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PubMedDate not supplied

Biodistribution of injected tritiated hyaluronic acid in mice: a comparison between macromolecules and hyaluronic acid-derived oligosaccharides.

BACKGROUND: Hyaluronan (HA) has been reported to bind specifically and with high affinity to various cell types and to directly modify cell behaviour. In a previous report we demonstrated that both high molecular weight molecules (HA(H)) and HA-derived oligosaccharides were efficient at triggering terminal differentiation of acute myeloid leukemia (AML) blasts, in vitro, through CD44 ligation. MATERIALS AND METHODS: To explore the possibility of using HA for a differentiation therapy in AML, we investigated whether intravenous injection of tritiated HA(H) and/or HA-derived oligosaccharides (HA10-20) into mice accumulated in bone marrow, the main site of AML cell proliferation. RESULTS: The present work showed that the level of HA in bone marrow: 1) was maximum 5 hours after injection of either HA(H) or HA10-20; 2) was about 40 times higher after HA(H) than after HA10-20 injection. The amount of HA in bone marrow (5.8% ID/g) was two-fold higher than in serum, indicating that it was not due to circulating blood. Finally, using chromatographic analysis, we showed that about 34% of tritiated HA present in bone marrow 5 hours after HA(H) injection displayed a size higher or equal to HA10. CONCLUSION: After a single injection of macromolecular hyaluronan in mouse bone marrow we obtained a concentration of oligosaccharides close to the one shown to trigger AML cell differentiation in vitro. A part of the oligosaccharides had a size higher than or equal to the minimal one required to interact with HA receptors.

Animals↗

PubMed1987

Exogenous glycosaminoglycans stimulate hyaluronic acid synthesis by cultured human trabecular-meshwork cells.

Addition of hyaluronic acid (50-200 micrograms ml-1) to the defined, serum-free media of cultured human trabecular-meshwork cells resulted in an increase of glycosaminoglycan (GAG) synthesis as measured by the incorporation of [14C]glucosamine. Lesser stimulatory effects were exerted by dermatan sulfate and chondroitin-4- or -6-sulfate. Nearly 90% of the labeled GAGs were found to be exerted into the medium and ea. 10% were associated with the cell layer. Mainly hyaluronic acid synthesis was stimulated by the exogenous GAGs. Analysis of the GAG-pattern revealed that exogenous hyaluronic acid stimulated hyaluronic acid synthesis (positive feedback), while exogenous dermatan sulfate and chondroitin sulfate had additional effects on chondroitin sulfate synthesis. Cell growth of these cultures, which exhibited a limited proliferative capacity (ca. 18 population doublings during their life span) was not affected by the GAG treatment. Thus, exogenous hyaluronic acid and to a lower degree dermatan sulfate or chondroitin sulfate appeared to interfere with the GAG-metabolism of these human trabecular-meshwork cells in culture.

Cells, Cultured↗

PubMed2001

Treatment of painful osteoarthritis of the knee with hyaluronic acid. Results of a multicenter Asian study.

Hyaluronic acid is a component of synovial fluid, in osteoarthritis (OA) and shows a change of property of hyaluronic acid especially its viscoelasticity causing degradation of the cartilage. Injection of hyaluronic acid into OA of the knee (Hyalgan 2 ml/wk for 4 doses) in international multicentres gave dramatic responses: decreased pain, increased mobility of the joint after 49 days of injections compared to a placebo (2 ml of normal saline) p<0.01.

Aged↗

PubMed1990

Hyaluronic acid--a versatile biopolymer.

Since its discovery from bovine synovial fluid, hyaluronic acid has found application in several diverse areas. It is now extensively used in ophthalmic surgery, in the treatment of lameness in racehorses and as an ingredient in cosmetics. It can also be used in drug delivery, orthopedics, cardiovascular aids and in wound healing. Even so, its potential as a therapeutic agent is yet to be fulfilled. New improved products, formed by crosslinking hyaluronic acid with itself or other chemicals, are being produced. Hyaluronic acid is clearly a most valuable therapeutic biopolymer. This article reviews the properties of hyaluronic acid, its biosynthetic pathway and its methods of commercial production, and provides an estimation of its current and future world demand. Experiments designed to improve production economics have been performed in our laboratory. These involved control of glucose and yeast extract concentrations and fermentation pH. Hyaluronic acid production by Streptococcus zooepidemicus was found to be lower at pH 6.5 than at pH 7.1. A new method of extending the production of hyaluronic acid by S. zooepidemicus into the stationary phase has also been achieved.

Biopolymers↗

PubMed1995

Hyaluronic acid enhances cell proliferation during eosinopoiesis through the CD44 surface antigen.

We examined the effect of hyaluronic acid in promoting proliferation of undifferentiated progenitor cells through the CD44 receptor during eosinopoiesis in vitro. Undifferentiated umbilical cord blood cells were purified on the first day to isolate primitive progenitor cells expressing the CD34 hemopoietic surface marker. Culture in wells coated with 100 micrograms/ml hyaluronic acid caused a 198 +/- 28.7% augmentation of proliferation of CD34+ progenitor cells at 3 wk (p < 0.01). By contrast, concentrations of hyaluronic acid > 10 micrograms/ml inhibited proliferation of unfractionated cord blood mononuclear cells. The augmented proliferation of precursor cells caused by hyaluronic acid was associated with complete (93.0 +/- 5.12%) differentiation to eosinophil morphology. By contrast, concentrations of hyaluronic acid > or = 10 micrograms/ml inhibited eosinophilic differentiation of unfractionated mononuclear cells. Wright-Giemsa staining demonstrated 95.4 +/- 2.92% eosinophils for CD34+ cells cultured for 3 wk without hyaluronic acid (control) and 93.8 +/- 5.11% for CD34+ cells cultured in hyaluronic acid-coated wells (100 micrograms/ml); for unfractionated cells, 94.0 +/- 3.02% demonstrated eosinophilic morphology in control wells at 3 wk vs 55.4 +/- 8.34% in hyaluronic acid-coated (100 micrograms/ml) wells (p < 0.05). Augmented proliferation caused by hyaluronic acid was attenuated completely by the anti-CD44 mAbs, 212.3 and IM7.8.1. Pretreatment of CD34+ cells with 5 micrograms/ml 212.3 inhibited the augmented proliferation caused by the optimal concentration of hyaluronic acid (100 micrograms/ml) from 260 +/- 39.2% of control growth to 114 +/- 16.4% of control growth (p = 0.02). Inhibition was comparable for IM7.8.1. Control mAb (LM2) to the beta 2 integrin subunit CD11b had no effect on proliferation induced by hyaluronic acid. We demonstrate that hyaluronic acid stimulates the growth of CD34+ selected umbilical cord blood cells into specifically differentiated mature eosinophils. This process is modulated by the CD44 receptor on the progenitor cell population.

Antigens, CD↗

PubMedDate not supplied

Viscoelasticity of hyaluronic acid with different molecular weights.

Storage and loss moduli of hyaluronic acid solutions with different molecular weights were observed as a function of frequency in the presence of sugars and salts. The hyaluronic acid solutions of higher molecular weight (Mw > 17 x 10(6)) fractions showed entanglement, whereas lower molecular weight fractions did not. For inducing the entanglement of molecular chains of hyaluronic acid, increasing the molecular weight of hyaluronic acid was more effective than increasing the concentration of the lower molecular weight fractions (Mw = 7. 8 x 10(5). Glucose, fructose, galactose, and sucrose increased both storage and loss moduli, while NaCl, KCl and CaCl2 decreased both moduli. It is suggested that sugars create hydrogen bonds and strengthen the transient network. Cations shield the electrostatic repulsion of hyaluronic acid molecules, and the polymer chains are shrunk into compact coils from expanded stiffened coils.

Carbohydrates↗

PubMed1997

Reduction of adhesion formation with hyaluronic acid after peritoneal surgery in rabbits.

OBJECTIVE: To examine the effect of hyaluronic acid, a high-molecular-weight glucosaminoglycan found in the extracellular matrix, on the formation of adhesions, a major source of postoperative complications. DESIGN: The ability of hyaluronic acid to reduce adhesion formation was evaluated using a standardized rabbit model. The material was administered i.p. at the end of surgery. SETTING: University laboratory. ANIMAL(S): New Zealand White female rabbits. INTERVENTION(S): Intraperitoneal administration of various formulations of hyaluronic acid at the end of surgery. MAIN OUTCOME MEASURE(S): One week after surgery, a second laparotomy was performed and the extent of adhesion formation was determined. RESULT(S): Five separate molecular weight ranges of hyaluronic acid representing eight viscosities between 1,000 and 12,000 centipoise (CPS) were shown to reduce adhesion formation in this model. All volumes, 1 to 30 mL, of hyaluronic acid tested reduced adhesion formation. In addition, the low-viscosity, low-molecular-weight hyaluronic acid significantly reduced adhesion formation when added to the trauma site or when injected at a site remote from the trauma area. CONCLUSION(S): This study showed that hyaluronic acid administered at the end of surgery reduced adhesion formation.

Animals↗

PubMed1986

Solubilization of hyaluronic acid synthetic activity from streptococci and its activation with phospholipids.

To date all hyaluronic acid synthetic systems have been of a particulate nature, and attempts at solubilization have been unsuccessful. This has hampered attempts to elucidate the mechanism by which hyaluronic acid is produced. In this paper we demonstrate that the hyaluronic acid synthetic activity from group C streptococcal membranes was solubilized using 2% digitonin and that the activity was optimized by reconstitution with cardiolipin at an optimum phospholipid/protein ratio (microgram/microgram) of 5:1. Furthermore, chromatography of the solubilized synthetase demonstrated that it eluted after the void volume of a Sepharose CL-6B column. CHAPSO, octyl glucopyranoside, sodium cholate, Triton X-100, and zwittergent 314 either inhibited or failed to solubilize the synthetic activity. Phospholipids other than cardiolipin also reconstituted the activity from the digitonin extract, particularly phosphatidylethanolamine and phosphatidylserine. In our system, the specific activity of hyaluronic acid synthetase was increased up to 63 times that of the system of the intact membrane. Furthermore, the total activity of the reconstituted system was 4.9 times greater than that of intact membranes. The soluble enzyme system showed similarities to the membrane-bound synthetase in the kinetics of production of trichloroacetic acid-soluble and -insoluble hyaluronic acid, and the hyaluronic acid produced was of comparable molecular weight.

Carbon Radioisotopes↗

PubMed1997

Preparation of cross-linked hyaluronic acid films of low water content.

Hyaluronic acid (HA) was chemically cross-linked with poly(ethylene glycol) diglycidyl ether, a diepoxy compound (EX-810), to yield low water content and slowly degradable films when brought into contact with water. The cross-linking reaction was performed under acidic and neutral conditions, since the epoxy group is readily hydrolysed in alkaline media. To allow the reaction to proceed at high HA concentrations, a solution casting method was employed for the cross-linking of HA. The lowest water content of the cross-linked HA films obtained was 60 wt% when swollen with buffered saline at 37 degrees C. Alginic acid and poly(vinyl alcohol), which possess hydroxyl groups, similar to HA, were also found to undergo cross-linking with the diepoxy compound. Since IR spectra of the cross-linked films had no significantly new absorption, intermolecular formation of ether bonds between the hydroxyl groups belonging to different polysaccharide molecules was assumed to take place. It seemed too difficult to detect the ether bonds in the cross-linked HA films, because the virgin HA film itself contained ether bonds in the molecule. The cross-linked HA film with a water content of 60 wt% exhibited practically no weight loss after 10 days of immersion in phosphate-buffered saline (pH 7.4), while this film underwent in vivo degradation by 30% weight loss after 7 days of subcutaneous implantation in rats. The inflammation reaction elicited around the implanted film was not significant.

Alginates↗

PubMed1983

Streptococcal hyaluronic acid: proposed mechanisms of degradation and loss of synthesis during stationary phase.

Streptococcal hyaluronic acid was found to distribute into two discrete sizes. Cellular hyaluronic acid from strain D181 had an average molecular weight of 10 X 10(6), whereas the average molecular weight of extracellular hyaluronic acid from the same strain was 2 X 10(6). Cellular streptococcal hyaluronic acid was purified to homogeneity. Proteases were unable to cleave the purified cellular polymer, indicating that a peptide was not involved in cross-linking five extracellular hyaluronate polymers to form a cell-bound complex. Lipids apparently are not part of the cellular hyaluronic acid because phosphorus and glycerol were not detected by radioisotopic techniques, and denaturing conditions did not change the size of the polymer. Membranes obtained from various strains of group A and C streptococci cleaved the cellular form of the hyaluronate polymer demonstrating the presence of a membrane-bound hyaluronidase-like activity. By contrast, this activity was not found in the extracellular products of the strains studied. Furthermore, membranes derived from streptococci at the stationary phase of growth no longer had the capacity to synthesize hyaluronic acid. The loss of this property appeared to be due to changes in the structure of the membrane.

Cell Membrane↗

PubMed1973

Binding of oligosaccharides of hyaluronic acid to proteoglycans.

Oligosaccharides derived from hyaluronic acid were shown to inhibit proteoglycan-hyaluronic acid interaction, as measured in a viscometer. The relative inhibition increased with the size of the oligosaccharide and the results suggested that decasaccharides were the smallest fragments able to bind strongly to the proteoglycan.

Animals↗

PubMed1981

Plasma clearance, tissue distribution and metabolism of hyaluronic acid injected intravenously in the rabbit.

The plasma clearance, tissue distribution and metabolism of hyaluronic acid were studied with a high average molecular weight [3H]acetyl-labelled hyaluronic acid synthesized in synovial cell cultures. After intravenous injection in the rabbit the label disappeared from the plasma with a half-life of 2.5--4.5 min, which corresponds to a normal hyaluronic acid clearance of approx. 10 mg/day per kg body weight. Injection of unlabelled hyaluronic acid 15 min after the tracer failed to reverse its absorption. Clearance of labelled polymer was retarded by prior injection of excess unlabelled hyaluronic acid. The maximum clearance capacity was estimated in these circumstances to be about 30 mg/day per kg body wt. The injected material was concentrated in the liver and spleen. As much as 88% of the label was absorbed by the liver, where it was found almost entirely in non-parenchymal cells. Degradation was rapid and complete, since volatile material, presumably 3H2O, appeared in the plasma within 20 min. Undegraded [3H]hyaluronic acid, small labelled residues and 3H2O were detected in the liver, but there was little evidence of intermediate oligosaccharides. No metabolite except 3H2O was recognized in plasma or urine. Two-thirds of the radioactivity was retained in the body water 24 h later, and small amounts were found in liver lipids. Radioactivity did not decline in the spleen as rapidly as in the liver. The upper molecular weight limit for renal excretion was about 25 000. Renal excretion played a negligible part in clearance. It is concluded that hyaluronic acid is removed from the plasma and degraded quickly by an efficient extrarenal system with a high reserve capacity, sited mainly in the liver.

Animals↗

PubMed1993

Suppressive effects of hyaluronic acid on elastase release from rat peritoneal leucocytes.

Effects of hyaluronic acid on the release of elastase from rat peritoneal leucocytes were studied by measuring the leucocyte elastase activity using a synthetic peptide substrate. Leucocyte elastase release was induced by opsonized zymosan, 12-O-tetradecanoyl phorbol-13-acetate (TPA) and N-formyl-L-methionyl-L-leucyl-L-phenylalanine combined with cytochalasin B. Calcium ionophore A23187 potentiated the action of TPA on leucocyte elastase release, whereas hyaluronic acid inhibited leucocyte elastase release regardless of the method of stimulation. Inhibitory effects of hyaluronic acid were dependent on its concentration and molecular weight. Hyaluronic acid of the highest molecular weight (2.0 x 10(6)) indicated a potent inhibitory effect on elastase release. Our present findings suggest that hyaluronic acid may elicit an anti-inflammatory effect by inhibiting leucocyte elastase-dependent pathological processes.

Animals↗

PubMed1998

Identification of csrR/csrS, a genetic locus that regulates hyaluronic acid capsule synthesis in group A Streptococcus.

The hyaluronic acid capsule of group A Streptococcus (GAS) is an important virulence factor, but little is known about mechanisms that regulate capsule expression. Transposon Tn916 mutagenesis of the poorly encapsulated M-type 3 GAS strain DLS003 produced a transconjugant that exhibited a mucoid colony morphology, reflecting increased hyaluronic acid capsule production. Analysis of chromosomal DNA sequence immediately downstream of the transposon insertion identified two open reading frames, designated csrR and csrS, which exhibited sequence similarity to bacterial two-component regulatory systems. We constructed an in-frame deletion mutation within csrR, which encodes the putative response component. Replacement of the native csrR gene in the DLS003 chromosome with the mutant allele resulted in a sixfold increase in capsule production and a corresponding increase in transcription of the has operon, which contains the essential genes for hyaluronic acid synthesis. Increased capsule production by the csrR mutant strain was associated with enhanced resistance to complement-mediated opsonophagocytic killing in vitro and with a 500-fold increase in virulence in mice. These results establish CsrR as a negative regulator of hyaluronic acid capsule synthesis and suggest that it is part of a two-component regulatory system that influences capsule expression and virulence.

Amino Acid Sequence↗

PubMed1993

Inhibition of fibroblast hyaluronic acid production by suramin.

Hyaluronic acid (HA) is an extracellular matrix glycosaminoglycan localized in the stroma of solid tumors, where it facilitates cell movement and thus tumor invasion and metastasis. This localization of HA is due to its synthesis by stromal fibroblasts in response to paracrine factors produced by the tumor. Such tumor-stromal interactions have been shown to be crucial to the development and progression of prostate cancer. Suramin is an effective antitumor agent in hormone-refractory prostate cancer, but its mechanism(s) of action is not well understood. However, the properties of suramin as an agent which disrupts growth factor action, and the importance of tumor-stroma interactions in prostate tumor development and in HA synthesis led us to study the effect of suramin on HA synthesis. Suramin inhibited HA synthesis by calf serum-stimulated Swiss 3T3 fibroblasts at clinically relevant concentrations (IC50 = 183 micrograms/mL). Increasing the serum concentration from 10 to 20% did not change the IC50 for HA synthesis, but increased the IC50 for [3H]thymidine incorporation from 206 to 342 micrograms/mL, indicating that the antiproliferative effect of suramin can be dissociated from its effect on HA synthesis. Suramin did not alter the cellular concentrations of the two precursors for HA synthesis (UDP-glucuronic acid and UDP-N-acetylglucosamine) at early time points and did not inhibit the HA synthetase activity of isolated membranes at concentrations up to 800 micrograms/mL.(ABSTRACT TRUNCATED AT 250 WORDS)

3T3 Cells↗

PubMed1982

Enhanced humoral immune response in rats by hyaluronic acid.

The effect of hyaluronic acid (HA) on antibody responses to egg albumin, dog albumin and birch pollen proteins, was studied in rats. The highest antibody responses to dog and egg albumin were obtained in rats immunized with a coprecipitate of the antigen with HA. However, pretreatment of rats with a subcutaneous injection of HA up to three (3) days prior to the priming injection of dog albumin also significantly enhanced the secondary antibody responses to that antigen. Possible explanations of this stimulatory effect on the humoral immune response are discussed.

Adjuvants, Immunologic↗

PubMed1993

Hyaluronic acid uptake by the isolated, perfused rat liver: an index of hepatic sinusoidal endothelial cell function.

Previous studies indicate that sinusoidal endothelial cells bind and internalize hyaluronic acid at much greater rates than do other liver cells. Thus hepatic hyaluronic acid removal rate may be indicative of sinusoidal endothelial cell function. In these studies the uptake of hyaluronic acid (molecular weight 1.3 x 10(6)) was measured in isolated perfused rat liver under a variety of conditions. Uptake was dependent on hyaluronic acid concentration. At all concentrations tested, the rate of hyaluronic acid uptake stabilized at a steady-state level 2 to 3 min after development of a high rate of apparent uptake. At saturating hyaluronic acid concentration (150 ng.ml-1), the steady-state uptake rate was 10.4 +/- 1.0 micrograms.gm-1 liver wet wt.hr-1, which is as high as or higher than the rates reported for isolated rat liver sinusoidal endothelial cells. The half-maximal rate of uptake was attained at a hyaluronic acid concentration of 80 ng.ml-1. Hyaluronic acid uptake was inhibited by heparin (80%), a competitive ligand for the hyaluronic acid receptor on sinusoidal endothelial cells; 4 beta-phorbol 12 beta-O-myristoyl 13 alpha-acetate (25% to 50%), a tumor promoter and activator of protein kinase C; prostaglandin F2 alpha (24% to 52%), an eicosanoid secreted in the liver by Kupffer cells; A23187 (33% to 66%), a Ca2+ ionophore; and Escherichia coli lipopolysaccharide (16% to 43%). Platelet activating factor did not affect hyaluronic acid uptake by the perfused liver. Hyaluronic acid uptake was increased by 50% after a 24-hr fast.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

The catabolic fate of hyaluronic acid.

Part of the hyaluronic acid (HA) synthesized in peripheral tissues enters the blood circulation through the lymph. It is rapidly taken up by the endothelial cells in the liver (half-life in blood is 2.5-5.5 minutes) and degraded. Pure primary cultures of liver endothelial cells were obtained by a newly developed technique and used to follow the metabolism of the polysaccharide on the cell surface. At 37 degrees C the HA is effectively endocytosed and degraded to acetate and lactate. A radioassay specific for HA and sensitive in the nanogram range has been developed to follow the concentration of HA in serum. The normal level in man is 10 to 100 micrograms/l. Elevated serum levels of HA are seen in liver cirrhosis, rheumatoid arthritis and scleroderma indicating that both an impaired catabolism in the liver and an increased synthesis in the peripheral tissues can modify the HA level.

Animals↗