Biomedical subjects

D F Rogers

Publications and source records attributed to D F Rogers.

89 records · Page 5Linked to original sources

PubMed1989

Neurogenic plasma extravasation: inhibition by morphine in guinea pig airways in vivo.

Opioid drugs have been shown to inhibit neurogenic plasma exudation in skin by a presynaptic mechanism. We determined whether a similar inhibitory effect operates in the airways of anesthetized guinea pigs in vivo with the use of Evans blue dye as a marker of plasma leakage. Stimulation of the vagus nerve significantly increased leakage of dye in trachea and main bronchi (by approximately 300 and 600%, respectively). Similar increases in leakage were seen in the presence of atropine and propranolol. Morphine (1-30 mg/kg iv) inhibited leakage in a dose-related manner with complete inhibition in the trachea at a dose of 30 mg/kg. The inhibition was blocked by the opioid receptor-antagonist naloxone (1 mg/kg iv). Intravenous substance P significantly increased leakage but was not inhibited by morphine. We conclude that morphine inhibits neurogenic plasma leakage by presynaptic inhibition of release of neuropeptides from sensory nerve endings. If similar mechanisms are operative in human airways, inhibition of neurogenic plasma leakage by opioid drugs devoid of central effects may be of value in the therapy of asthma.

Animals↗

PubMed1989

Effect of antiasthma drugs on microvascular leakage in guinea pig airways.

We have studied the effect of intravenous epinephrine, albuterol, verapamil, and aminophylline on airway microvascular leakage in guinea pigs. Microvascular leakage was induced by platelet-activating factor (PAF; 50 ng/kg intravenously), which acts directly on venular endothelial cells, and measured by quantifying extravasation of Evans blue (EB) dye. Epinephrine (20 micrograms/kg) inhibited PAF-induced changes in dye leakage in larynx and main bronchi; at 80 and 160 micrograms/kg, significant inhibition was observed in all airways studied. This effect was reversed by phentolamine (2.5 mg/kg) or prazosin (100 micrograms/kg). By contrast, albuterol (20 to 320 micrograms/kg) and aminophylline (12.5 to 50 mg/kg) failed to inhibit dye leakage at any dose studied. Verapamil inhibited PAF-increased leakage in larynx, main bronchi, and intrapulmonary airways at the lowest dose tested (125 micrograms/kg), although inhibition was not dose dependent. These results suggest that the antiedema effect of epinephrine may be due to vasoconstriction rather than to a direct effect on endothelial cell contractility and that neither beta-agonists nor theophylline have an inhibitory effect. The inhibitory effect of epinephrine on airway microvascular leakage may have therapeutic implications for asthma.

Adrenergic alpha-Agonists↗

PubMed1989

Oral N-acetylcysteine or S-carboxymethylcysteine inhibit cigarette smoke-induced hypersecretion of mucus in rat larynx and trachea in situ.

Two weeks exposure of rats to cigarette smoke (CS) significantly (p less than 0.05) increased the secretion of fucose-containing glycoconjugates above normal in an in situ preparation of larynx and trachea. After equilibration mean basal secretion in CS-exposed rats was 24 micrograms (per 30 min collection) which was 8 times higher than that of unexposed animals (p less than 0.01). N-acetylcysteine (NAC) or S-carboxymethylcysteine (SCMC) given as 1% of the drinking water, before and after daily exposure to CS, significantly inhibited the development of the CS-induced increase in fucose secretion reducing the mean for basal secretion in each group to 7 and 5 micrograms, respectively (p less than 0.05). Neither NAC nor SCMC had significant effects on baseline glycoconjugate secretion in control animals. Albumin was inconsistently present in the secretions of both control and CS-exposed animals, whereas in those exposed to CS and also given one of the two cysteine derivatives there was a consistent increase in albumin transudation.

Acetylcysteine↗

PubMed1988

Effect of a Paf antagonist, WEB 2086, on airway microvascular leakage in the guinea-pig and platelet aggregation in man.

1. The triazolodiazepine WEB 2086 has been evaluated as an antagonist of platelet-activating factor (Paf) by studying its effects on Paf-induced human platelet aggregation and microvascular leakage in guinea-pigs. 2. WEB 2086 inhibited Paf-induced platelet aggregation in platelet-rich plasma in vitro (IC50 = 117 +/- 35 nM, mean +/- s.d.) but had no effect on adenosine 3',5'-diphosphate-induced aggregation. 3. Paf-induced microvascular leakage, measured by the extravasation of intravenously-injected Evans blue dye, was inhibited in a dose-related fashion in the airways and other tissues by WEB 2086, achieving a maximal inhibitory effect at 10 micrograms kg-1, i.v. 4. However, WEB 2086 (10 micrograms kg-1, i.v.) did not inhibit a comparable increase in vascular permeability induced by ovalbumin in sensitized guinea-pigs. 5. We conclude that WEB 2086 is a potent antagonist of Paf and that Paf does not appear to be responsible for antigen-induced microvascular leakage.

Adenosine Diphosphate↗

PubMed1988

Effects and interactions of sensory neuropeptides on airway microvascular leakage in guinea-pigs.

1. We have studied the effect of the sensory neuropeptides substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and calcitonin gene-related peptide (CGRP) on microvascular permeability in guinea-pig airways in vivo and investigated whether CGRP would potentiate the effect of SP. We used the extravasation of intravenously-injected Evans blue dye as an index of permeability. 2. The tachykinins SP, NKA and NKB (0.025-5.0 nmol kg-1, i.v.) significantly (P less than 0.05) increased extravasation of dye in a dose-related manner and with a similar pattern of distribution; they were most potent in the trachea and main bronchi, less potent in the larynx and intrapulmonary airways, and had little significant effect in the bladder. 3. SP was significantly more potent in causing extravasation of dye than NKA or NKB with ED50 values (nmol kg-1) in the range 0.04-0.1, depending on the airway level, compared with values in the range 0.3-0.7 for the neurokinins. 4. CGRP (0.0025-2.5 nmol kg-1, i.v.) had no significant effect on microvascular permeability and did not potentiate SP-induced extravasation of dye. 5. Each neuropeptide decreased mean arterial blood pressure, indicating vasodilatation, in a dose-related manner. Co-injection of CGRP and SP produced additive decreases in arterial pressure. 6. We conclude that, in guinea-pig airways, tachykinins increase microvascular permeability via tachykinin receptors of the NK-1 sub-type (indicated by an order of potency of SP greater than NKA = NKB) on endothelial cells. The response appears to be related to mechanisms in addition to vasodilatation. The relevance of the responses to the tachykinins in asthma is discussed.

Animals↗

PubMed1988

Inflammatory mediators involved in antigen-induced airway microvascular leakage in guinea pigs.

Antigen challenge of ovalbumin (OA)-sensitized guinea pigs results in significant (p less than 0.05) increases in vascular permeability to Evans blue (EB) dye in the airways, esophagus, and bladder. Mean values +/- SEM in ng EB/mg wet weight tissue for unsensitized versus sensitized animals were: trachea, 23.6 +/- 6.6 versus 92.5 +/- 11.1; main bronchi, 31.1 +/- 12.2 versus 153.1 +/- 14.9; "central" intrapulmonary airways (ipa), 34.6 +/- 11.2 versus 101.3 +/- 6.2; and "peripheral" ipa, 26.2 +/- 6.8 versus 93.5 +/- 13.6. We investigated the involvement of several mediators of inflammation in this process. FPL 55712, a sulfidopeptide leukotriene receptor antagonist, caused significant inhibition of leakage in trachea (to 55.1 +/- 9.8) and main bronchi (91.7 +/- 15.8). Blockade of the cyclooxygenase and lipoxygenase pathways with BW 755C, but not of the cyclooxygenase pathway alone with indomethacin, also significantly reduced EB dye extravasation in trachea (55.1 +/- 18.0), main bronchi (71.7 +/- 23.0), and "central" ipa (62.7 +/- 16.4). The histamine antagonists, chlorpheniramine and cimetidine, only inhibited microvascular leakage in main bronchi (94.4 +/- 20.0). PAF-receptor blockade with the ginkgolide mixture BN 52063 had no effect. Nedocromil sodium, a mast cell stabilizer and an inhibitor of inflammatory cell activation, caused significant inhibition throughout the airways: trachea, 50.4 +/- 10.6; main bronchi, 72.0 +/- 15.3; "central" ipa 61.0 +/- 8.6; "peripheral" ipa 41.9 +/- 12.2. Thus, histamine and lipoxygenase products (in particular, leukotrienes), but not PAF, may mediate the antigen-induced increase in vascular permeability to different degrees in differing regions of the respiratory tract in guinea pigs.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

PubMed1988

Oral N-acetylcysteine speeds reversal of cigarette smoke-induced mucous cell hyperplasia in the rat.

We set out to determine whether or not the "mucolytic" drug N-acetylcysteine would speed the reversal of cigarette smoke-induced secretory-cell hyperplasia to normal, similar to that found previously for two nonsteroidal antiinflammatory drugs. Cigarette smoke alone significantly (p less than 0.01) increased the number of secretory cells in seven out of eight airway levels studied and maintained a significant increase in five of the levels at least 3 weeks after cessation of exposure. Treatment of rats with N-acetylcysteine, as 1% of their drinking water during the recovery period, reduced the time taken for secretory cell number to return to normal to between 4 days and 3 weeks, depending on airway level.

Acetylcysteine↗

PubMed1987

Cigarette smoke-induced 'chronic bronchitis': a study in situ of laryngo-tracheal hypersecretion in the rat.

Mucous secretion and mucosal permeability by the larynx and trachea, isolated in situ, was investigated in normal rats and in those in which 'chronic bronchitis' was induced by daily exposure to cigarette smoke for 2 weeks. Fucose was used as a specific marker for the secretion of mucus glycoprotein, and hexose and protein were markers both for mucus and plasma-type glycoproteins present in tissue fluid transudate. Albumin was used as an indicator of the contribution of serum to the secretions. After equilibration, the mean basal secretion of fucose (microgram/30 min collection) was significantly higher in 'bronchitic' rats than in the controls (P less than 0.01). Mean values for controls were: fucose 3 (SEM 1: n = 9), hexose 41 (SEM 9; n = 8), protein 1082 (SEM 385; n = 8), albumin less than 2 (n = 8); for 'bronchitic' rats the values were: 24 (SEM 6; n = 7), 101 (SEM 26; n = 8), 2000 (SEM 520; n = 8) and less than 2 micrograms (n = 7) respectively. In control and bronchitic animals acute administrations of cigarette smoke, blown directly through the laryngo-tracheal segment after equilibration, caused significant (P less than 0.05) transient increases in the secretion of fucose, hexose and protein, but not of albumin.

Animals↗

PubMed1987

Effect of platelet-activating factor on airway vascular permeability: possible mechanisms.

We studied the effects of the potent inflammatory mediator, platelet-activating factor (PAF), on vascular permeability in airways (and other tissues) of guinea pigs by measuring extravasation of circulating Evans blue dye. PAF caused a dose-dependent increase in vascular permeability. At 1 ng/kg iv, PAF caused an increase in Evans blue extravasation of 220% (P less than 0.05) in the trachea, with the greatest effect at a dose of 100 ng/kg (858%; P less than 0.01). Histamine (150 micrograms/kg iv) caused a 320% increase over base line in the trachea and 200% in main bronchi; this effect was equivalent to that induced by 10 ng/kg PAF in the trachea and 1 ng/kg in main bronchi. The duration of effect of PAF was greatest in main bronchi (less than 10 min). Platelet depletion with a cytotoxic antibody, or the cyclooxygenase inhibitor, indomethacin, or the cyclooxygenase-lipoxygenase inhibitor, BW 7556, did not affect the vascular permeability response to PAF. The PAF-receptor antagonist, BN 52063, inhibited Evans blue extravasation in the airways in a dose-dependent manner, with complete inhibition at 5 mg/kg. Thus PAF-induced airway vascular leakage is mediated by specific receptors but not by products of arachidonic acid metabolism or by platelets. Increased airway microvascular leakage induced by PAF may lead to plasma extravasation and airway edema, factors that may contribute to the airway narrowing and hyperresponsiveness induced by PAF.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

PubMed1986

Nicotine does not cause 'bronchitis' in the rat.

Nicotine is of interest as a major constituent of cigarette smoke and as an additive to chewing gum used to help patients to stop smoking. Specific pathogen-free rats were given an aerosol or injections of nicotine hydrogen (+)tartrate (L-isomer) for 2 or 3 weeks at three doses and the number of secretory cells in the surface epithelium of airways was determined. By aerosol, a dose giving 10 ng of nicotine/ml of plasma had no effect on secretory cell number. By injection, nicotine had a 'bi-phasic' effect depending on dose: it reduced secretory cell number at plasma concentrations of 650 ng/ml of plasma or increased it at 2360 ng/ml of plasma. Thus nicotine alone, given to rats at doses similar to those found in cigarette smokers and those who chew nicotine gum, does not cause secretory cell hyperplasia in the conducting airways of the rat.

Aerosols↗

PubMed1986

Inhibition by oral N-acetylcysteine of cigarette smoke-induced "bronchitis" in the rat.

Specific pathogen-free rats were exposed to the cigarette smoke (CS) of 25 cigarettes daily for 14 days and concurrently given N-acetylcysteine (Nac) as 1% of their drinking water (average daily dose 973 mg/kg). The thickness of the epithelium was measured at four airway levels and the numbers of mucus-containing secretory cells, stained for neutral or acidic glycoprotein (NGP or AGP respectively), were counted in surface epithelium at eight airway levels. Cigarette smoke increased the thickness of the epithelium at three of the airway levels studied by between 37 and 72%. The number of secretory cells was increased at all airway levels distal to the upper trachea by between 102 and 421%. Secretory cells containing NGP were reduced in number but this was more than offset by a large increase in the number of secretory cells containing AGP at all airway levels. N-acetylcysteine inhibited CS-induced epithelial thickening. Nac also inhibited the CS-induced increase in the number of secretory cells with AGP, but had little effect on the CS-induced reduction in the number of cells with NGP. Thus, prophylactic oral N-acetylcysteine led to an overall inhibition of CS-induced mucous cell hyperplasia and epithelial hypertrophy. The results suggest a novel anti-inflammatory action for a drug with known mucolytic effects.

Acetylcysteine↗

PubMed1986

Inhibition of cigarette smoke-induced airway secretory cell hyperplasia by indomethacin, dexamethasone, prednisolone, or hydrocortisone in the rat.

As the nonsteroidal anti-inflammatory drug indomethacin has already been shown to inhibit cigarette smoke (CS)-induced secretory cell hyperplasia in the airway epithelium of the rat, the present study was undertaken to determine the effects of prophylactic interaperitoneal injection of indomethacin (4 mg/kg body weight) compared with each of three steroidal anti-inflammatory drugs given at comparable doses. The results show that dexamethasone (given initially at 4 mg/kg), prednisolone (4 mg/kg) and hydrocortisone (4 mg/kg) were also inhibitory. Dexamethasone proved to be toxic and its dose had to be reduced to give an average dose of 2 mg/kg over the experimental period. Prednisolone and hydrocortisone were toxic only when in combination with CS. The order of descending effectiveness in inhibiting secretory cell hyperplasia was indomethacin, dexamethasone, prednisolone and hydrocortisone. Indomethacin was the most effective drug in the trachea, whilst in distal intra-pulmonary airways dexamethasone was the most effective. Depending on airway level, inhibition was between 69 and 115% of the value obtained after CS alone. The inhibition was complete in all but one instance. The results show that steroids also inhibit secretory cell hyperplasia but at a comparable dose they are generally less effective than indomethacin and may have unacceptable side effects.

Animals↗

PubMed1986

Indomethacin and flurbiprofen speed recovery of rat bronchial epithelium after exposure to cigarette smoke.

The cigarette smoke-induced rat model of chronic bronchitis was used to study the time course of the return of cigarette smoke-induced secretory cell hyperplasia to the normal and the capacity of two non-steroidal anti-inflammatory drugs to speed this recovery. Cigarette smoke alone significantly increased (P less than 0.05) the number of secretory cells in all of the eight airway levels studied to between 52-225% above control values. After cessation of exposure, recovery was complete by 9 days in the trachea, between 10-21 days in 'proximal' intrapulmonary airways and 43-84 days in distal bronchioli. Indomethacin and flurbiprofen, given by intraperitoneal injection at 4 mg/kg body weight for 21 days of the recovery period, significantly reduced the time taken for recovery to between 4 and 9 days in intrapulmonary airways but had no effect in the trachea.

Animals↗

PubMed1985

Effect of oral acetylcysteine on tobacco smoke-induced secretory cell hyperplasia.

The present investigation explores whether N-acetylcysteine (NAC) inhibits the secretory cell hyperplasia known to occur experimentally in specific pathogen-free (SPF) bronchitic rats. The animals were divided into 4 groups: no tobacco smoke (TS), no drug, no TS but NAC (1040 mg/kg body weight), TS but no drug, and TS plus NAC. NAC-treated animals showed no ill effects, TS exposed animals showed an initial fall in weight gain which never fully recovered (P less than 0.01): NAC did not protect. TS caused a significant increase (62-421%) in secretory cell number at all airway levels distal to the upper trachea (P less than 0.01) and NAC significantly inhibited it (P less than 0.01-0.05) in all, mostly in secretory cells containing acidic glycoprotein. TS exposure also induced a significant rise in epithelial cell concentration and of ciliated, mucous and especially basal cell number (P less than 0.001). NAC inhibited the mucous cell increase (P less than 0.001) and had 3 effects on the peak of dividing cells: it was (a) delayed until 3 days (b) greatly reduced in size and (c) prolonged at a lower level until its return to control values at 10 days of TS exposure.

Acetylcysteine↗

PubMedDate not supplied

Potential effectiveness of quality assurance screening using large but imperfect databases.

To examine the effect of imprecise classification of patient risk (severity of illness) on an otherwise highly accurate quality assurance screening technique, data on clinical outcomes were generated for a simulated hospital system consisting of 108 facilities treating approximately 565,000 patients a year. In these simulations, marked differences in facility size, casemix distribution, and quality of care were combined with random variations in outcome. Pooled data for all 108 facilities were used to create algorithms that combined 468 discrete patient risk classifications into either ten or three groups with broad, overlapping ranges of patient-specific risks of unfavorable clinical results. When derived algorithms were applied to independently generated facility-specific data, the ability to identify hospital systems with and without quality of care problems was maintained with ten, but not with three, risk groups. However, even three moderately heterogeneous risk groups were sufficient to preserve a high degree of sensitivity and specificity in screening for potential quality of care problems within individual facilities. Thus, outcome-based quality assurance screening can be highly accurate in actual health care situations in which only imprecise estimations of patient-specific risk can be achieved.

Algorithms↗

PubMedDate not supplied

Tracheal potential difference in the reserpine and isoproterenol rat models of cystic fibrosis.

Basic research into cystic fibrosis (CF) has been hampered by the lack of a suitable animal model. Reserpinized or isoproterenol-treated rats have been proposed as models because they exhibit certain morphological and physiological features characteristic of CF. Recent evidence suggests that abnormal epithelial transport of Na+ [corrected] and Cl- may underlie pathogenesis, defects that may contribute to the markedly more negative transepithelial electrical potential differences (PD) recorded in CF airways compared with controls. To test the models further, we measured tracheal PD in vivo in treated rats (reserpinized - 6.9 mV, SEM 0.7 mV, n = 7; isoproterenol-treated -10.2 mV, SEM 1.5 mV, n = 12) and found it to be no different from that of controls (-8.7 mV, SEM 0.6 mV, n = 25). The animals did, however, demonstrate a reduced gain in body weight as well as increased submaxillary gland weight, which reflected an increased mucus content in the acini. These observations suggest that although the reserpinized or isoproterenol-treated rat may be useful in the study of the pathogenesis of exocrine disturbances in disease, their use as models for the effect of the basic defect of CF in the airways may be limited.

Animals↗

PubMedDate not supplied

Impaired stimulus-evoked mucus secretion in cystic fibrosis bronchi.

Baseline and agonist-stimulated secretion of fucose, hexose, and protein (markers of mucus secretion) was investigated in vitro in 45 bronchial segments from 14 patients with cystic fibrosis (CF) (three after heart-lung transplant, the remainder < 4.5 h after autopsy), in 51 segments from 26 patients with carcinoma (24 resection, 2 after autopsy), and in 4 segments from 3 patients with bronchiectasis (resection). Basal rates of secretion of each mucus marker by CF bronchi were not significantly different from those by carcinoma bronchi bronchiectatic bronchi. However, rates of secretion of each marker in response to the cholinomimetic methacholine (10 microM; n = 11-18, depending on marker) and the beta 2-adrenoceptor agonist terbutaline (10 microM; n = 9-11) were significantly (p < .05) increased in carcinoma bronchi (by 50-117% above basal), but not in CF airways (n = 11-14). The secretory response to the sensory neuropeptide substance P (1 nM to 10 microM; n = 5-7) was also reduced in CF compared with carcinoma bronchi. Physiological and morphological data indicated that the reduced response by CF tissue could not be accounted for by inclusion of autopsy tissue in the study. These data suggest a defect in autonomic control of bronchial secretion in CF, not in the basal rate of secretion, but in its response to receptor stimulation.

Autopsy↗