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Biomedical subjects

C R Turner

Publications and source records attributed to C R Turner.

36 records · Page 2Linked to original sources
PubMed1990

Microwave fixation of the lung.

A technique for microwave fixation of inflated rat lung is described. Conventional intratracheal fixation with instillation of fixative into the airways at a constant pressure results in pressure artifacts as well as flushing and disruption of cells and exudates. Microwave fixation fixes these elements in situ without disruption and thus is valuable when evaluating the distribution of inflammatory infiltrates. Exudative pneumonitis was produced in the rat using intratracheal instillations of either endotoxin or silica and comparisons were made between histologic sections fixed using either standard formalin fixation or microwave fixation.

Animals↗
PubMed1990

Therapeutic intervention in a rat model of ARDS: I. Dual inhibition of arachidonic acid metabolism.

The protective effects of altered arachidonic acid metabolism, using either methylprednisolone or a dual cyclooxygenase and 5-lipoxygenase inhibitor (SK&F 86002), were compared in a rat model of adult respiratory distress syndrome (ARDS). Rats were either unexposed (n = 9) or pretreated with vehicle (n = 25), 100 mg/kg SK&F 86002 (n = 8) or 30 mg/kg methylprednisolone (MP, n = 7) 1 h prior to the intratracheal administration of 7 mg/kg aerosolized endotoxin (LPS) or phosphate buffered saline (PBS). Twenty-four hours later, blood samples were collected and the rats were anesthetized and exsanguinated. The lungs were surgically removed, weighed and bronchoalveolar lavage (BAL) was performed. LPS caused 30-35% mortality and induced significant differences in body weight, BAL erythrocyte and neutrophil counts, lung wet/dry weight ratio (W/D), total BAL protein (TP), hemoglobin (Hb), hematocrit (HCT), and circulating leukocyte and platelet counts as compared with controls. Pretreatment with MP reduced mortality to zero and also attenuated the LPS-induced alterations in body weight, W/D, TP, BAL erythrocyte count, and circulating platelet count. However, MP exacerbated LPS-induced increases in Hb, HCT and circulating neutrophil counts while enhancing lymphopenia. Pretreatment with SK&F 86002 also reduced mortality to zero and attenuated LPS-induced alterations in W/D, TP, HCT and circulating platelet count. Like MP, SK&F 86002 exacerbated the LPS-induced lymphopenia, and increased circulating neutrophils above baseline values. We conclude that both MP and SK&F 86002 provided protection against LPS-induced responses in this model of ARDS. Mechanistically, this indicates the critical role of eicosanoid mediators in this model. Therapeutically, SK&F 86002, or a similar compound, may be beneficial in preventing the acute phase responses so harmful to ARDS patients.

Animals↗
PubMed1989

Dermal mast cell releasability and end organ responsiveness in atopic and nonatopic dogs.

The Basenji greyhound (BG) has been proposed as a model of atopic disease because of its chronic relapsing atopic dermatitis as well as airway hyperresponsiveness. We attempted to characterize this model further by comparing its skin wheal-and-flare responses to morphine sulfate and histamine with those of control, nonatopic mongrel dogs. We found that BG dogs had significantly smaller skin responses than did the control dogs to all but two concentrations of histamine used. In contrast, BG dogs demonstrated greater skin response to morphine at the three lowest concentrations used but had a significantly smaller skin response at the highest dose of morphine. Skin punch biopsy specimens revealed decreases in histamine content after morphine exposure but no difference in histamine content of the unexposed skin or of morphine-exposed skin for the two groups of dogs. When percent histamine release was compared, however, BG dogs were found to release a significantly greater proportion of histamine in response to morphine than control dogs. Although there was no significant difference in total mast cell counts for the two groups, the BG dogs had significantly fewer formalin-insensitive mast cells in unexposed skin than control dogs. We conclude that skin responses in BG dogs are characterized by decreased end organ responsiveness and greater releasability of mast cells in response to nonimmunologic stimulation.

Animals↗
PubMed1989

Preexposure to ozone blocks the antigen-induced late asthmatic response of the canine peripheral airways.

The influence of exposure of the airways to ozone on acute allergic responsiveness has been investigated in several species. Little is known, however, about the effect of this environmental pollutant on the late asthmatic response (LAR) in animals in which it is exhibited. The purpose of this study was to evaluate this effect in the canine peripheral airways and to assess the potential role of mast cells in modulating the effect. A series of experiments on seven mongrel dogs demonstrated that the numbers of mast cells at the base of the epithelial region of small subsegmental airways exposed to 1 ppm ozone for 5 min were significantly (p less than .01) increased 3 h following exposure compared to air exposed or nonexposed control airways. In a second series of experiments performed on eight additional mongrel dogs with inherent sensitivity to Ascaris suum antigen, antigen aerosol was administered to the sublobar segment 3 h following ozone preexposure when mast cell numbers were presumed to be increased. These experiments were performed to determine whether ozone preexposure could enhance the late-phase response to antigen by virtue of acutely increasing the number of mast cells available to bind the antigen. Four of the eight dogs tested displayed a late-phase response to antigen following air-sham preexposure. In these four dogs, simultaneous ozone preexposure of a contralateral lobe completely blocked the late-phase response to antigen. These results indicate that the consequences of a single exposure to ozone persist beyond its effects on acute antigen-induced bronchoconstriction and extend to the complex processes involved with the late response. This attenuating effect of ozone is seen under conditions where mast-cell numbers in the airways are increased above baseline levels.

Administration, Inhalation↗
PubMed1989

Cardiovascular and pulmonary effects of human recombinant tumor necrosis factor in the conscious rat.

The purpose of this study was to examine the dose response to a highly purified human recombinant tumor necrosis factor (TNF alpha) preparation (1-2 x 10(7) U/mg; less than 0.05 ng endotoxin/mg TNF alpha) in the conscious rat. Rats received intravenous bolus injections of 0.3 mg/kg (n = 6), 1.0 mg/kg (n = 17), 3.0 mg/kg (n = 11), or 10 mg/kg (n = 15) of TNF alpha, 30 mg/kg (n = 7) Salmonella enteritidis endotoxin (LPS), or isotonic saline (n = 11). Upon termination of the experiment, the lungs were removed for lavage or histology. Survival was 0% 24 hr after the injection of LPS and 83, 59, 73, and 73% after the lowest to highest doses of TNF alpha, respectively. As with endotoxin, TNF alpha caused a dose-dependent increase in heart rate (HR) (P less than 0.05) within 0.5 hr of administration, which remained elevated throughout the 24 hr period. TNF alpha had no effect on mean arterial blood pressure (MABP) acutely, but it caused a 15-20% decrease in MABP 24 hr post exposure (P less than 0.05). TNF alpha increased hematocrit within 0.5 to 3 hr in all dose groups by 10-15%. Furthermore, TNF alpha produced a thrombocytopenia in all dose groups, although the decrease in platelet count was less than that produced by endotoxin. TNF alpha doses of 1-10 mg/kg caused leukopenia within 0.5 hr (P less than 0.05). Lavage and histology revealed no changes in the number of pulmonary neutrophils. These results suggest that TNF alpha stimulated dose-dependent responses, which were consistent with those produced by LPS. However, these responses to TNF alpha were appreciably smaller than those reported for either LPS or for TNF alpha from other sources.

Animals↗
PubMed1988

Rapid increase in mast cell numbers in canine central and peripheral airways.

In preliminary studies of antigen-induced airway inflammation, we noted an apparent increase in peribronchiolar mast cell number. Experiments were thus undertaken to investigate the nature of this migration of mast cells into the central and peripheral airway epithelium and to determine its time course. The tracheae and small airways of 10 anesthetized mongrel dogs were exposed via a bronchoscope to Ascaris suum antigen (Ag), fMet-Leu-Phe (fMLP), ovalbumin (OVA), and isotonic saline (SAL). In the central airways, all stimuli provoked a significant increase (P less than 0.05) in mast cell numbers at the base of the airway epithelium within 3 h. In the peripheral airways, only Ag aerosol stimulated a significant mast cell increase compared with unexposed tissue. In a second series of experiments, the trachea of seven dogs were exposed to 0.026, 0.26, and 2.6 micrograms of Ag. The tissue was collected at 1, 3, 6, and 10 h after exposure. In these experiments, there was a significant mast cell increase seen within 1 h but it was not dose dependent. By 6-10 h after exposure, mast cell counts were not significantly different from the unexposed condition, which is consistent with the idea that some of the cells either degranulated or migrated into the airway lumen. We conclude that mast cell migration is an acute response that can be demonstrated within 1 h of stimulation with Ag. The observation that nonimmunological stimuli may, in some cases, also stimulate mast cell movement affords the possibility that this process represents a generalized response to airway irritation.

Animals↗
PubMed1985

Binding of benzo[a]pyrene by purified cytochrome P-450c.

Benzo[a]pyrene (BP) fluorescence-emission intensities in phospholipid micelles are quantitatively described over a broad range of lipid and BP concentrations by excitation that is linearly dependent upon BP concentration and an offsetting excimer quenching that is dependent upon the square of the BP concentration. The fluorescence of BP is quenched by the presence of cytochrome P-450c in proportion to the concentration of the cytochrome in the micelles and in accord with stoichiometric complex formation. Parallel optical titrations indicate a change in spin state of P-450c to a predominantly high-spin state that correlates directly with the percentage fluorescence quenching of complexed BP. Neither change occurs with five other purified forms of rat liver P-450 that have low activity in BP metabolism. N-Octylamine, a ligand that binds to the heme of P-450, competitively inhibits both the spin-state changes and the fluorescence quenching in equal proportion. The Kd for the interaction of BP with P-450c is exceptionally low (10 nM) relative to the Km for monooxygenation (ca. 1 microM). Decreasing the concentration of either dilauroylphosphatidylcholine or dioleoylphosphatidylcholine concomitantly increases the high-spin state (from 30% to 80%) of fully complexed P-450c and the fluorescence quenching (50-100%) of the complexed BP (half-maximal at 80 micrograms of lipid/mL). It is concluded that spin state and fluorescence quenching both reflect the same changes in the interaction of the BP with the P-450 heme.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Selectivity in the binding of hydroxylated benzo[a]pyrene derivatives to purified cytochrome P-450c.

The interaction of rat liver microsomal cytochrome P-450c with potential benzo[a]pyrene (BP) metabolites has been compared with the binding of BP by optical and fluorescence spectroscopy. Fluorescence quenching of the phenolic derivatives of BP derives from 1:1 complex formation with P-450c, is a function of the position of the hydroxyl substituent, and correlates with the concomitant increase in high-spin cytochrome observed in parallel optical titrations. The proportion of high-spin cytochrome seen when P-450c was reconstituted in dilauroylphosphatidylcholine vesicles (60 micrograms/mL) ranged from about 7% for the 3- and 7-phenols to 75% for 11- and 12-phenols. BP and all 12 methyl-BP derivatives have comparable high affinities for P-450c (50-70% high spin). Kd determinations with purified P-450c indicated very strong binding of BP phenols that induce high-spin complexes (4-, 5-, 9-, 10-, 11-, and 12-phenols; Kd = 3-25 nM). Inhibition of n-octylamine binding by the 3- and 7-phenols indicated weak interactions (Kd = 80-90 nM), even though low-spin complexes were formed. Inhibition of BP metabolism catalyzed by P-450c with BP phenols correlated with their respective dissociation constants. These results suggest that phenolic substitution at certain positions on BP (1, 2, 3, 7, or 8) interferes with binding to the active site while substitutions at the other positions either enhance or have no effect on binding. BP dihydrodiols [including the (+)- and (-)-BP 7,8-dihydrodiols] were relatively ineffective in forming high-spin complexes (approximately 20%), and fluorescence quenching of dihydrodiols by P-450c also saturated at low levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Binding and metabolism of benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene by seven purified forms of cytochrome P-450.

Seven different forms of cytochrome P-450 have been purified from rat liver microsomes. The major 3-methylcholanthrene (MC) inducible cytochrome P-450 (form c) exhibits the greatest activity toward both benzo[a]pyrene (BP) (58 min-1) and 7,12-dimethylbenz[a]anthracene (DMBA) (29 min-1) and forms substantially high spin, high affinity complexes (Kd = 10 nM) with both hydrocarbons. Cytochrome P-450d, a minor MC-inducible form, has far lower activity for metabolism of both polycyclic aromatic hydrocarbons (PAH), yet also forms high affinity complexes (Kd approximately 100 nM) with both PAH, retaining the full high spin state of the free cytochrome. Although two phenobarbital (PB)-induced forms (P-450's b and e) differ by only 13 amino acids, they exhibit significant differences in metabolism of PAH and in complex formation. Whereas P-450b is only active in metabolism of DMBA (9.8 min-1 versus 1.9 min-1 for BP), P-450e has low activity for both substrates (3.3 and 1.2 min-1). Nevertheless, P-450e forms a high affinity complex (Kd approximately 100 nM) with both PAH that enhances the proportion of the high spin state (from 30% to 70%). Failure to displace n-octylamine (NOA) suggests binding that is removed from the heme. P-450b remains low spin in the presence of PAH and NOA is again not displaced. In addition, the two forms can be distinguished by their regioselectivities for both PAH. P-450's a, h, and pregnenolone-16 alpha-carbonitrile (PCN) exhibit little activity toward BP or DMBA, but P-450 PCN does form a low spin complex with BP (not DMBA). Regioselectivity in metabolism of DMBA by PB-induced microsomes does not agree with that of the major constituent forms. Only the minor, less active purified forms (e and a) mediate substantial 12-hydroxylation and 3,4-epoxidation of DMBA. Thus, additional factors in microsomal reactions must contribute to these differences.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1970

Evaluation of compounds for insecticidal activity on adult mosquitos. 1. Responses of adult mosquitos to some new insecticides.

Responses shown by female mosquitos to topical applications of solutions, to deposits from water-dispersible-powder formulations, or to exposure to the vapour from such deposits, are described for a number of compounds that have shown promise as residual contact insecticides.The behaviour of Anopheles stephensi females in laboratory tests indicates that departures of mosquitos from treated buildings, and their survival rates, are likely to be increased as a result of irritation and consequent activity after only a brief period of contact with phthalthrin (OMS-1011) and other synthetic pyrethroids but not with dieldrin (OMS-18) and lindane (OMS-17) or the carbamates and organophosphorus compounds tested. Mosquitos were not disturbed by exposure to the vapour from deposits of any of the compounds.The rates of action of the different compounds following their application in solution directly to the insect cuticle or contact of the mosquitos with deposits on plywood and plaster emphasize the importance of the lipid-solubility and partitioning properties of an insecticide in determining its passage from a surface deposit into, and through, the cuticle to the site of action.

Animals↗
PubMed1970

Evaluation of compounds for insecticidal activity on adult mosquitos. 2. Toxicity to adult mosquitos and the physical properties of some new carbamates.

The N,N-dimethylcarbamates are much less toxic and much more volatile than the corresponding N-methylcarbamates. N-acylation of N-methylcarbamates is also generally accompanied by a loss in intrinsic toxicity to adult mosquitos by topical application, but the reduction in toxicity may be relatively small and in some N-acetyl derivatives may not occur at all. N-acylation is also accompanied by changes in physical properties such as lipid solubility and partition coefficient, which influence contact toxicity, and volatility, which affects residual activity. In the series of compounds examined, contact toxicity is maximal in the N-acetyl derivatives but their volatility is often so high that they lack the persistence required of residual insecticides. This does not apply, however, to the N-acetyl derivatives of OMS-597 and OMS-708 because the volatility of the parent compound is so low that some degree of persistence can be sacrificed to obtain some improvement in contact activity.OMS-1064 is the only N-chloroacetyl derivative tested so far that shows promise as a residual insecticide.

Animals↗
PubMed1970

Evaluation of compounds for insecticidal activity on adult mosquitos. 4. Insecticidal activity and physical properties of some halogenated organophosphorus esters.

The effects of changes in structure upon toxicity to adult mosquitos and upon physical properties which are important in determining contact effectiveness and residual activity are described for a group of O,O-dialkyl O-halogenated-phenyl phosphates, phosphorothionates and phosphamido(thio)ates. This group includes such established insecticides as fenchlorphos, bromophos and iodofenphos.

Animals↗
PubMed1970

Evaluation of compounds for insecticidal activity on adult mosquitos. 5. Toxicity to adult mosquitos and residual properties of some pyrethroids.

New pyrethrin-like compounds are compared with earlier synthetic pyrethroids and natural pyrethrins for intrinsic toxicity to adult mosquitos and for residual contact activity. Two of the compounds are at least as toxic as pyrethrin I to female Anopheles stephensi and Aedes aegypti. Residues of these compounds are very persistent in the dark or in very subdued lighting but they decompose on exposure to normal intensities of daylight and rapidly lose their insecticidal activity.

Animals↗