the activity of caspase 1 in CD14+ cells, whereas there was no significant effect on IL-18 messenger RNA in CD14+ cells and only a slight induction of IL-18 secretion from thioglycolate medium-induced caspase 1-deficient peritoneal cells. In the in vivo experiment, MSU crystals injected into the air pouch promoted neutrophil accumulation along with an increase in concentrations of keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-1alpha in air-pouch fluids in both IL-18-deficient and wild-type mice. However, there was no increase in the concentration of IL-18 in air-pouch fluids in either mouse strain. Our results suggest that plasma IL-18, IL-6, IL-8, and C-reactive protein (CRP) levels reflect local inflammation associated with gouty arthritis, though IL-18 does not play an important role in neutrophil accumulation. Further, they suggest that MSU crystals accelerate the processing of IL-18 from an inactive to active form via the activation of caspase 1.

Adult↗

PubMed1998

Esculentoside A inhibits tumor necrosis factor, interleukin-1, and interleukin-6 production induced by lipopolysaccharide in mice.

Esculentoside A, a kind of saponin isolated from the root of the Chinese herb Phytolaca esculenta, is reported to possess potent anti-inflammatory effects in acute and chronic experimental models. In the present study, we investigated the effects of esculentoside A on the production of tumor necrosis factor (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6) induced by lipopolysaccharide (LPS) in mice. In vitro experiments demonstrated that esculentoside A (0.1-10 mumol/l) significantly reduced the release of TNF from the peritoneal macrophages derived from mice pretreated with thioglycolate. IL-1 and IL-6 secretion was also obviously inhibited in a concentration-dependent manner by esculentoside A from 0.01 to 10 mumol/l. In vivo experiments demonstrated that detectable TNF was observed 0.25 h after injection, was maximal at 0.5 h, and returned to baseline at 4 h. Maximal production of IL-1 and IL-6 were observed to be 1 and 2 h, respectively, after injection of LPS. Pretreatment of mice with 5, 10, or 20 mg/kg esculentoside A once a day for 7 consecutive days dose-dependently decreased the TNF, IL-1 and IL-6 levels in the sera of mice following LPS challenge. TNF, IL-1, and IL-6 are important cytokines involved in the pathogenesis of inflammatory lesions. Inhibition of inflammatory cytokine production may contribute to the anti-inflammatory effects of esculentoside A.

Animals↗

PubMed1973

Increasing activity of germinating Bacillus subtilis spores to incorporate thymidine triphosphate into deoxyribonucleic acid after detergent treatment.

The incorporation of (3)H-labeled thymidine triphosphate ((3)H-dTTP) into deoxyribonucleic acid (DNA) of germinated and then Brij 58-treated Bacillus subtilis spores was measured to study DNA replication activity of cells. The dTTP incorporation rate was very low in dormant spores, gradually increased as germination proceeded, and reached a level of the vegetative cell activity approximately 4 hr after the start of germination. This is in contrast to the DNA polymerase activity in the cell extract which remained at the same level throughout the germination period. The increase of the dTTP incorporation activity was inhibited by chloramphenicol or phenethyl alcohol. When these inhibitors were added after germination had proceeded, the elevated dTTP incorporation activity gradually decreased. Permeability to dTTP of spores germinated in the presence of chloramphenicol and then treated with Brij 58 was confirmed by (i) (3)H-dTTP incorporation into the treated spores following either electron or ultraviolet irradiation and (ii) release of radioactivity from the treated spores containing radioactively labeled DNA after deoxyribonuclease I treatment.

Alcohols↗

PubMed1986

Platelet activating factor raises intracellular calcium ion concentration in macrophages.

Peritoneal cells from thioglycollate-stimulated mice were allowed to adhere to coverglasses for 2 h to give a dense monolayer of adherent cells greater than 95% of which were macrophages. After incubation with the tetra-acetoxymethyl ester of quin2, coverglasses were rinsed with Ca2+-free saline, oriented at a 45 degree angle in square cuvettes containing a magnetically driven stir bar, and analyzed for changes in quin2 fluorescence in a spectrofluorimeter. Such fluorescence, taken as an indication of intracellular calcium ion concentration ([Ca2+]i), increased as exogenous calcium ion concentration ([Ca2+]o) was raised to 1 mM. At [Ca2+]o approximately equal to 10 microM, [Ca2+]i = 72 +/- 14 nM (n = 26); at [Ca2+]o = 1 mM, [Ca2+]i = 140-220 nM, levels not increased by N, N, N', N'-tetrakis (2-pyridylmethyl) ethylenediamine, a membrane-permeant chelator of heavy metals than can quench quin2. Addition of mouse alpha + beta fibroblast interferon, lipopolysaccharide, thrombin, collagen, vasopressin, ADP, compound 48/80, or U46619 did not change [Ca2+]i. However, addition of platelet activating factor (PAF) (2-20 ng/ml) raised [Ca2+]i by 480 nM within 1 min if [Ca2+]o = 1 mM. In the presence of 5 mM EGTA, PAF raised [Ca2+]i by 25 nM. This suggests that PAF causes influx of exogenous Ca2+, as well as releasing some Ca2+ from intracellular stores. Consistent with these results, when PAF was added to 1 mM Ca2+ in the presence of 100 microM Cd2+ or Mn2+ to block Ca2+ influx, [Ca2+]i increased by only intermediate amounts; at the times of such dampened peak response, [Ca2+]i could be raised within 1 min to normal PAF-stimulated levels by chelation of the exogenous heavy metals with diethylenetriaminepentaacetic acid. Normal PAF responses were observed in the presence of indomethacin. The lowest dose of PAF observed to raise [Ca2+]i was 0.1 ng/ml. Response of [Ca2+]i to 2-20 ng/ml PAF was transient, and second applications had no effect. The PAF response also was seen in cell suspensions. These results suggest that an increase in [Ca2+]i may be an early event in PAF activation of macrophages.

Animals↗

PubMed1994

Elimination of mouse splenic macrophages correlates with increased susceptibility to experimental disseminated candidiasis.

To evaluate the role of macrophages in experimental disseminated candidiasis, mouse splenic macrophages were eliminated by i.v. delivery of liposome-entrapped dichloromethylene diphosphonate (L-Cl2MDP). Splenic tissue sections that were immunoperoxidase-stained with mAbs against marginal zone macrophages (MONTS-4), red pulp macrophages (SK39), and neutrophils (SK208) showed that 3 days after L-Cl2MDP treatment, macrophages but not neutrophils were depleted, and circulating neutrophils responded normally to an irritated peritoneum and showed normal phagocytic ability. That is, in response to thioglycollate in the peritoneum, neutrophils migrated in normal numbers to the peritoneal cavity and expressed the normal activation phenotype of high Mac-1 and low Mel-14 Ag levels. These neutrophils also showed normal ability to ingest Candida albicans yeast cells in both in vitro and in vivo assays. However, the spleens from L-Cl2MDP-treated mice lost their ability to bind yeast, which agrees with our previous findings that yeast cells bind specifically to marginal zone macrophages. When macrophage-depleted were systemically challenged with C. albicans, clearance of viable fungal elements from blood was slower, their kidneys had higher recoverable CFU, and both BALB/cByJ and congenitally thymic-deficient (nude) mouse strains did not survive as long as control mice. Mice given L-Cl2MDP recovered most of their macrophage function by 56 days and became normal in their resistance to C. albicans. These results indicate that macrophages play an important role in host resistance to experimental disseminated candidiasis, but the mechanism does not appear to involve T cell functions.

Animals↗