concanavalin-a and Edema

A series of novel fluorine-containing lupane triterpenoid acid derivatives with fluoroaromatic amide moieties at the C-28 position (1-8) or with 2-(fluoroacyl)cyclopentane-1,3-dione fragments at the C-3 position (9-18) of lupane skeleton was synthesized. A simple synthesis of novel lupane triterpenoid hybrids with 2-(fluoroacyl)-2-cyclopenten-1-one moieties was developed. An interaction of 2-acyl-3-chlorocyclopent-2-en-1-ones, obtained from corresponding cyclic β-triketones, with methyl 3-amino-3-deoxybetulinate gave 3β-isomers (9-13) and 3α-isomers (14-18) of target hybrids, which were isolated as individual compounds. Anti-inflammatory properties of selected synthesized compounds were studied in vivo using the histamine-, concanavalin A- and sheep erythrocytes immunization-induced mouse paw edema models. The antioxidant activity was investigated in vivo on the model of tetracycline-induced hepatitis. Majority of synthesized fluorine-containing lupane triterpenoid acid derivatives exhibited significant anti-inflammatory and antioxidant effects. Among studied compounds, 3β-hybrid 11 with 2-perfluorobutanoyl-2-cyclopenten-1-one moiety was the most potent bioactive compound.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Betulinic Acid; Concanavalin A; Disease Models, Animal; Drug Design; Edema; Female; Fluorine; Hepatitis; Histamine; Male; Mice; Mice, Inbred C57BL; Molecular Conformation; Pentacyclic Triterpenes; Tetracycline; Triterpenes

With the purpose to improve anti-inflammatory activity, the impact of introduction of 1,2,5- and 1,3,4-oxadiazole fragments to betulonic acid core as well as hybrids tethered with short ω-amino acids has been studied. The anti-inflammatory activity of synthesized compounds was tested in vivo using models of inflammation induced by concanavalin A and histamine. The majority of new compounds demonstrated higher anti-inflammatory activity compared with starting betulonic acid. To confirm the molecular targets of new derivatives in NRf2 and NFκB pathways the docking at Kelch and BTB active sites of Keap1 as well as IKK was done. The novelty of the present work is the development of new class of low toxic anti-inflammatory substances consisting of amino acid-linked betulonic acid - oxadiazole conjugates. These compounds can be considered as prospective chemopreventive agents.

Topics: Amino Acids; Animals; Anti-Inflammatory Agents; Computer Simulation; Concanavalin A; Disease Models, Animal; Edema; Female; Fibroblasts; Histamine; Inflammation; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Molecular Conformation; Molecular Docking Simulation; NF-E2-Related Factor 2; NF-kappa B; Oxadiazoles; Triterpenes

Schisandrin A (Sch A) and schisandrin B (Sch B) are active components of Schisandrae Fructus. We compared the biochemical mechanism underlying the anti-inflammatory action of Sch A and Sch B, using cultured lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and concanavalin (ConA)-stimulated mouse splenocytes. Pre-incubation with Sch A or Sch B produced an anti-inflammatory action in LPS-stimulated RAW264.7 cells, as evidenced by the inhibition of the pro-inflammatory c-Jun N-terminal kinases/p38 kinase/nuclear factor-κB signaling pathway as well as the suppression of various pro-inflammatory cytokines and effectors, with the extent of inhibition by Sch A being more pronounced. The greater activity of Sch A in anti-inflammatory response was associated with a greater decrease in cellular reduced glutathione (GSH) level and a greater increase in glutathione S-transferase activity than corresponding changes produced by Sch B. However, upon incubation, only Sch B resulted in the activation of the nuclear factor (erythroid-derived 2)-like factor 2 and the induction of a significant increase in the expression of thioredoxin (TRX) in RAW264.7 cells. The Sch B-induced increase in TRX expression was associated with the suppression of pro-inflammatory cytokines and effectors in LPS-stimulated macrophages. Studies in a mouse model of inflammation (carrageenan-induced paw edema) indicated that while long-term treatment with either Sch A or Sch B suppressed the extent of paw edema, only acute treatment with Sch A produced a significant degree of inhibition on the inflammatory response. Although only Sch A decreased the cellular GSH level and suppressed the release of pro-inflammatory cytokines and cell proliferation in ConA-simulated splenocytes in vitro, both Sch A and Sch B treatments, while not altering cellular GSH levels, suppressed ConA-stimulated splenocyte proliferation ex vivo. These results suggest that Sch A and Sch B may act differentially on activating GST/ depleting cellular GSH and inducing an antioxidant response involved in their anti-inflammatory actions.

Topics: Acetylcysteine; Animals; Anti-Inflammatory Agents; Antioxidants; Concanavalin A; Cyclooctanes; Cytokines; Edema; Enzyme-Linked Immunosorbent Assay; Female; Glutathione; Glutathione Transferase; Inflammation; Lignans; Lipopolysaccharides; Mice; Mice, Inbred ICR; Polycyclic Compounds; RAW 264.7 Cells

This study investigated a putative contribution of mast cells and C-sensory fibers to differences in the development of inflammatory edema following the injection of concanavalin A (Con A) into the hind paws of Dark Agouti (DA) and Albino Oxford (AO) rats. The treatment of adult rats with mast cell-depletor compound 48/80 and neonatal depletion of C-sensory fibers independently revealed that leukocyte composition of the inflamed paws and lymph nodes during local inflammatory response to Con A was generally regulated in a similar way in DA and AO rat strains. However, in DA and AO rats, the decrease and the increase of Con A-induced plasma extravasation were associated with mast cell depletion and activation, respectively, whereas neonatal capsaicin treatment activated dermal mast cells and potentiated inflammatory plasma extravasation only in adult rats of DA strain. Hence, strain differences in the development of the inflammatory response to Con A are probably controlled by the differences in the interplay between mast cells and C-sensory fibers in DA and AO rats.

Topics: Animals; Animals, Newborn; Cells, Cultured; Concanavalin A; Edema; Male; Mast Cells; Nerve Fibers, Unmyelinated; Rats; Species Specificity

We have discovered a new class of colchicine-derived therapeutic agents for immune diseases including rejection of organ-transplantation and autoimmune disease. Compound 2, which had been developed to overcome poor pharmacokinetic properties of compound 1, a first-generation colchicine analog, turned out to show toxicity such as intestinal toxicity and loss of weight during in vivo tests. The deletion of 7-carboxamide group and middle ring-truncation in colchicine allowed us to have structurally simplified analogs with strong immunosuppressive activity. Herein, we report non-alkaloid tricyclic compound 7 and 12 as immunosuppressants which exhibited a strong immunosuppressive in vivo efficacy on the T-dependent antibody response, the Zymosan A-induced arthritis model and the Carrageenan-induced edema model. Compound 7 and 12 revealed less toxicity than the previous lead compound 2, and their minimum lethal doses (MLD) were proved to exceed 100 mg/kg.

Topics: Animals; Arthritis; B-Lymphocytes; Carrageenan; Cell Proliferation; Colchicine; Concanavalin A; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Edema; Humans; Immunosuppressive Agents; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Molecular Structure; Structure-Activity Relationship; T-Lymphocytes; Zymosan

To advance therapy for the treatment of concurrent uveitis and post-cataract surgical inflammation; we evaluated pharmacokinetics and pharmacodynamics of Bioerodible Dexamethasone Implant (BDI) containing 0.3 mg of dexamethasone (DXM) in Concanavalin A (Con A) induced uveitis followed by phacoemulsification in New Zealand White (NZW) rabbits.. The BDI was implanted in the inferior fornix of the capsular bag after intravitreal injection of Con A and ensuing phacoemulsification in NZW rabbits; standard-of-care topical 0.1% dexamethasone drops served as control. DXM was quantified by liquid chromatography-tandem mass spectrometry and pharmacokinetics of DXM in disease vs. healthy eyes was compared. All eyes were assessed clinically using slit lamp biomicroscopy and Draize scoring scale. Retinal thickness and histological analyses were performed to evaluate retinal edema, inflammation and implant biocompatibility respectively.. In Con A-induced inflammatory uveitic cataract model the BDI controlled anterior and posterior segment inflammation as well as retinal thickening more effectively than topical drops. The exposure (AUC0-t) of DXM with BDI is superior in all ocular tissues, while topical drops did not achieve therapeutic posterior segment levels and did not control inflammation nor prevent retinal edema and architectural disruption.. Our results demonstrate the superiority of the BDI in suppressing Con A-induced inflammation and retinal edema in NZW rabbits and highlight the need for sustained bidirectional delivery of potent anti-inflammatory agents for 5 to 6 weeks to optimize clinical outcomes.

Topics: Absorbable Implants; Animals; Anti-Inflammatory Agents; Cataract; Concanavalin A; Dexamethasone; Disease Models, Animal; Drug Delivery Systems; Edema; Female; Inflammation; Ophthalmic Solutions; Rabbits; Retina

Farrerol, a new type of 2,3-dihydro-flavonoid, has been isolated from the leaves of Rhododendron dauricum L. In the present study, we found that farrerol exerted potent immunosuppressive effects on murine T cells both in vitro and in vivo. In vitro, farrerol markedly suppressed concanavalin A (ConA)-induced lymphocyte proliferation, Th1 and Th2 cytokine production, cluster of differentiation 4-positive (CD4(+)) T cell populations, and the ratio of CD4(+)/cluster of differentiation 8-positive (CD8(+)) T cells. Moreover, farrerol significantly inhibited the T cell-mediated delayed-type hypersensitivity (DTH) reaction in vivo. In addition, we investigated signal transduction mechanisms to determine the effects of farrerol by Western blotting. The data revealed that farrerol could downregulate the activation of the nuclear factor κB (NF-қB) and nuclear factor of activated T cells 2 (NFAT2) signal transduction pathways. These findings suggested that farrerol has potential effects on the regulation of the immune system and could be developed as a practicable immunosuppressive compound.

Topics: Animals; Cell Proliferation; Cells, Cultured; Chromones; Concanavalin A; Cytokines; Dinitrofluorobenzene; Ear; Edema; Female; Hypersensitivity, Delayed; Immunosuppressive Agents; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Spleen; T-Lymphocyte Subsets; T-Lymphocytes

In this paper, we reported the synthesis of bifendate derivatives and evaluation of anti-inflammatory activity by detecting the production of the Nitric Oxide (NO) in the lipopolysaccharide(LPS)-stimulated RAW 264.7 cell lines. Among the newly derivatives, compound 7k was the most potent one and two other compounds (7e and 7f) also exhibited greater anti-inflammatory activity than bifendate. Further in vivo studies confirmed that 7k significantly and dose-dependently inhibited carrageenan-induced paw edema and decreased the serum levels of alanine aminotransaminase, and aspartate aminotransaminase in concanavalin A-induced hepatitis model. Histopathological evaluation demonstrated that 7k has better hepatoprotective effect on acute liver injury induced by concanavalin A than bifendate, suggesting that 7k is a potential drug candidate for the treatment of hepatic injuries.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Cell Line; Concanavalin A; Edema; Female; Hepatitis, Animal; Lipopolysaccharides; Liver; Macrophages; Male; Mice; Mice, Inbred BALB C; Nitric Oxide; Rats

Eleven sesquiterpenoids have been isolated from the whole plants of Youngia japonica (Asteraceae). Among these sesquiterpenoids, five were identified as new compounds on the basis of spectroscopic methods and chemical analysis. Their structures were 3-oxo-8alpha-(4-hydoxyphenyl)acetoxy-10(14),11(13)-guaiadien-12,6-olide ( 1), 3beta-[3-(4-hydroxyphenyl)acetyl-beta- D-glucopyranosyloxy]-8alpha-hydroxy-4(15),10(14),11(13)-guaiatrien-12,6-olide ( 2), 3beta-[3-(4-hydroxyphenyl)acetyl-beta- D-glucopyranosyloxy]-4(15),10(14),11(13)-guaiatrien-12,6-olide ( 3), 3alpha,5beta,6alpha-trihydroxy-4alpha-(beta- D-glucopyranosyloxy)-7-megastigmen-9-one ( 4), and 3alpha-(beta- D-glucopyranosyloxy)-4(15),11(13)-eudesmadien-12-oic acid ( 5). The three known components 3beta-(beta- D-glucopyranosyloxy)-8alpha-(4-hydroxyphenyl)acetoxy-4(15),10(14),11(13)-guaiatrien-12,6-olide ( 8), 3beta-(beta- D-glucopyranosyloxy)-4(15),10(14),11 (13)-guaiatrien-12,6-olide ( 9), and 3alpha-hydroxy-4alpha-(beta- D-glucopyranosyloxy)-5,7-megastigmadien-9-one ( 11) showed inhibitory activity against the proliferation of T and B lymphocytes of mice in vitro at concentrations of 1 x 10 ( - 7), 1 x 10 ( - 6), and/or 1 x 10 ( - 5) M without obvious cytotoxicity. Compound 9, the major component of the plant extract, exhibited weak anti-inflammatory activity at a dosage of 50 mg/kg ( p. o.) in in vivo anti-inflammatory experiments of mice.

Topics: Animals; Anti-Inflammatory Agents; Asteraceae; B-Lymphocytes; Carrageenan; Cell Proliferation; Concanavalin A; Edema; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Norisoprenoids; Nuclear Magnetic Resonance, Biomolecular; Plant Extracts; Sesquiterpenes; Sesquiterpenes, Eudesmane; Sesquiterpenes, Guaiane; T-Lymphocytes

It is well documented that neuropeptides participate in local inflammatory reaction and modulate functions of inflammatory cells. The aim of the study was to determine a link between in vivo and in vitro effects of NPY-related peptides on inflammatory response with respect to ageing. Peptide YY (PYY) intraplantarly applied decreases concanavalin A-induced paw edema in 3 and 8 months, but not in 24 months old male rats of Albino Oxford strain. The use of NPY-related receptor-specific peptides and Y1 receptor antagonist revealed that anti-inflammatory effect of PYY is mediated via NPY Y1 receptors. PYY in vitro decreases adherence of macrophages from 8 months, but not from 3 and 24 months old rats and this effect is also mediated via NPY Y1 receptor. Additionally, PYY (10(-6)M) decreases NBT reduction in macrophages from 3 and 8 months old rats, and suppresses NO production in cells from 24 months old rats, albeit regardless of absence of in vivo effect of PYY on inflammation in aged rats. It is concluded that aged rats are less responsive to anti-inflammatory action of PYY compared to adult and young rats, and that ageing is associated with altered NPY Y1 receptor functioning.

Topics: Acute Disease; Aging; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Adhesion; Cells, Cultured; Concanavalin A; Dose-Response Relationship, Drug; Edema; Inflammation; Macrophages, Peritoneal; Male; Nitric Oxide; Peptide YY; Rats; Receptors, Neuropeptide Y

It has been shown that inflammation of rat paws elicits accumulation of opioid peptide beta-endorphin-containing immune cells in the inflamed subcutaneous tissue, contributing to immunocyte-produced pain suppression. However, the possible mechanisms involved in the pharmacological application of beta-endorphin in rat paw inflammation have not been investigated. The present study was set up to explore the effects of intraplantar injection of beta-endorphin on Concanavalin A-induced paw edema in two inbred rat strains, Albino Oxford (AO) and Dark Agouti (DA). Both high dose-induced suppression and low dose-induced potentiation of edema development in AO and DA rats, respectively, were blocked with antagonists specific for delta (naltrindole) and kappa (nor-binaltorphimine) opioid receptors. beta-endorphin in vitro decreased phagocytosis and increased nitric oxide (NO) production in air pouch granulocytes obtained from AO rats. However, in cells from DA rat strain beta-endorphin modulated both phagocytosis and NO production in a concentration-dependent manner. It could be concluded that the strain-dependent opposing effects of beta-endorphin on paw inflammation are mediated through delta and kappa opioid receptors and probably involve changes in the production of reactive oxygen species by inflammatory cells. Our results point to the importance of genotype for pharmacological manipulations and the development of inflammation.

Topics: Animals; beta-Endorphin; Concanavalin A; Dose-Response Relationship, Drug; Edema; Female; Granulocytes; Hindlimb; Inflammation; Male; Naltrexone; Narcotic Antagonists; Neurotransmitter Agents; Nitric Oxide; Phagocytosis; Rats; Rats, Inbred Strains; Receptors, Opioid, delta; Receptors, Opioid, kappa; Species Specificity

The therapeutic effect of olipiphate was demonstrated for chronic inflammation of advanced arthritis and concanavalin A-related acute edema. The best systemic effect was obtained with 50 mg/kg, symptomatic--100 mg/kg. Skin wounds treated with 5% olipiphate (26 + 2) healed faster than those treated with 2% solcoseryl (30 + 0.8) or in control (33 + 0.6). It was shown histologically that the proliferative and antiphlogistic effect of olipiphate involved no scars.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Infectious; Concanavalin A; Dose-Response Relationship, Drug; Edema; Freund's Adjuvant; Lignin; Male; Mice; Mice, Inbred CBA; Mycobacterium tuberculosis; Rats; Skin; Wound Healing

We synthesized various 6-fluoro-7-(1-piperazino)quinazolines based on the structure of 1 and evaluated their inhibitory activities toward both TNF-alpha production and T cell proliferation responses. Among these compounds, 7a, having the 3,4-(methylenedioxy)phenyl moiety at the C(4)-position of the quinazoline ring, showed both inhibitory activities. Furthermore, the oral treatment with 7a exhibited an anti-inflammatory effect in rats with adjuvant arthritis as well as an inhibitory activity toward LPS-induced TNF-alpha production.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Area Under Curve; Arthritis, Experimental; B-Lymphocytes; Cell Division; Concanavalin A; Depression, Chemical; Drug Design; Edema; Humans; In Vitro Techniques; Lipopolysaccharides; Magnetic Resonance Spectroscopy; Male; Mice; Neutrophils; Quinazolines; Rats; Rats, Sprague-Dawley; Spleen; Structure-Activity Relationship; T-Lymphocytes; Tumor Necrosis Factor-alpha

The preparation and characterization of a series of C-10 substituted 5-allyl-2,5-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines as a novel class of selective ligands for the glucocorticoid receptor is described. Substitution at the C-10 position of the tetracyclic core with linear, two-atom appendages (OCH(3), OCF(2)H, NHMe, SMe, CH=CH(2), Ctbd1;CH, CH(2)OH) provided molecules of high affinity (K(i) = 2-8 nM) for the human glucocorticoid receptor (hGR) with limited cross-reactivity with other steroid receptors (PR, MR, AR, ER). Optimal analogues showed slightly less potent but highly efficacious E-selectin repression with reduced levels of GRE activation efficacy in reporter gene assays relative to prednisolone. Preliminary SAR of analogues containing substitution at the C-9 and C-10 positions identified the 9-OH, 10-OMe analogue 50 and the 9-OH, 10-Cl analogue 58 as compounds that demonstrated potent, GR-mediated inhibition in a conconavalin A stimulated T-cell proliferation assay in both rodent and human whole blood monocytes. When evaluated for their in vivo effects in carrageenan-induced paw edema in rats, 50, 58, and 10-OCF(2)H analogue 35 showed dose-dependent anti-inflammatory effects (50, ED(50) = 16 mg/kg; 58, ED(50) = 15 mg/kg; 35, ED(50) = 21 mg/kg vs ED(50) = 15 mg/kg for 18 and ED(50) = 4 mg/kg for prednisolone).

Topics: Allyl Compounds; Animals; Anti-Inflammatory Agents, Non-Steroidal; Binding, Competitive; Carrageenan; Cell Division; Concanavalin A; E-Selectin; Edema; Humans; In Vitro Techniques; Ligands; NF-kappa B; Protein Isoforms; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid; Response Elements; Species Specificity; Structure-Activity Relationship; T-Lymphocytes; Transcription Factor AP-1; Transcription, Genetic

Several lines of evidence suggest that neuropeptide Y (NPY) may exert regulatory effects in local inflammatory responses. Here, we show that intraplantarly (i.pl.) applied NPY, peptide YY (PYY), and an NPY Y5 receptor-selective agonist dose-dependently potentiate concanavalin A (Con A)-induced paw edema in the rat. The NPY Y1 receptor antagonist BIBO 3304 abolishes the pro-inflammatory action of both NPY and PYY while the dipeptidyl-peptidase IV (CD26) inhibitor Ile-thiazolidide exerted synergistic and potentiating effects in vivo. Taken together, the present data reveal an NPY Y1/Y5 receptor interplay and an involvement of CD26 in the NPY-induced potentiation of paw edema in the rat.

Topics: Animals; Arginine; Cells, Cultured; Concanavalin A; Dipeptidyl Peptidase 4; Dose-Response Relationship, Drug; Edema; Hydrogen Peroxide; Inflammation; Isoleucine; Macrophages; Male; Neuropeptide Y; Peptide Fragments; Peptide YY; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Thiazoles

Natural or synthetic melanin (CAS 8049-97-6) is a high molecular weight heteropolymer, product of the enzyme tyrosinase, found to possess radical scavenging and antioxidant functions. It was of interest, therefore, to study in detail the possible anti-inflammatory and/or immunosuppressive properties of a melanin isolated from grapes. The inhibitory effect of melanin on carrageenin-induced edema, as well as on edemas produced by other phlogistics, was remarkable suggesting that melanin interferes with the prostaglandin as well as the leukotriene and/or complement system mediated inflammation. Grape melanin showed potent inhibitory effect on adjuvant induced disease (AID) in rat, suppressing significantly the primary inflammation and almost totally the secondary lesions of arthritis. Melanin under the present experimental conditions not only strongly inhibited the in vitro lipid peroxidation of rat liver microsomal membranes, but furthermore protected the in vivo hepatic peroxidation occurring in AID rats, demonstrating its antioxidant and cytoprotective properties. The serum proinflammatory cytokines IL-1, IL-6 and TNF-a and the serum globulin fraction were elevated in AID rats, parameters which were more or less normalised by melanin treatment in contrast to the reduced serum levels of IL-2 which were not affected. Similarly to other lipoxygenase inhibitors and hydroxyl radical scavenger NSAIDs, melanin treatment did not affect IL-1 neither increased the splenic mitogenic responses, unlike the classical cyclooxygenase inhibitory NSAIDs. The subpopulation Th1 (T4+ or T8+) of lymphocytes is mainly responsible for cellular immune responses and thus their possible inhibition by melanin could lead to suppression of the development of AID, a model for cell-mediated immunity. The effect of melanin on T-cells is exhibited by the reduced spleen mitogenic responses to a T-cell mitogen and the reduced serum levels of IL-2 of treated rats. In conclusion, grape melanin is an interesting anti-inflammatory and immunomodulating natural product which appears to have multiple cellular targets within the reticuloendothelial and immune system.

Topics: Adjuvants, Immunologic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Concanavalin A; Cytokines; Edema; Foot; Lipid Peroxidation; Melanins; Mice; Mice, Inbred BALB C; Mitogens; Organ Size; Phagocytosis; Plant Lectins; Rats; Rats, Inbred F344; Rosales; Spleen; Weight Gain

Interleukin-8 (IL-8) plays a crucial role in the pathogenesis of inflammatory and hyperproliferative diseases in various organs. The purpose of the present investigation was to establish whether there is any naturally occurring inhibitor of IL-8. Here we demonstrate that an IL-8 inhibitor (IL-8INH) is present in the supernatant of polymorphonuclear (PMN) leukocytes. The release of IL-8INH could be increased by stimulating the PMN leukocytes by concanavalin A. IL-81NH blocks the IL-8-induced chemotaxis and Candida albicans killing activity of PMN leukocytes and epidermal cells in vitro, and IL-8-induced neutrophil infiltration in the mouse ear in vivo. The mechanism of action of IL-8INH involves blocking of 125I-IL-8 binding to the IL-8 receptor. Binding of 125I-IL-8 to neutrophils could not be displaced by the IL-8INH, however, preincubation of 125I-IL-8 with IL-8INH increased binding inhibition, suggesting an interaction between IL-8 and the inhibitor. Crosslinking of 125I-IL-8 to IL-8INH shows that IL-8INH binds specifically to 125I-IL-8, and the IL-8INH protein has an apparent molecular weight of 52 kDa in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The partial purification of the IL-8INH on DEAE-Sephadex anion-exchange chromatography column also suggests a 50-60-kDa inhibitor protein which blocks IL-8-induced effects on neutrophils by binding to IL-8.

Topics: Animals; Antigens, CD; Binding, Competitive; Biological Factors; Candida albicans; Cells, Cultured; Chemotaxis, Leukocyte; Chromatography, Ion Exchange; Concanavalin A; Cross-Linking Reagents; Ear, External; Edema; Epidermal Cells; Epidermis; Humans; Interleukin-8; Mice; Molecular Weight; Neutrophils; Protease Inhibitors; Receptors, Interleukin; Receptors, Interleukin-8A; Solubility

Exposure to bis-(2-chloroethyl)sulfide (BCES; "sulfur mustard") causes delayed formation of slowly healing skin blisters. Although the histopathology of BCES injury is well characterized [reviewed in Smith et al., J Am Acad Dermatol 32: 767-776, 1995], little is known of the cutaneous toxicity at the molecular level. To identify biological markers of exposure, epidermal and subepidermal extracts were prepared from 48 individual hairless guinea pigs (HGP) at successive 3-hr intervals following exposure to BCES vapor, and compared using gel electrophoresis, and lectin- and antisera-binding. Inflammation was assessed by measuring edema and myeloperoxidase activity. Edema reached peak levels at 15-18 hr and remained elevated above controls at 24 hr. Recruitment of neutrophils, deduced from increased myeloperoxidase, occurred as early as 3 hr after BCES exposure with maximum infiltration at 6-12 hr. Binding of concanavalin-A lectin revealed increased amounts, relative to contralateral control sites, of two approximately 180,000 Mr polypeptides in subepidermal protein extracts from the BCES-exposed skin obtained > or = 12 hr after exposure. This alteration was not found in epidermal protein extracts prepared from the same animals. Based upon the determined amino acid compositions, both polypeptides had significant collagenous triple helical content (>75%). They could be distinguished immunologically from collagen types I, III, and IV by using polyclonal antisera. We conclude that exposure of HGP skin to BCES results in an early neutrophil infiltration that precedes epidermal-dermal separation and selective alterations of the subepidermal extracellular matrix.

Topics: Amino Acids; Animals; Blister; Collagen; Concanavalin A; Edema; Guinea Pigs; Immune Sera; Male; Molecular Weight; Mustard Gas; Neutrophils; Peroxidase; Skin Absorption; Solubility

We investigated the in vivo selective anti-inflammatory effect of L-156,602, which was first identified as a preferential delayed-type hypersensitivity-suppressant in our screening program and first reported to be a C5a antagonist. The agent most profoundly suppressed footpad edema 4 h after elicitation by concanavalin A (con A) and also caused a significantly impaired response after a further 20 h. Footpad edema induced by either serotonin, carrageenan or zymosan was not much influenced by the agent. Although the dominant cell population that migrated in response to con A and zymosan 4 h after elicitation was neutrophils, L-156,602 specifically prevented the con-A-induced migration of neutrophils, suggesting a distinct mechanism of neutrophil recruitment between con A and zymosan-induced inflammation. The agent also reduced the contact-sensitivity response, especially in host mice sensitized with a moderate dose of picryl chloride and almost completely suppressed the infiltration of mononuclear leukocytes and neutrophils into the site of inflammation. These selective effects of L-156,602 on inflammatory reactions appeared to be not merely via C5a antagonism.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibiotics, Antineoplastic; Carrageenan; Complement C5a; Concanavalin A; Dermatitis, Contact; Edema; Female; Hindlimb; Mice; Mice, Inbred DBA; Neutrophils; Peptides, Cyclic; Picryl Chloride; Serotonin; Specific Pathogen-Free Organisms; Zymosan

The mechanism of the anti-inflammatory activity of fepradinol (CAS 67704-50-1) has been investigated. The effect of fepradinol was compared with that of indometacin and other non-steroidal anti-inflammatory drugs. Oral dosing of fepradinol and cyproheptadine suppressed zymosan-induced paw edema in rats. Indometacin and piroxicam were without effect. Fepradinol inhibited the early and late stages of concanavalin A-induced edema in rats; indometacin and piroxicam only inhibited the late stage. Fepradinol and indometacin prevented the carrageenin-induced inflammation in rats: they acted on the exudate, on the increase of protein and gamma-glutamyltransferase levels, and also reduced the number of leucocytes. But, in contrast to indometacin, fepradinol did not inhibit prostaglandin E2 biosynthesis. Fepradinol and indometacin prevented diarrhoea induced by intravenous injection of endotoxin in mice or by oral administration of castor oil in rats. In in vitro tests, fepradinol did not inhibit prostaglandin biosynthesis from arachidonic acid by bovine seminal vesicle microsomal enzyme or 15-lipoxygenase. These results indicate that fepradinol possesses a potent inhibitory activity on the acute inflammation in rodents and that its anti-inflammatory activity does not seem to be related to an inhibitory effect on prostaglandin biosynthesis.

Topics: Air; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antidiarrheals; Castor Oil; Chemotaxis, Leukocyte; Concanavalin A; Cyclooxygenase Inhibitors; Dinoprostone; Edema; Endotoxins; Ethanolamines; Exudates and Transudates; gamma-Glutamyltransferase; Lipoxygenase Inhibitors; Male; Mice; Mice, Inbred ICR; Microsomes; Rats; Rats, Wistar; Zymosan

Lectins from Dioclea grandiflora (DG) and Canavalia brasiliensis (CB) were compared with Concanavalin A (ConA) for their ability to induce paw edema and peritoneal cell immigration in rats. ConA caused a slight edema with a peak at 1 h after injection, while DG or CB induced a pronounced and long-lasting edema that reached a maximum at about 6 h. Different antiinflammatory drugs partially inhibited the edema. alpha-D-glucose (GLU) partially blocked the edema caused by ConA and markedly inhibited that due to CB, but had no effect on the edema induced by DG. alpha-Methyl mannoside (alpha-MM) blocked the edema caused by DG and ConA, but did not affect that caused by CB. At doses much lower than those used to induce paw edema, the lectins promoted an intense accumulation of neutrophil and mononuclear cells in the rat peritoneal cavity. CB and DG were more potent than ConA, which also presented a different profile of cell immigration. GLU significantly inhibited leukocyte accumulation caused by all lectins. alpha-MM impaired ConA- and DG-induced cell immigration, but only partially inhibited CB. Thus, despite their physicochemical similarities with ConA, DG and CB have more powerful pro-inflammatory effects. This difference seems to be related to their sugar-binding properties. However, while ConA- and DG-induced effects were inhibited more by alpha-MM than by GLU, CB-induced effects were inhibited more by glucose.

Topics: Animals; Anti-Inflammatory Agents; Cell Movement; Concanavalin A; Edema; Glucose; Hindlimb; Lectins; Leukocytes; Methylmannosides; Peritoneal Cavity; Plant Lectins; Rats; Rats, Wistar

The effect of etodolac (CAS 41340-25-4) on the inflammatory reactions induced by histamine and bradykinin was compared with that of indomethacin and other nonsteroidal anti-inflammatory drugs. Etodolac (50 mg/kg p.o.), indomethacin (20 mg/kg p.o.), diclofenac Na (20 mg/kg p.o.) and acetylsalicylic acid (200 mg/kg p.o.) had no effect on the increase of vascular permeability induced by histamine or bradykinin and on passive cutaneous anaphylaxis in rats. Etodolac (5, 10 and 20 mg/kg p.o.) suppressed concanavalin A-induced paw edema in rats. Etodolac (10 mg/kg p.o.) and bromelain (10 mg/kg i.v.) significantly suppressed the heat-induced elevation of bradykinin in perfusates of rat paws, but indomethacin (20 mg/kg p.o.) and diclofenac Na (20 mg/kg p.o.) did not. Etodolac inhibited bradykinin-forming enzyme activity in a concentration-dependent manner (IC50 = 1.5 x 10[-4) mol/l). These results suggest that etodolac is a unique nonsteroidal anti-inflammatory drug which can inhibit bradykinin formation, unlike indomethacin or diclofenac Na.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Capillary Permeability; Concanavalin A; Edema; Etodolac; Histamine; Histamine Release; Indoleacetic Acids; Male; Passive Cutaneous Anaphylaxis; Perfusion; Radioimmunoassay; Rats; Rats, Inbred Strains

A series of 4-hydroxy-(or-amino)-ethyl-amino butyrophenones or butyrothienones were synthesized. For detail studies on antiinflammatory effects, gamma-(2-aminoethylamino)-2-butyrothienone (gamma-ABT) was chosen as representative of these new non-steroidal anti-inflammatories (NSAID). The effect on mouse paw edema induced by various phlogistic agents was first investigated. The inhibitory effect of gamma-ABT on carrageenin-induced edema was remarkable and nearly equal to that of indometacin. Similarly to indometacin, gamma-ABT inhibited the early and late stage of yeast-induced edema in contrast to concanavalin A (Con A) induced edema which was only inhibited by gamma-ABT. Both the above induced edema are supposed to be unrelated to prostaglandins in the rat system. gamma-ABT displayed an inhibitory effect on nystatin-induced edema similar to indometacin suggesting that gamma-ABT has significant membrane stabilizing action and a strong blocking action on synthesis of prostaglandins. gamma-ABT inhibited as well the sustained edema induced by mustard. In conclusion gamma-ABT is an effective agent not only on acute but also on subacute and chronic inflammation and its mode of action appears similar to other NSAID. gamma-ABT posses in addition the advantage of antioxidant activity which is not shared by selective cyclooxygenase inhibitors and thus should be potentially effective in autoimmune diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Concanavalin A; Edema; Female; Foot; Indomethacin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mustard Plant; Nystatin; Plant Lectins; Plants, Medicinal; Thiophenes; Yeasts

ST 679 dose-dependently inhibited carrageenan-, concanavalin A-, and nystatin-induced oedema. Studies in rats with adjuvant arthritis showed that a long dosing regimen inhibited primary and secondary lesions. ST 679 was significantly active in reducing the severity of the already established disease and, when given in a short course at the time of adjuvant injection, permanently prevented the development of secondary lesions. Experimental allergic encephalomyelitis in guinea-pigs was not affected by ST 679.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Carrageenan; Concanavalin A; Dose-Response Relationship, Drug; Drug Administration Schedule; Edema; Female; Glycine; Inflammation; Nystatin; Pyrroles; Rats; Rats, Inbred Strains

A comparison has been made of the release of histamine from tissues of conventional rats, induced by injections of antigen, concanavalin A and clinical dextran, with that from rat isolated peritoneal mast cells. Concanavalin A was less active than dextran when injected into the skin or paws, but the reverse was found when the substances were tested on isolated cells. Similar results were obtained when a pure line of rats relatively resistant to dextran was used, concanavalin A being much more active on isolated cells than on intact mast cells. Antigen was equally active in the two types of rat. It is important, therefore, to state the experimental conditions when comparisons of the activities of histamine releasers are being made.

Topics: Animals; Antigens; Capillary Permeability; Concanavalin A; Dextrans; Edema; Foot; Histamine Release; Male; Mast Cells; Rats; Rats, Inbred Strains; Skin; Species Specificity

Subplantar administration of either Phytohaemagglutinin-P (PHA), Concanavalin-A (Con A) or kaolin into the rat hind paw produced a dose related oedema which was still present at 48 h. Both of the lectins were more inflammagenic than kaolin on a weight per weight basis. As a result of studies using mediator inhibitors and depletors it appears that 5HT, but not histamine, may play a role in the early phases (0.5-1.5 h) of both PHA and Con A responses. Neither mediator appears to be involved in the kaolin oedema. Kinins are also likely mediators of the inflammatory response to all three irritants and could be detected in irritant injected air blebs in the rat. Prostaglandins are unlikely to play a significant role in PHA or Con A oedema since indomethacin-induced inhibition of their synthesis has only a slight inhibitory effect on the lectin induced paw oedemas and only small amounts of prostaglandin-like material could be detected in PHA or Con A blebs. However, kaolin oedema appears to have a significant prostaglandin component since large amounts of prostaglandin-like materials were detected in kaolin blebs and also indomethacin reduced the kaolin induced paw oedema. Other mediators of the inflammatory process such as complement are likely to be involved in all three irritant induced oedemas.

Topics: Animals; Anti-Inflammatory Agents; Concanavalin A; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Edema; Histamine; Inflammation; Kaolin; Kinins; Lectins; Male; Prostaglandins; Rats; Serotonin

Daily intraperitoneal doses of concanavalin A (Con A) produced a dose-related inhibition of adjuvant-induced arthritis in rats. Con A was also effective on established arthritis, markedly relieving the disease after only three doses. The inhibitory effect of Con A was neutralised by pre-incubation with ovalbumin, although this treatment did not modify the delayed phlogistic action of Con A in rat paws.

Topics: Animals; Arthritis, Rheumatoid; Concanavalin A; Dose-Response Relationship, Drug; Edema; Female; Foot; Hindlimb; Immunosuppressive Agents; Ovalbumin; Rats; Time Factors

Topics: Animals; Concanavalin A; Disease Models, Animal; Edema; Inflammation; Injections, Intra-Articular; Iodine Radioisotopes; Joint Diseases; Knee Joint; Lectins; Mice; Mice, Inbred BALB C; Rabbits; Serum Albumin, Radio-Iodinated

Topics: Animals; Azo Compounds; Biphenyl Compounds; Concanavalin A; Cyanosis; Edema; Forelimb; gamma-Globulins; Humans; Immunotherapy; Lectins; Mice; Mice, Inbred Strains; Multiple Myeloma; Necrosis; Paresis; Skin Diseases; Time Factors; Vaccines