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PubMed2002

Analysis of O-linked reducing oligosaccharides released by an in-line flow system.

Reducing O-linked oligosaccharides from bovine submaxillary mucin, bovine fetuin, and porcine gastric mucin were recovered by nonreductive alkaline beta-elimination from an in-line flow system. Glycoproteins where attached to a solid support using hydrophobic interaction with alkali-resistant Poros reversed phase beads and a flow of alkali released the oligosaccharides. The alkali was subsequently neutralized by a continuous flow through cation exchange resin. The released oligosaccharides in the flow were trapped in a cartridge filled with graphitized carbon. Salt-free oligosaccharides could be recovered as a concentrated solution by elution with organic solvents from the cartridge. The glycosylation pattern of the released oligosaccharides was compared with the conventionally released and reduced oligosaccharides recovered from alkaline beta-elimination in the presence of borohydride. In general, the recovery from the in-line release was sometimes lower than from the reductive elimination method, but it was shown that alkaline degradation of reducing oligosaccharides was limited in this system. Liquid chromatography using graphitized carbon packing and high pH mobile phases together with negative ion electrospray mass spectrometry showed that both neutral and acidic reducing oligosaccharides could be analyzed in a single run. Reducing O-linked oligosaccharides could also be recovered in this way from human glycophorin separated by SDS-PAGE. The polyacrylamide was sufficient to retain the glycoprotein in the gel while the flow of alkali released the oligosaccharides. It was also shown that the alkaline conditions for releasing O-linked oligosaccharides from fetuin would partially release some N-linked oligosaccharides, particularly in the presence of reducing agent.

Animals↗
PubMed1995

Identification of the major lipoproteins in crayfish hemolymph as proteins involved in immune recognition and clotting.

Lipid-containing hemolymph proteins from males of the crayfish Pacifastacus leniusculus were isolated by density gradient ultracentrifugation. Two major lipoproteins, one high density lipoprotein (HDL) and one very high density lipoprotein (VHDL), were characterized. The HDL and the VHDL were found to be identical to two proteins previously studied for their roles in immune recognition and hemolymph clotting, namely the beta-1,3-glucan binding protein and the clotting protein. These results imply that crayfish lipoproteins have dual functions, and that they are involved in immunity, hemolymph clotting, and lipid transport in these animals. Also, the oxygen-transporting protein hemocyanin was found to have a small lipid content.

Amino Acid Sequence↗
PubMed2000

The effect of monovalent ions on polyphosphate binding to Escherichia coli exopolyphosphatase.

The thermodynamic driving force for the interaction of Escherichia coli exopolyphosphatase (PPX) with polyphosphate was investigated by varying salt choice and concentration. This interaction was found to be cation concentration independent but weakly dependent on the concentration of certain anions. Both of these traits are very uncommon for nonspecific protein-polyelectrolyte interactions. Interpretation of these results based on theory indicated that binding was not entropy driven due to release of polyelectrolyte-condensed counterions, as is the case for nearly all protein-polyelectrolyte interactions. The thermodynamics of the PPX-polyphosphate interaction showed similarity only to the interaction of polynucleotides with single stranded binding proteins.

Acid Anhydride Hydrolases↗
PubMed2001

Plasma membrane localization of palmitoylated tubulin.

PC12 pheochromocytoma cells incorporate [(3)H]palmitic acid into tubulin in a time- and cell-density-dependent manner. The plasma membrane-enriched fraction contains most of the radioactivity of the membrane pellet. While palmitoylated tubulin is found in both the cytoplasm and particulate fraction, the bulk of [(3)H]palmitic acid bound to tubulin is present in the crude membrane pellet and the tubulin extracted from the plasma membrane is more heavily palmitoylated than that extracted from endoplasmic reticulum. Detergent-extracted tubulin from plasma membrane is, to a large extent, polymerization competent; a substantial fraction, increasing as a function of labeling time, is not hydroxylamine-labile. The requirement for detergent extraction, the accompanying changes in tubulin properties and the present findings of preferential incorporation of labeled tubulin into plasma membranes, make it clear that direct incorporation of tubulin into the plasma membrane can occur.

Animals↗
PubMed1993

Isolation of a non-sedimenting membrane fraction from the water soluble fraction of bovine lens.

A membrane fraction was isolated from the water soluble fraction of bovine lens by increasing the density of the water soluble fraction with KBr and subjecting it to overnight centrifugation at 100000 g. We have called this fraction, which floats to the top of the mixture upon centrifugation, the non-sedimenting membrane fraction (NSMF). Electron microscopy of the NSMF revealed that it is composed of the expected membrane structures of unit membrane, fiber junction and cytoskeleton. Significantly less of the total membrane of the NSMF was devoted to fiber junction (22.8%) than in the sedimenting membrane fraction (SMF) (41.1%) prepared by sucrose density centrifugation of the water insoluble fraction. The NSMF accounted for about 7-12% of the total bovine lens membrane, and preliminary experiments demonstrated that a similar fraction could be isolated from the water soluble fraction of lenses from rats, rabbits, chickens and humans. The NSMF contained about 0.9 mg total lipid per mg total membrane protein, which was significantly greater than the value obtained for the SMF (0.5 mg total lipid per mg total membrane protein). The greater relative amount of total lipid in the NSMF was due to a significantly greater relative amount of phospholipid in the NSMF which was further reflected by the observation that the cholesterol: phospholipid molar ration of the NSMF (0.58) was significantly less than that of the SMF (0.88). Thus the relative lipid composition of the NSMF was significantly different than that of the SMF. Although the phospholipid content of the NSMF was greater than that of the SMF, the compositions of the phospholipids in the two membrane fractions were similar. The NSMF possessed essentially the same polypeptides (both extrinsic and intrinsic) which were found in the SMF. The NSMF was found to be distributed throughout the lens in a proportionate manner. We conclude that the NSMF may account for most of the lipid which remains in the water soluble fraction of the normal bovine lens after sedimentation of the water insoluble fraction. This membrane fraction substantially differs from the SMF in terms of structure and relative lipid composition. We speculate that the NSMF may represent a specialised domain of the fiber cell plasma membrane which has been previously unrecognized.

Animals↗
PubMed1993

The effect of angiostatic steroids and beta-cyclodextrin tetradecasulfate on corneal neovascularization in the rat.

Folkman and coworkers have described angiostatic steroids that markedly inhibit neovascularization of the rabbit cornea when given topically with beta-cyclodextrin tetradecasulfate (beta-CD), yet have minimal or no glucocorticoid or mineralocorticoid activity. Our objective was to extend these observations to another species, the rat. We induced neovascularization by cauterizing rat corneas with silver nitrate/potassium nitrate; drugs were applied topically four times per day for 4 days in most experiments. Submicron sized emulsions of lipid-soluble dexamethasone and the angiostatic steroids 17 alpha-hydroxyprogesterone (1 or 10 mg ml-1) and cortexolone (1 or 10 mg ml-1) were prepared by lecithin encapsulation of drug microcrystals. The vehicle for water-soluble hydrocortisone 21-phosphate (HCP) +/- beta-CD (Molecusol; Pharmatec, Inc) was 10% Tween 20 in Tris-buffered 0.9% saline. Angiogenesis was significantly inhibited only by 1 mg ml-1 dexamethasone (-63.2% when compared with controls), 0.5 mg ml-1 HCP + 1 mg ml-1 beta-CD (-33.4%), and 1 mg ml-1 HCP (-40.2%). HCP (0.5 mg ml-1) or beta-CD (1 or 2 mg ml-1) alone had no significant effect on neovascularization; the inhibition by 1.0 mg ml-1 HCP was not potentiated by 2 mg ml-1 beta-CD. We also tested HCP and tetrahydro-S (TH-S) using 1.5% hydroxypropyl methylcellulose vehicle and beta-CD from Takeda Chemical Industries, Ltd., to simulate the procedure of Folkman and coworkers.(ABSTRACT TRUNCATED AT 250 WORDS)

17-alpha-Hydroxyprogesterone↗
PubMed1995

Immunocytochemical and morphometric study of TSH, PRL, GH, and ACTH cells in Bufo arenarum larvae with inhibited thyroid function.

Changes in the pituitary cells involved in amphibian metamorphosis were studied in Bufo arenarum tadpoles with inhibited thyroid function. After hatching, larvae were treated for 5 months with potassium perchlorate (KClO4), a goitrogenic substance known to prevent absorption of iodine from water or food, resulting in impaired thyroid hormone synthesis. Treated larvae continued to grow but halted their development in premetamorphosis, showing hyperplastic thyroid glands with disorganized follicles lacking colloid. Thyrotrop (TSH), lactotrop (PRL), somatotrop (GH), and corticotrop (ACTH) cells were stained immunocytochemically and the changes observed were evaluated morphometrically using an automatic image analyzer. Pars distalis volume increased in treated larvae. Morphometric results showed that, in treated tadpoles, TSH and PRL cell populations and cell volumes increased compared to normal larvae at the same stage. Changes in the GH and ACTH cell morphometry were slight. These results indicate that in Bufo tadpoles, after chronic thyroid hormone withdrawal, TSH, PRL, GH, and ACTH cells are able to develop and that thyroid hormones exert a strong feedback control on the synthesis and storage of TSH and PRL.

Adrenocorticotropic Hormone↗
PubMed1997

The effects of exogenous thyroxine (T4) or triiodothyronine (T3), in the presence and absence of potassium perchlorate, on the incidence of metamorphosis and on serum T4 and T3 concentrations in larval sea lampreys (Petromyzon marinus L.).

Larval sea lampreys (Petromyzon marinus) measuring 100-119 mm in length were exposed to thyroxine (T4; 10 mg liter-1) or 3,5,3'-triiodothyronine (T3; 1 mg liter-1) in the presence and absence of the goitrogen potassium perchlorate (KClO4; 0.01%), for 4-24 weeks. Every 4 weeks, treated and untreated (control) groups of sea lampreys were examined for external signs of metamorphosis and serum was assayed for T4 and T3 concentrations. Precocious metamorphosis was observed following 8, 12, and 24 weeks of KClO4 treatment; however, metamorphosis was not observed in any control, or T4-, T3-, T4+KClO4-, and T3+KClO4-treated larvae. In addition, serum T4 and T3 concentrations were 62 and 72% lower in KClO4-treated individuals than in control animals, respectively. Treatment with exogenous thyroid hormones (TH), in the presence or absence of KClO4, resulted in serum T4 concentrations which were significantly greater (1.2- to 58-fold) than those of the controls in all sampling periods except one, but serum T3 concentrations were not significantly elevated in more than 50% of the cases. TH+KClO4 treatments produced serum T3 concentrations which were significantly greater than those of KClO4-treated animals and never less than those of controls. These data indicate that larval sea lampreys have a tremendous capacity to take up and store exogenous T4 in their serum, but the uptake and/or serum storage of T3 appears to be stringently regulated. Also, the absence of both metamorphosis and a decline in serum TH concentrations in TH+KClO4-treated animals suggests that a decline in serum TH concentrations may be an essential factor contributing to the induction of metamorphosis by KClO4.

Animals↗
PubMed1998

Blocking of KC1O4-induced metamorphosis in premetamorphic sea lampreys by exogenous thyroid hormones (TH); effects of KC1O4 and TH on serum TH concentrations and intestinal thyroxine outer-ring deiodination.

Immediately premetamorphic larval sea lampreys (Petromyzon marinus) (>/=120 mm in length) were treated for 4, 8, or 16 weeks with one of two concentrations of either exogenous thyroxine (T4; 1 or 0.5 mg/L) or 3,5,3'-triiodothyronine (T3; 1 or 0.25 mg/L) in the presence or absence of the goitrogen potassium perchlorate (KC1O4; 0.05%) as well as with KC1O4 alone. Larvae from all treatments were examined for signs of metamorphosis, changes in serum T4 and T3 concentrations (serum T4 and serum T3), and changes in intestinal T4 outer-ring (5') deiodination to T3 (T4ORD). KC1O4 depressed both serum T4 and T3 and induced metamorphosis in 80% of larvae treated for 8 weeks or longer. However, neither effect was observed in larvae exposed to KC1O4 combined with either thyroid hormone (TH). These data confirm previous suggestions that exogenous TH blocks KC1O4-induced metamorphosis by elevating serum TH concentrations, and provide evidence that declines in serum TH concentrations are mandatory for precocious metamorphosis. Serum T4, but not serum T3, was elevated following exogenous T4 treatment in the presence or absence of KC1O4. This maintenance of serum T3 at control levels, in the presence of a T4 challenge, was not due to decreases in intestinal T4ORD activity, since T4ORD activity was not affected by any treatments in the study. Exogenous T3 elevated both serum T4 and T3. However, serum T3 in T3-treated larvae decreased with time, suggesting a stringent T3 regulation. Elevation of serum T4 following T3 treatment may have been a result of either inhibition of T4 metabolism, or stimulation of T4 secretion by the endostyle. Based on these results, we conclude that (i) exogenous TH blocks KClO4-induced metamorphosis in sea lampreys and (ii) serum T3 is maintained at control levels despite elevations in serum T4 (its immediate precursor), but this does not involve any changes in intestinal T4ORD activity.

Animals↗
PubMed2002

Adsorption of N-tallow 1,3-propanediamine-dioleate collector on albite and quartz minerals, and selective flotation of albite from greek stefania feldspar ore.

The adsorption behavior of tallow 1,3-propanediamine-dioleate (Duomeen TDO) collector on albite and quartz minerals is assessed through Hallimond flotation, zeta potential, and diffuse reflectance FTIR investigations, together with the species distribution of the collector. The collector performance on albite separation from a natural feldspar material is evaluated in bench scale flotation tests. The Hallimond flotation responses of the minerals as a function of pH and collector concentration indicate that albite can be selectively floated from quartz at pH 2 where the doubly positively charged collector species adsorb on albite but not on quartz. However, the zeta potential and infrared spectra reveal that the adsorption behavior of the collector is similar on both minerals. The discrepancy in the flotation and adsorption results is attributed to the coarse and fine particle size fractions, and the shorter and longer equilibration periods employed in these studies respectively. The comparable adsorption on fine particles of albite and quartz at pH 2 is explained by the interaction of ammonium ions on silanol groups by hydrogen bonding as well as electrostatic interactions. The changes in zeta potentials are in good agreement with the formation of ionic species and free molecular forms of the collector. The IR spectra show the coexistence of neutral oleic acid together with charged amine species at low pH values in accordance with the species distribution diagram. Selective flotation of albite is accomplished from a natural feldspar material with tallow diamine-dioleate collector at pH 2 using sulfuric acid, only when the feed is deslimed prior to the bench scale flotation tests. An albite recovery exceeding 85% is achieved from a feed material containing about 50% albite.

Adsorption↗
PubMed2002

The influence of stern layer conductance on the dielectrophoretic behavior of latex nanospheres.

The influence of the Stern layer conductance on the dielectrophoretic behavior of sub-micrometer-sized latex spheres is examined. The dielectrophoretic response of the particles is measured and analyzed in terms of a model of surface conductance divided into discrete components related to the structure of the double layer. The effect of both co- and counterions in the bulk solution on the Stern layer conductance is demonstrated.

Electric Conductivity↗
PubMed2002

Textural and chemical characterizations of adsorbent prepared from palm shell by potassium hydroxide impregnation at different stages.

Preparation and characterization of activated carbon from palm shell, a carbonaceous agricultural solid waste, by potassium hydroxide treatment at different stages were studied. The effects of activation temperature and chemical to sample ratio on the characteristics of the activated carbon were investigated. Fixed-bed adsorption of sulfur dioxide (SO(2)) gas was carried out to evaluate the adsorptive capacity of the samples. Desorption tests were conducted to verify the occurrence of chemisorption due to some surface functional groups or of chemical reaction between SO(2) and KOH. It was found that pre-impregnation of raw palm shell was involved in replacement of some hydrogen ions with potassium ions to form cross-linked complexes, which retarded the tar formation during carbonization, resulting in a relatively high yield. Moreover, these potassium ions accelerated the reaction as catalysts during gasification of chars by carbon dioxide. For chars with mid-impregnation, potassium hydroxide acted in two ways: (i) formation of metallic potassium by dehydration and (ii) conversion into potassium carbonate. Metallic potassium intercalated to the carbon matrix accounted for pore development and potassium carbonate layer prevented the sample from over burn-off. Post-impregnation of final products modified the textural characteristics of the sample as some pore entrances were blocked by chemicals. However, potassium hydroxide enhanced the amount of SO(2) uptaken via formation of potassium sulfite.

Adsorption↗
PubMed1994

Stability against denaturation mechanisms in halophilic malate dehydrogenase "adapt" to solvent conditions.

Malate dehydrogenase from Haloarcula marisomortui (hMDH) is active, soluble and mildly unstable in an unusually wide range of salt conditions and temperatures, making it a particularly interesting model for the study of solvent effects on protein stability. Its denaturation (loss of activity due to concomitant dissociation and unfolding) kinetics was studied as a function of temperature and concentration of NaCl, potassium phosphate or ammonium sulphate in H2O or 2H2O. A transition-state-theory analysis was applied to the data. In all cases, stability (resistance to denaturation) increased with increasing salt concentration, and when 2H2O replaced H2O. Each salt condition was associated with a particular energy regime that dominated stability. In NaCl/H2O, a positive enthalpy term, delta H not equal to 0, always dominated the activation free energy of denaturation, delta G not equal to 0. In potassium phosphate/H2O and ammonium sulphate/H2O, on the other hand, stability was dominated by a negative activation entropy, delta S not equal to 0. and delta H not equal to 0 changed sign between 10 degrees C and 20 degrees C, consistent with a strong hydrophobic effect contribution, in these salting-out solvents. Decreasing stability at low temperatures, favouring cold denaturation, was observed. Replacing H2O by 2H2O strengthened the hydrophobic effect in all conditions. As a consequence, conditions were found in which hMDH was not halophilic; below 10 degrees C, it was stable in approximately 0.1 M NaCl/2H2O. The solution structure and preferential solvent interactions of hMDH in H2O or 2H2O solvents containing NaCl were studied by densimetry and neutron scattering. Despite the different stability of the protein in H2O or 2H2O, an experimentally identical invariant solution particle was formed in both solvents. It had a total volume of 1.165 cm3 g-1 and bound about 0.4 g of H2O (0.44 g of 2H2O) and about 0.08 g NaCl g protein. The impact of these results on a stabilisation model for hMDH, involving ion binding, is discussed.

Ammonium Sulfate↗
PubMed1998

The effects of salt on the TATA binding protein-DNA interaction from a hyperthermophilic archaeon.

This study investigates the thermodynamics of the interaction of the TATA box binding protein (TBP) from Pyrococcus woesei (Pw) with an oligonucleotide containing a specific binding site. Pw is a hyperthermophilic archeal organism which exists under conditions of high salt and high temperature. A measurable protein-DNA interaction only occurs at high salt concentrations. Isothermal titration calorimetric binding studies were performed under a range of salts (potassium chloride, potassium phosphate, potassium acetate and sodium acetate) at varying concentrations (0.8 to 1.6 M). At the high salt concentrations used the observed equilibrium binding constant increases with increasing salt concentration. This is very different to the effect reported for all other protein-DNA interactions which have been studied at lower salt concentrations. Thermodynamic data suggest that the protein-DNA interaction at high salt concentration is accompanied by the removal of large numbers of water molecules from the buried hydrophobic surface area. In addition, the involvement of ions appears to influence the binding which can be explained by binding of cations in the interface between the electrostatically negative lateral lobes on the protein and the negatively charged DNA.

Amino Acid Sequence↗
PubMed1998

Impairment of the sarcolemmal phospholipase D-phosphatidate phosphohydrolase pathway in diabetic cardiomyopathy.

Experimental evidence suggests that the myocardial phospholipase D (PLD)-phosphatidate phosphohydrolase (PAP) signalling pathway may regulate Ca2+ movements and contractile performance of the heart. As abnormal Ca2+ homeostasis is associated with diabetic cardiomyopathy, we examined the functional status of the PLD/PAP pathway in sarcolemmal (SL) membranes isolated from insulin-dependent diabetic rat hearts at 8 weeks after a single i.v. injection of streptozotocin (65 mh/kg b.w.). Compared to age-matched controls, SL PLD hydrolytic (producing phosphatidic acid, PtdOH) and transphosphatidylation activities were significantly depressed in diabetic animals, while SL PAP was significantly augmented. The net effect of the altered enzyme activities in diabetic animals was a severely diminished (by 67% of controls) membrane level of PLD-derived PtdOH. Two weeks of insulin therapy to the 6 week diabetic animals normalized PLD, while PAP activity and PtdOH level were significantly modified, but had not completely reverted to control values. The observed changes were not due to hypothyroidism associated to the diabetic model as the induction of hypothyroidism in healthy non-diabetic animals did not affect SL PLD and PAP. The results suggest that the severe reduction of PLD-derived PtdOH and increased production of sn-1,2-diacylglycerol by phosphatidate phosphohydrolase may lead to an impairment of the bioprocesses mediated by these signalling lipids.

Animals↗
PubMed1994

Development of a pharmacokinetic model for chromium in the rat following subchronic exposure. I. The importance of incorporating long-term storage compartment.

A pharmacokinetic model of chromium depuration in the rat has been developed under subchronic exposure conditions. Rats were exposed to 100 ppm Cr(VI) in their drinking water for 6 weeks, followed by a 140-day period of depuration. Tissue concentrations of Cr at the end of the 6-week exposure period were greatest in the bone, spleen, and kidney, with lower concentrations present in the liver and blood. The overall kinetics of Cr depuration from the tissues were relatively slow, especially for the largest compartment which included bone. The results indicated that the half-life of Cr in bone exceeded 100 days. A three-compartment model was developed to fit the data. Liver, kidney, and spleen were grouped into a single compartment which was linked to a major storage compartment (i.e., bone, skin, hair, and muscle) via the blood. Using this model, the time to a 50% reduction of whole body Cr (i.e., loss of total Cr mass for the whole rat) was calculated to be about 80 days. The higher half-life for the storage compartment of 100 days is due to the relative weights of the compartments and the more rapid loss of Cr from the liver, kidney, and spleen compartment. The data suggest that Cr may be sequestered and release of Cr by the storage compartment over an extended period of time, thereby, may play an important role in maintaining elevated body burdens and tissue concentrations of Cr following long-term exposure to this toxic metal.

Animals↗
PubMed1997

Human ingestion of chromium (VI) in drinking water: pharmacokinetics following repeated exposure.

Regulatory agencies have established safe drinking water concentrations for hexavalent chromium [Cr(VI)] based in part on the presumed capability of human gastric juices to rapidly reduce Cr(VI) to nontoxic trivalent chromium [Cr(III)] prior to systemic absorption. This study examines dose-related pharmacokinetics in humans following repeated oral exposure to Cr(VI) in drinking water. In particular, we sought to examine whether plausible drinking water exposures to Cr(VI) caused a sustained increase in red blood cell chromium levels, a specific marker for systemic uptake of Cr(VI). Adult male volunteers ingested a liter (in three volumes of 333 ml, at approximate 6-hr intervals) of deionized water containing Cr(VI) concentrations ranging from 0.1 to 10.0 mg/liter. Samples of urine, plasma, and red blood cells were collected and analyzed for chromium. A dose-related increase in urinary chromium excretion was observed in all volunteers. Red blood cell and plasma chromium concentrations became elevated in certain individuals at the highest doses. The RBC chromium profiles suggest that the ingested Cr(VI) was reduced to Cr(III) before entering the bloodstream, since the chromium concentration in the RBCs dropped rapidly postexposure. These findings suggest that the human gastrointestinal tract has the capacity to reduce ingested Cr(VI) following ingestion of up to 1 liter of water containing 10.0 mg/liter of Cr(VI), which is consistent with USEPA's position that the Cr(VI) drinking water standard of 0.10 mg Cr(VI)/liter is below the reductive capacity of the stomach.

Administration, Oral↗
PubMed2001

Biodegradability of inhaled para-aramid respirable-sized fiber-shaped particulates: mechanistic in vivo and in vitro studies.

Biopersistence represents an important health-related issue in fiber toxicology. These studies were undertaken to elucidate the mechanism(s) through which inhaled p-aramid respirable-sized fiber-shaped particulates (RFP) are biodegraded in the lungs of exposed rats and hamsters. Previously, we and others have reported that, following deposition in the lung, long p-aramid RFPs are cleaved into shorter fibrous fragments. To investigate the mechanisms of RFP biodegradation, we have postulated that lung fluids coat/activate p-aramid RFP following deposition in the alveolar regions of the lung, thus predisposing the RFP to enzymatic attack and consequent shortening. This process enhances the rate of clearance of the inhaled RFP. To test this hypothesis, we have conducted both in vivo and in vitro cellular and noncellular investigations. First, p-aramid or cellulose RFP were instilled into the lungs of rats and the lungs were digested 24 h postexposure using two different digestion techniques: (1) a conventional ethanolic KOH method and (2) an enzymatic method that simulates the action of lung enzymes. Cellulose RFP were utilized as a control organic fiber-type that is known to be biopersistent. The results demonstrated that the enzymatic but not the KOH method resulted in transverse cleavage of the p-aramid RFP; the lengths of cellulose RFP recovered from rat lungs were not reduced by either method. Next, standardized preparations of p-aramid RFP or cellulose RFP were incubated with saline or lung fluids and then processed by one of two tissue digestion techniques. Mean lengths of p-aramid RFP incubated with saline and processed with KOH or the enzyme method were not found to be altered. Indeed, only the preparation of p-aramid RFP that had been incubated with bronchoalveolar lavage (BAL) fluids and processed with the enzyme solution resulted in cleavage of p-aramid RFP. Moreover, when the BAL fluids were autoclaved to denature proteins, the length dimensions of p-aramid RFP were intermediate between saline controls and RFP incubated with normal BAL fluids and processed via the enzymatic technique. In contrast to the in vitro noncellular studies with p-aramid RFP, the combination of BAL fluid incubation and enzyme digestion method had no measurable effect on shortening of cellulose RFP, indicating that the results with p-aramid were specific to that fiber-type. In a final set of in vitro cellular studies, cultures of rat lung epithelial cells, alveolar macrophages, or co-cultures of epithelial cells and macrophages were treated with p-aramid RFP for 1 h, 1 day, or 1 week to determine whether RFP shortening occurs directly in the phagocytic cells. The lengths of fibrils were measured using scanning electron microscopy techniques. The results demonstrated that (1) no shortening occurred in the epithelial cell cultures at any time point; however, (2) in the macrophage and cocultures, cleavage of p-aramid RFP was observed at 1 day and 1 week postexposure. Our data suggest that components of lung fluids coat and catalyze the p-aramid RFP as a prerequisite for enzymatic cleavage. This process could play a significant role in facilitating the transverse cleavage or shortening of inhaled p-aramid RFP in the lungs of exposed rats and hamsters.

Administration, Inhalation↗