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Biomedical subjects

D F Rogers

Publications and source records attributed to D F Rogers.

At least 37 records · Page 2Linked to original sources
PubMed1999

Differential effect of formoterol on adenosine monophosphate and histamine reactivity in asthma.

Short-acting beta2-agonists provide greater protection against bronchoconstriction induced by adenosine 5'-monophosphate (AMP) than by direct-acting bronchoconstrictors such as histamine and methacholine. AMP is thought to cause bronchoconstriction via release of mediators from mast cells, which suggests that these drugs stabilize mast cells in vivo. This in vivo property has not yet been demonstrated for long-acting beta2-agonists. We undertook a double-blind, randomized, placebo-controlled, cross-over study to investigate the effects of a single dose of formoterol inhaled via Turbuhaler (12 micrograms) and of albuterol inhaled via Turbuhaler (200 micrograms) on airway responsiveness to AMP and histamine in 16 subjects with mild atopic asthma. Albuterol reduced airway responsiveness to AMP and histamine by 4.1 +/- 0.5 and 3.5 +/- 0.4 doubling doses, respectively. In contrast, formoterol caused a greater protective effect against AMP than against histamine challenge, decreasing airway responsiveness by 6.0 +/- 0.8 and 4.2 +/- 0.4 doubling doses, respectively (p < 0.05). Thus, the long-acting beta2-agonist formoterol appears to have a mast cell-stabilizing effect in vivo in mild asthma.

Adenosine Diphosphate↗
PubMed1998

Neuroregulation of mucus secretion by opioid receptors and K(ATP) and BK(Ca) channels in ferret trachea in vitro.

1. Opioid agonists inhibit neurogenic mucus secretion in the airways. The mechanism of the inhibition is unknown but may be via opening of potassium (K+) channels. We studied the effect on neurogenic secretion in ferret trachea in vitro of the OP1 receptor (formerly known as delta opioid receptor) agonist [D-Pen2,5]enkephalin (DPDPE), the OP2 receptor (formely kappa) agonist U-50,488H, the OP3 receptor (formerly micro) agonist [D-Ala2, N-Me-Phe, Gly-ol5]enkephalin (DAMGO), the ATP-sensitive K+ (K(ATP)) channel inhibitor glibenclamide, the large conductance calcium activated K+ (BK(Ca)) channel blocker iberiotoxin, the small conductance K(Ca) (SK(Ca)) channel blocker apamin, the K(ATP) channel opener levcromakalim, a putative K(ATP) channel opener RS 91309, and the BK(Ca) channel opener NS 1619. Secretion was quantified by use of 35SO4 as a mucus marker. 2. Electrical stimulation increased tracheal secretion by up to 40 fold above sham-stimulated levels. DAMGO or DPDPE (10 microm each) significantly inhibited neurogenic secretion by 85% and 77%, respectively, effects which were reversed by naloxone. U-50,488H had no significant inhibitory effect on neurogenic secretion, and none of the opioids had any effect on ACh-induced or [Sar9]substance P-induced secretion. 3. Inhibition of neurogenic secretion by DAMGO or DPDPE was reversed by iberiotoxin (3 microM) but not by either glibenclamide or apamin (0.1 microM each). Iberiotoxin alone did not affect the neurogenic secretory response. 4. Levcromakalim, RS 91309 or NS 1619 (3 nM-3 microM) inhibited neurogenic secretion with maximal inhibitions at 3 microM of 68%, 72% and 96%, respectively. Neither levcromakalim nor RS 91309 at any concentration tested significantly inhibited acetylcholine (ACh)-induced secretion, whereas inhibition (60%) was achieved at the highest concentration of NS 1619, a response which was blocked by iberiotoxin. 5. Inhibition of neurogenic secretion by levcromakalim (3 microM) or RS 91309 (30 nM) was inhibited by glibenclamide but not by iberiotoxin. In contrast, inhibition by NS 1619 (30 nM and 3 microM) was blocked by iberiotoxin but not by glibenclamide. 6. We conclude that, in ferret trachea in vitro, OP1 or OP3 opioid receptors inhibit neurogenic mucus secretion at a prejunctional site and that the mechanism of the inhibition is via opening of BK(Ca) channels. Direct opening of BK(Ca) channels or K(ATP) channels also inhibits neurogenic mucus secretion. In addition, opening of BK(Ca) channels inhibits ACh-evoked secretion of mucus. Drugs which open BK(Ca) channels may have therapeutic anti-secretory activity in bronchial diseases in which neurogenic mechanisms and mucus hypersecretion are implicated in pathophysiology, for example asthma and chronic bronchitis.

Adenosine Triphosphate↗
PubMed1998

Effects of the cysteinyl leukotriene receptor antagonists pranlukast and zafirlukast on tracheal mucus secretion in ovalbumin-sensitized guinea-pigs in vitro.

1. We investigated the inhibitory effects of the cysteinyl leukotriene (CysLT1) receptor antagonists, pranlukast and zafirlukast, on 35SO4 labelled mucus output, in vitro, in guinea-pig trachea, induced by leukotriene D4 (LTD4) or by antigen challenge of sensitized animals. Agonists and antagonists were administered mucosally, except in selected comparative experiments where drugs were administered both mucosally and serosally to assess the influence of the epithelium on evoked-secretion. 2. LTD4 increased 35SO4 output in a concentration-related manner with a maximal increase of 23 fold above controls at 100 microM and an approximate EC50 of 2 microM. Combined mucosal and serosal addition of LTD4 did not significantly affect the secretory response compared with mucosal addition alone. Neither LTC4 nor LTE4 (10 microM each) affected 35SO4 output. Pranlukast or zafirlukast significantly inhibited 10 microM LTD4-evoked 35SO4 output in a concentration-dependent fashion, with maximal inhibitions of 83% at 10 microM pranlukast and 78% at 10 microM zafirlukast, and IC50 values of 0.3 microM for pranlukast and 0.6 microM for zafirlukast. Combined mucosal and serosal administration of the antagonists (5 microM each) gave degrees of inhibition of mucosal-serosal 10 microM LTD4-evoked 35SO4 output similar to those of the drugs given mucosally. Pranlukast (0.5 microM) caused a parallel rightward shift of the LTD4 concentration-response curve with a pKB of 7. Pranlukast did not inhibit ATP-induced 35SO4 output. 3. Ovalbumin (10-500 microg ml(-1) challenge of tracheae from guinea-pigs actively sensitized with ovalbumin caused a concentration-related increase in 35SO4 output with a maximal increase of 20 fold above vehicle controls at 200 microg ml(-1). The combination of the antihistamines pyrilamine and cimetidine (0.1 mM each) did not inhibit ovalbumin-induced 35SO4 output in sensitized guinea-pigs. Neither mucosal (10 microM or 100 microM) nor mucosal-serosal (100 microM) histamine had any significant effect on 35SO4 output. 4. Pranlukast or zafirlukast (5 microM each) significantly suppressed ovalbumin-induced secretion in tracheae from sensitized guinea-pigs by 70% and 65%, respectively. 5 We conclude that LTD4 or ovalbumin challenge of sensitized animals provokes mucus secretion from guinea-pig trachea in vitro and this effect is inhibited by the CysLT1 receptor antagonists pranlukast and zafirlukast. These antagonists may be beneficial in the treatment of allergic airway diseases in which mucus hypersecretion is a clinical symptom, for example asthma and allergic rhinitis.

Adenosine Triphosphate↗
PubMed1998

Effect of repeated sputum induction on cell counts in normal volunteers.

BACKGROUND: Sputum induction is becoming more commonly used to assess airway inflammation. Since it is a relatively non-invasive procedure it may be useful for repeated measurements over a short period of time. METHODS: To assess the repeatability of the method over a 24 hour period, eight healthy, non-smoking, non-atopic subjects (four men) of mean age 30 years underwent sputum induction, repeated at eight hours and 24 hours. Sputum was induced by inhalation of 3.5% saline. Absolute and differential counts of inflammatory cells were performed on the whole sputum after dilution in Hank's balanced salt solution containing 1% dithiothreitol to solubilise the mucus content of the samples. RESULTS: There was a significant rise in the percentage of neutrophils in the eight hour sample compared with the baseline (57%, range 25-94% at eight hours compared with 28%, range 19-60%: median difference 26%). The median baseline percentage of macrophages was 55% (range 26-69%) which fell to 38% (range 3-56%: median difference 22%) at eight hours and 19% (range 14-59%: median difference 25%) at 24 hours. There was no significant change in the differential counts of eosinophils, lymphocytes or columnar epithelial cells, nor in any of the absolute cell counts, at any time point. CONCLUSIONS: Sputum induction may have limited utility in serial assessment of neutrophilic airway inflammation in normal subjects within a 24 hour period.

Adult↗
PubMed1998

New ideas on the pathophysiology and treatment of lung disease.

There is a continuing need for development of new treatments for lung disease. Basic scientific investigations are identifying novel targets for the development of new approaches to therapy of a range of respiratory conditions. Coupled with the advances in technology being harnessed by the pharmaceutical and biotechnological industries, there is now an impressive range of potential treatments including gene therapy, not just for cystic fibrosis but also for a range of inflammatory lung conditions, anti-cytokine and anti-adhesion molecule approaches, and targeting of intracellular signal transduction pathways including cyclic AMP metabolism, tyrosine kinases and MAP kinases. "Old" molecules such as heparin and secretory leukoprotease inhibitor (SLPI) are demonstrating new beneficial activities. Simple molecules such as nitric oxide (NO) gas may be involved in the pathophysiology of different airway conditions. It is an exciting time for respiratory science and a time for optimism for those seeking new approaches to the treatment of lung diseases.

Asthma↗
PubMed1998

Effect of inhaled endotoxin on induced sputum in normal, atopic, and atopic asthmatic subjects.

BACKGROUND: Inhalation of lipopolysaccharide (LPS) causes an inflammatory response in the lungs. To explore this response, inflammatory indices were measured in induced sputum from atopic asthmatic patients and compared with atopic and non-atopic subjects after inhalation of LPS. METHODS: The effects of inhaled LPS (60 micrograms) or placebo (0.9% saline) were examined in a randomised, double blind, crossover trial in 11 non-atopic normal subjects, seven atopic, non-asthmatic individuals, and eight atopic, asthmatic patients. Sputum was induced by inhalation of 3.5% saline before the test inhalation and again at six hours and 24 hours. Spirometry (forced expiratory volume in one second (FEV1), forced vital capacity (FVC)), heart rate, blood pressure, and temperature were recorded before challenge and at intervals until eight hours, and at 24 hours after challenge. RESULTS: There was no change in cardiovascular parameters or spirometry with either exposure in any group. In the asthmatic patients only, inhalation of LPS caused a rise in temperature, with a peak of 0.6 degree C at seven hours, which was significantly higher than following placebo inhalation (p < 0.05). In normal subjects, LPS caused a significant rise in absolute neutrophil counts at 24 hours compared with placebo (median 1.1 x 10(6) cells/ml after LPS; median 0.2 x 10(6) cells/ml after placebo, p < 0.01), but no change in differential counts. In asthmatic patients, LPS caused a significant rise in differential neutrophil counts at six hours compared with placebo (median 88% after LPS; median 56% after placebo, p < 0.05), but no change in absolute cell counts at any time point. There was no change in neutrophil counts in the atopic subjects. There was a significant rise in sputum interleukin 8 (IL-8) concentrations in normal subjects at six hours compared with placebo (mean placebo 1.1 ng/ml; LPS 3.0 ng/ml, p < 0.05) and in asthmatics at 24 hours (mean placebo 2.0 ng/ml, LPS 6.9 ng/ml, p < 0.05). There were no changes in sputum concentrations of tumour necrosis factor alpha or granulocyte macrophage colony stimulating factor at any time. CONCLUSIONS: Inhalation of LPS causes a neutrophilic inflammation with increases in IL-8 in both normal and asthmatic subjects.

Administration, Inhalation↗
PubMed1997

In vivo preclinical test models for studying airway mucus secretion.

There are many in vivo animal models for studying airway mucus secretion and hypersecretion, each with advantages and disadvantages. Use of a particular test system will depend upon the aspect of secretion to be modelled. Airway hypersecretory diseases exhibit chronic mucus hypersecretion, of which the clinical impact is predominantly in the distal airways. The majority of documented test preparations study acute secretion, invariably using tracheal preparations, but have been invaluable in elucidating the normal physiology of airway mucus secretion. Chronic models of the hypersecretory state in the distal airways have been developed, but are predominantly histologic in nature (for example quantification of increased goblet cell number). There are few investigations of mucus hypersecretion. Examination of the 'antisecretory' potential of pharmaceutical compounds has been investigated predominantly in chronic histologic models with the drug being given 'prophylactically' rather than 'therapeutically'. Refinement of chronic hypersecretory models should lead to elucidation of the connection between airway irritation, inflammation, MUC gene expression, mucous cell hyperplasia/metaplasia, airway hypersecretion and bronchial hypersecretory disease.

Animals↗
PubMed1997

Cigarette smoke-inhibition of neurogenic bronchoconstriction in guinea-pigs in vivo: involvement of exogenous and endogenous nitric oxide.

1. We investigated the effect of acute inhalation of cigarette smoke on subsequent non-adrenergic, non-cholinergic (NANC) neural bronchoconstriction in anaesthetized guinea-pigs in vivo by use of pulmonary insufflation pressure (PIP) as an index of airway tone. The contribution of endogenous nitric oxide (NO) was investigated with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). The contribution of plasma exudation to the response was investigated with Evans blue dye as a plasma marker. 2. Inhalation of 50 tidal volumes of cigarette smoke or air had no significant effect on baseline PIP. In the presence of propranolol and atropine (1 mg kg(-1) each), electrical stimulation of the vagus nerves in animals given air 30 min previously induced a frequency-dependent increase in PIP above sham stimulated controls (16 fold increase at 2.5 Hz, 24 fold increase at 10 Hz). In contrast, in smoke-exposed animals, the increase in subsequent vagally-induced PIP was markedly less than in the air controls (90% less at 2.5 Hz, 76% less at 10 Hz). 3. L-NAME (10 mg kg[-1]), given 10 min before air or smoke, potentiated subsequent vagally-induced (2.5 Hz) NANC bronchoconstriction by 338% in smoke-exposed animals, but had no significant effect in air-exposed animals. The inactive enantiomer D-NAME (10 mg kg[-1]) had no effect, and the potentiation by L-NAME was partially reversed by the NO-precursor L-arginine (100 mg kg[-1]). Vagal stimulation did not affect the magnitude of vagally-induced bronchoconstriction 30 min later. 4. Cigarette smoke exposure reduced the magnitude of subsequent bronchoconstriction induced by neurokinin A (NKA) by 37% compared with the effect of NKA in air-exposed animals. L-NAME had no significant effect on the smoke-induced inhibition of NKA-induced bronchoconstriction. 5. Vagally-induced plasma exudation in the main bronchi was greater in smoke-exposed animals compared with air-exposed animals (120% greater at 2.5 Hz, 82% greater at 10 Hz). 6. We conclude that cigarette smoke-induced inhibition of subsequent NANC neurogenic bronchoconstriction is not associated with inhibition of airway plasma exudation and is mediated in part via exogenous smoke-derived NO, or another bronchoprotective molecule, and by endogenous NO.

Animals↗
PubMed1997

Full-mouth porcelain rehabilitation.

The understanding and development of cosmetic choreography as both an art and a science has enabled clinicians to restore structure and function to damaged dentitions while restoring aesthetic harmony to their patients' oral and facial appearance. This review presents a case of full-mouth, all-porcelain rehabilitation, embracing the interplay between diagnosis, treatment planning, material selection, and cosmetic choreography.

Crowns↗
PubMed1996

On muscarinic control of neurogenic mucus secretion in ferret trachea.

1. Muscarinic receptor subtypes mediating neurogenic mucus secretion in ferret trachea were characterized in vitro and in vivo using 35SO4 as a label for secreted mucus, and the muscarinic receptor antagonists telenzepine for the M1 receptor subtype, methoctramine for the M2 subtype and 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP) for the M3 receptor. We also performed receptor binding and mapping studies. 2. Each muscarinic antagonist displaced [N-methyl-3H]scopolamine binding with high-affinity binding constant (KH) values of 1.9, 2.7 and 5.0 nM for telenzepine, methoctramine and 4-DAMP, respectively. Muscarinic M1 and M3 receptors localized to submucosal glands, whereas M2 receptors did not. 3. In vitro, electrical stimulation (50 V, 10 Hz, 0.5 ms for 5 min) increased 35SO4 output by 160%. Telenzepine did not inhibit the neurogenic secretory response at concentrations two-or twentyfold its KH value, nor did it inhibit secretion induced by acetylcholine (ACh). 4-DAMP inhibited neurogenic secretion by 80 and 95%, respectively, at concentrations two-and twentyfold its KH value, and also inhibited ACh-induced secretion. Methoctramine potentiated neurogenic secretion induced at 2.5 Hz (50 V, 0.5 ms for 5 min) in a dose-related (5.4-100 nM) manner with increases of 33-451% above electrically stimulated values. Methoctramine did not potentiate secretion induced at 10 Hz and did not have any effect on ACh-induced secretion. 4. In vivo, vagal stimulation (10 V, 10 Hz, 2 ms for 8 min) increased output of 35SO4 by approximately 120%. Telenzepine had no significant effect on neurogenic secretion. Methoctramine approximately doubled the stimulated response, whereas 4-DAMP abolished the stimulated secretory response. 5. We conclude that in ferret trachea, cholinergic nerve stimulation increases mucus secretion via muscarinic M3 receptors on the submucosal glands. The magnitude of the secretory response is regulated by neuronal M2 muscarinic receptors. The muscarinic M1 receptors localized to the submucosal glands do not appear to be involved with mucus secretion.

Animals↗
PubMed1996

Tachykinins: receptor to effector.

Tachykinins belong to an evolutionarily conserved family of peptide neurotransmitters. The mammalian tachykinins include substance P, neurokinin A and neurokinin B, which exert their effects by binding to specific receptors. These tachykinin receptors are divided into three types, designated NK1, NK2 and NK3, respectively. Tachykinin receptors have been cloned and contain seven segments spanning the cell membrane, indicating their inclusion in the G-protein-linked receptor family. The continued development of selective agonists and antagonists for each receptor has helped elucidate roles for these mediators, ranging from effects in the central nervous system to the perpetuation of the inflammatory response in the periphery. Various selective ligands have shown both inter- and intraspecies differences in binding potencies, indicating distinct binding sites in the tachykinin receptor. The interaction of tachykinin with its receptor activates Gq, which in turn activates phospholipase C to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on specific receptors in the sarcoplasmic reticulum to release intracellular stores of Ca2+, while DAG acts via protein kinase C to open L-type calcium channels in the plasma membrane. The rise in intracellular [Ca2+] induces the tissue response. With an array of actions as diverse as that seen with tachykinins, there is scope for numerous therapeutic possibilities. With the development of potent, selective non-peptide antagonists, there could be potential benefits in the treatment of a variety of clinical conditions, including chronic pain, Parkinson's disease, Alzheimer's disease, depression, rheumatoid arthritis, irritable bowel syndrome and asthma.

Amino Acid Sequence↗
PubMed1996

Involvement of hydroxyl radicals in neurogenic airway plasma exudation and bronchoconstriction in guinea-pigs in vivo.

1. Cigarette smoke induces plasma exudation in the airways of rodents by activation of capsaicin-sensitive 'sensory-efferent' nerves. The response is mediated predominantly by substance P (SP) and the magnitude of exudation is regulated by neutral endopeptidase (NEP). The component(s) of the smoke responsible for the activation of the nerves may be reactive oxygen radicals. We investigated the effect of the hydroxyl radical scavenger dimethylthiourea (DMTU), a regulator of superoxide anion, superoxide dismutase (SOD), and a regulator of hydrogen peroxide, catalase, on plasma exudation (measured using Evans blue dye) induced by cigarette smoke in guinea-pig main bronchi in vivo. The effect of DMTU on plasma exudation and non-cholinergic bronchoconstriction (measured as pulmonary insufflation pressure, PIP) induced by electrical stimulation of the vagus nerves was also assessed. Interaction between hydroxyl radicals and NEP was assessed with the NEP inhibitor phosphoramidon. 2. In each of the experiments, cigarette smoke increased plasma exudation by approximately 200% above air-exposed controls. Acute administration of DMTU (1.5 g kg-1, i.v. for 20 min) significantly reduced cigarette smoke-induced plasma exudation by 69%. In contrast, neither SOD (240,000 u kg-1, i.v.) nor catalase (400,000 u kg-1, i.v.) significantly affected the exudative response. 3. Chronic pretreatment with DMTU (1.25 g kg-1 over 4 days) significantly reduced bronchial plasma exudation induced by cigarette smoke by 72%. Phosphoramidon (1.5 mg kg-1, i.v.) completely reversed the inhibition by DMTU of cigarette smoke-induced plasma exudation. 4. Vagal stimulation increased plasma exudation by approximately 200% and PIP by approximately 250%. Acute treatment with DMTU had no significant inhibitory effect on these responses, whereas chronic pretreatment inhibited them by approximately 80%. Phosphoramidon reversed the inhibition by chronic DMTU. 5. SP (1 nmol kg-1) increased plasma exudation by approximately 250%, a response which was not inhibited by either acute or chronic DMTU. 6. We conclude that hydroxyl radicals, rather than superoxide anion or hydrogen peroxide, are involved in the induction of neurogenic plasma exudation and bronchoconstriction induced by cigarette smoke or by electrical stimulation of the vagus nerves. These radicals also affect the activity of NEP. Acute DMTU may affect directly the neural actions of hydroxyl radicals contained in the cigarette smoke. Chronic pretreatment with DMTU may inhibit the neurogenic airway responses by effects on tachykinin biosynthesis and/or axonal transport.

Animals↗
PubMed1996

Nitric oxide inhibition of basal and neurogenic mucus secretion in ferret trachea in vitro.

1. In order to examine the role of nitric oxide (NO) on airway mucus secretion we studied the effects of the nitric oxide synthase (NOS) inhibitor L-N(G)-monomethyl-L-arginine (L-NMMA), a novel nitric oxide donor, (+/-)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide (FK409), and the NO precursor L-arginine on basal mucus secretion in the ferret trachea in vitro in Ussing chambers. We also determined the effects of these agents upon secretion induced by electrical stimulation of nerves or by acetylcholine (ACh). We used 35SO4 as a mucus marker. 2. L-NMMA (0.01-1 mM) increased basal output of 35SO4-labelled macromolecules with a maximal increase above baseline of 248% at 0.1 mM L-NMMA. L-Arginine (1 mM) alone had no significant effect on basal secretion but reversed the potentiating effect of L-NMMA on basal secretion. L-NMMA-induced increases in basal mucus secretion were sustained for at least 30 min in the continuing presence of the NOS inhibitor. In contrast to the potentiating effects of L-NMMA, FK409 (100 nM) reduced basal secretion by 60% (at 1 nM and at 10 nM it was without effect). 3. Electrical stimulation (50 V, 10 Hz, 0.5 ms for 5 min) increased 35SO4 output by 174%. L-NMMA (1 and 10 mM) present during stimulation of tracheal segments resulted in significant potentiations of 214% and 116%, respectively, of the neurogenic response. The potentiated response to 10 mM L-NMMA was reversed by L-arginine (1 mM). At this dose L-arginine had no effect itself on basal secretion. In contrast to the potentiating effects of L-NMMA on neurogenic secretion, FK409 at 10 nM and 100 nM inhibited the neurogenic response by 98% and 99%. 4. At all concentrations tested, neither L-NMMA (0.01 mM-1 mM) nor FK409 (1-100 mM) had any significant effect on ACh-induced mucus secretion. 5. These observations lead us to conclude that nitric oxide, derived from constitutive NO synthase, acts as an endogenous inhibitor of both basal and neurogenic mucus secretion in ferret trachea in vitro.

Animals↗
PubMed1996

Scorpion venoms: taking the sting out of lung disease.

Scorpion venoms contain specific toxins which block large conductance calcium-activated potassium (BKCa) channels. Use of these toxins has shown that a significant proportion of the action of bronchodilators such as beta-agonists, theophylline, and nitric oxide occurs as a result of the opening of BKCa channels. Similarly, these toxins have shown that inhibitors of airway neurotransmission also operate via BKCa channels. Drugs that open BKCa channels may be alternative bronchodilators (possibly "airway selective" and with fewer side effects) as well as inhibitors of pathophysiological neurogenic influences in asthma, chronic coughing and sneezing, and chronic bronchitis.

Bronchodilator Agents↗
PubMed1996

Microanatomy of secretory granule release from guinea pig tracheal goblet cells.

The microanatomy of mucin granule release from epithelial goblet cells has been investigated in guinea pig tracheae. Using a tannic acid arrest procedure, granule release under basal conditions and after high K+ or acetylcholine (ACh) application was arrested and a variety of granule fusion sites were identified in ultrathin sections and freeze-fracture replicas. Rather than there being subclasses of secretory cells containing either electron-lucent granules (indicative of mucin) or smaller electron-dense (serous) granules, the majority of secretory cells in both control and treated groups contained granules with an electrondense core surrounded by an electron-lucent region. Granule release sites were of three principal types: (1) simple exocytosis, where the membranes of single granules fused directly with the plasma membrane to give an "omega" profile; (2) compound exocytosis, where granule membranes, fused together intracellularly, were found in continuity with the plasma membrane; and (3) apocrine-like secretion, which involved the loss of the central apical mass of granules together with elements of the cell cytoplasm. In treated preparations, there was an increase in the number of cells exhibiting fusion sites; the percentage showing simple fusions fell from 82% to 59% (with ACh) and 57% (with KCl), whereas the percentage of cells exhibiting compound and apocrine-like secretion increased. Dense cores were frequently retained at the sites of fusion and, despite the expansive decondensation of mucin known to occur, there was also evidence of some retention of the electron-lucent material.

Acetylcholine↗
PubMed1995

Neurogenic goblet cell secretion and bronchoconstriction in guinea pigs sensitised to trimellitic anhydride.

Trimellitic anhydride is a cause of occupational asthma in humans. We have previously found that tracheal instillation of trimellitic anhydride conjugated to guinea pig serum albumin induces acute bronchoconstriction and airway plasma exudation in sensitised animals, responses mediated primarily via histamine release. In the present study, neural mechanisms mediating bronchoconstriction and goblet cell secretion were determined in trimellitic anhydride-sensitised guinea pigs using the ganglionic blocker hexamethonium to eliminate efferent reflex mechanisms, pretreatment with capsaicin to eliminate afferent mechanisms, or cimetidine and mepyramine to eliminate histamine-mediated mechanisms. The magnitude of secretion of intracellular mucus from tracheal goblet cells was quantified morphometrically as a mucus score which is inversely related to the degree of discharge. Guinea pigs were injected intradermally either with 0.1 ml 0.3% trimellitic anhydride in corn oil or with corn oil alone as control. Fourteen to eighteen days later all sensitised animals had developed specific immunoglobulin (Ig) G1 antibodies whereas the controls had not. Tracheal instillation of conjugated trimellitic anhydride in anaesthetised animals significantly increased airway lung resistance (RL) 24-fold in sensitised guinea pigs (34.3 +/- 7.9 cm H2O.ml-1.s) compared with controls (1.4 +/- 0.1 cm H2O.ml-1.s). Mucus score was significantly reduced by 51% (indicating goblet cell secretion) in sensitised guinea pigs (183 +/- 22 mucus score units) compared with controls (372 +/- 41 mucus score units). The antihistamines significantly inhibited conjugated trimellitic anhydride-induced bronchoconstriction by 89%, but did not significantly affect goblet cell discharge. Hexamethonium alone did not significantly affect conjugated trimellitic anhydride-induced bronchoconstriction or goblet cell secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗