The Experts below are selected from a list of 8346 Experts worldwide ranked by ideXlab platform
Duncan F. Rogers - One of the best experts on this subject based on the ideXlab platform.
-
physiology of airway Mucus Secretion and pathophysiology of hyperSecretion
Respiratory Care, 2007Co-Authors: Duncan F. RogersAbstract:Mucus Secretion is the first-line defense against the barrage of irritants that inhalation of approximately 500 L of air an hour brings into the lungs. The inhaled soot, dust, microbes, and gases can all damage the airway epithelium. Consequently, Mucus Secretion is extremely rapid, occurring in tens of milliseconds. In addition, Mucus is held in cytoplasmic granules in a highly condensed state in which high concentrations of Ca 2+ nullify the repulsive forces of the highly polyanionic mucin molecules. Upon initiation of Secretion and dilution of the Ca 2+ , the repulsion forces of the mucin molecules cause many-hundred-fold swelling of the secreted Mucus, to cover and protect the epithelium. Secretion is a highly regulated process, with coordination by several molecules, including soluble N-ethyl-maleimide-sensitive factor attachment protein receptor (SNARE) proteins, myristoylated alanine-rich C kinase substrate (MARCKS), and Munc proteins, to dock the mucin granules to the secretory cell membrane prior to exocytosis. Because Mucus Secretion appears to be such a fundamental airway homeostatic process, virtually all regulatory and inflammatory mediators and interventions that have been investigated increase Secretion acutely. When given longer-term, many of these same mediators also increase mucin gene expression and mucin synthesis, and induce goblet cell hyperplasia. These responses induce (in contrast to the protective effects of acute Secretion) long-term, chronic hyperSecretion of airway Mucus, which contributes to respiratory disease. In this case the homeostatic, protective function of airway Mucus Secretion is lost, and, instead, Mucus hyperSecretion contributes to pathophysiology of a number of severe respiratory conditions, including asthma, chronic obstructive pulmonary disease, and cystic fibrosis.
-
effect of the long acting tachykinin nk1 receptor antagonist men 11467 on tracheal Mucus Secretion in allergic ferrets
British Journal of Pharmacology, 2001Co-Authors: Safina Khan, Yuchih Liu, Aamir M Khawaja, Stefano Manzini, Duncan F. RogersAbstract:We investigated the effect of MEN 11467 ((1R,2S)-2-N[1(H)indol-3-yl-carbonyl]-1-N-{Nα(p-tolylacetyl)-Nα(methyl)-D-3-(2-naphthyl)alanyl}diaminocyclohexane) on tachykinin-induced Mucus Secretion in ferret trachea in vitro and determined its effect on Secretion by tracheae from allergic ferrets in response to allergen challenge. Repeated administration of [Sar9,Met(O2)11]-substance P ([Sar9]SP, 1 μM) maintained Mucus output above control values for at least 1.75 h. MEN 11467 inhibited Secretion in a concentration-dependent manner with maximal inhibition at 10 μM and an approximate IC50 of 0.3 μM. Inhibition by MEN 11467 (0.1 – 10 μM) was maintained, to varying degree, for at least 1.75 h after washout in the continued presence of [Sar9]SP. In electrically stimulated tracheae, tachykininergic neural Secretion was virtually abolished by 1 μM MEN 11467. In tracheae from ovalbumin-sensitised animals, repeated administration of ovalbumin maintained Mucus output above controls for 1.5 h. MEN 11467 inhibited ovalbumin-induced Secretion in a concentration-dependent manner, with complete inhibition at 1 μM. Inhibition by MEN 11467 (1 and 10 μM) was maintained, to varying degree, after drug washout for the 1.5 h of ovalbumin stimulation. MEN 11467 1 μM did not affect Secretion induced by either acetylcholine or histamine, whereas 10 μM MEN 11467 did inhibit agonist-induced Secretion. We conclude that, in ferret trachea in vitro, MEN 11467 at concentrations of 0.1 – 1 μM is a long acting and selective inhibitor of tachykininergic-induced Mucus Secretion, and may have therapeutic potential for bronchial hyperSecretion associated with allergic conditions, for example in asthma. Keywords: Airway, allergy, asthma, mucin, Mucus, MEN 11467, respiratory tract, sensitisation, tachykinin receptor, tachykinin receptor antagonist Introduction Mucus Secretion is a vital component of airway homeostasis, providing the ‘front-line' barrier to inhaled irritants. The rate of Secretion is controlled by both humoral and neuronal mechanisms. In mammalian airways, the dominant neural control is cholinergic (Rogers, 2000a). Adrenergic neural mechanisms contribute little to control, particularly in human airways. Capsaicin-sensitive ‘sensory-efferent' nerves also control Secretion, although their relative contribution varies with species (Rogers, 2000a). Asthma and chronic obstructive pulmonary disease (COPD) are two severe respiratory conditions that are associated with airway Mucus hyperSecretion (Liu et al., 1998a; Rogers, 2000b). In both conditions, abnormalities in neural control are implicated in pathophysiology. Consequently, investigation of the neural control of airway Secretion is linked to design of therapeutic drugs for bronchial Mucus hyperSecretion. Preclinical test systems have, therefore, been developed to assess compounds with potential to inhibit neurogenic Secretion. One such system is the in vitro ferret trachea. Neurogenic Secretion in ferret trachea is mediated via cholinergic nerves and capsaicin-sensitive ‘sensory-efferent' nerves (Rogers, 2000a). Tachykinin receptor agonist studies (Geppetti et al., 1993; Meini et al., 1993) and tachykinin receptor antagonist studies using a range of peptide and non-peptide compounds (Ramarine et al., 1994; Khawaja et al., 1999) show that the sensory-efferent secretory response is mediated exclusively via tachykinin NK1 receptors. Thus, Mucus Secretion from the in vitro ferret trachea is a useful experimental system for investigating drugs acting at tachykinin NK1 receptors. Allergy is one component of asthma. Consequently, antigen-sensitized animals are commonly employed as models of allergic asthma (Chung, 1995). In guinea-pigs, the later-phase of antigen-induced tracheal plasma exudation is mediated via tachykinin interaction with tachykinin NK1 receptors (Bertrand et al., 1993a). The involvement of tachykininergic pathways in antigen-induced airway Mucus Secretion is not reported. In the present study, we used the pseudopeptide tachykinin NK1 receptor antagonist, MEN 11467 ((1R,2S)-2-N[1(H)indol-3-yl-carbonyl]-1-N-{Nα(p-tolylacetyl)-Nα (methyl)-D-3-(2-naphthyl) alanyl}diaminocyclohexane) (Cirillo et al., 1998), to study tachykininergic involvement in antigen-induced Mucus Secretion in ferret trachea in vitro. We used this antagonist because its long duration of action was required if antigen-induced neurogenic secretory responses were late in onset (Bertrand et al., 1993a). Firstly, we determined the inhibitory profile and duration of action of MEN 11467 against Secretion induced by the selective tachykinin NK1 receptor agonist [Sar9,Met(O2)11]-substance P ([Sar9]SP). Secondly, we examined inhibition by MEN 11467 of electrically stimulated tissue in the presence of adrenoceptor and cholinoceptor blockade (i.e. tachykininergic neural Secretion). Thirdly, we assessed the inhibitory profile and duration of action of MEN 11467 in tracheae from ovalbumin-sensitised animals challenged with ovalbumin (‘allergic' Secretion). Finally, the selectivity of MEN 11467 for tachykininergic-induced Mucus Secretion was assessed using acetylcholine and histamine to induce Secretion. We used 35SO4 as a Mucus marker because it localises to secretory structures and is released upon stimulation (Gashi et al., 1987), and the released material has a molecular weight and buoyant density characteristic of a Mucus glycoprotein (Davies et al., 1990).
-
effect of fenspiride a non steroidal antiinflammatory agent on neurogenic Mucus Secretion in ferret trachea in vitro
Pulmonary Pharmacology & Therapeutics, 1999Co-Authors: A M Khawaja, Duncan F. RogersAbstract:Abstract Neural mechanisms contribute to control of Mucus Secretion in the airways. Fenspiride is a non-steroidal antiinflammatory agent which has a variety of actions, including inhibition of neurogenic bronchoconstriction. The effect of fenspiride on neurally-mediated Mucus Secretion was investigated in vitro in electrically-stimulated ferret trachea, using 35 SO 4 as a Mucus marker. Cholinergic secretory responses were isolated using adrenoceptor and tachykinin receptor antagonists. Tachykinin responses were isolated using cholinoceptor and adrenoceptor antagonists. Electrical stimulation increased cholinergic Secretion by 90% and tachykininergic Secretion by 40%. Fenspiride (1 μM–1 mM) tended to inhibit cholinergic Secretion in a concentration-dependent manner, although only at 1 mM was inhibition (by 87%) significant. Inhibition by fenspiride of tachykininergic Secretion was not concentration-dependent, and again significant inhibition (by 85%) was only at 1 mM. Inhibition was not due to loss of tissue viability, as assessed by restitution of secretory response after washout. Fenspiride also inhibited Secretion induced by acetylcholine, but did not inhibit substance P-induced Secretion. Histamine receptor antagonists increased basal Secretion by 164%, whereas fenspiride did not affect basal Secretion. We conclude that, in ferret trachea in vitro, fenspiride inhibits neurally-mediated Mucus Secretion, with antimuscarinic action the most plausible mechanism of action, but not necessarily the only mechanism.
-
effect of non peptide tachykinin nk1 receptor antagonists on non adrenergic non cholinergic neurogenic Mucus Secretion in ferret trachea
European Journal of Pharmacology, 1999Co-Authors: Aamir M Khawaja, Yuchih Liu, Duncan F. RogersAbstract:Abstract We investigated, in ferret trachea in vitro, the binding characteristics and the inhibition of non-adrenergic, non-cholinergic (NANC) neural Mucus Secretion of four tachykinin receptor antagonists: the non-peptide tachykinin NK 1 receptor antagonists CGP 49823 ((2 R ,4 S )-2-benzyl-1-(3,5-dimethylbenzoyl)-4-(quinolin-μ-ylmethyl amino) piperidine), CGP 55000 ((2 R ,4 S )-2-benzyl-1-(3,5-bistrifluoromethyl-benzoyl)-4-(quinolinyl-methylamino)piperidine) and CP 99,994 ((+)-(2 S ,3 S )-3-methoxybenzyl amino)-2-phenylpiperidine), and the peptide tachykinin NK 2 receptor antagonist MEN 10,627 (cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2β–5β)). CGP 49823, CGP 55000 and CP 99,994 concentration-dependently displaced [ 125 I]Bolton–Hunter substance P binding in tracheal membranes with Hill coefficients not different from unity and IC 50 values of 1.4, 1.7 and 1.3 nM, respectively. In contrast, MEN 10,627 displaced binding according to a two-site model, with IC 50 s of 0.2 nM and 1.3 μM. Electrical stimulation of tracheal segments with adrenoceptor and cholinoceptor blockade increased output of the Mucus marker 35 SO 4 by 59% above baseline (representing the NANC neural secretory response). CGP 49823, CGP 55000 or CP 99,994 concentration-dependently inhibited NANC neural Secretion with IC 50 values of 30, 8 and 120 nM, respectively. In contrast, MEN 10,627 (3 μM) did not inhibit Secretion. The NK 1 antagonists, but not the NK 2 antagonist, inhibited [Sar 9 ]substance P-induced Secretion, while none of the antagonists affected acetylcholine-induced Secretion. We conclude that NANC neural Secretion in ferret trachea in vitro is a useful test system for tachykinin NK 1 receptor antagonists with therapeutic potential in conditions of the airways in which tachykininergic mechanisms and Mucus hyperSecretion are implicated in pathophysiology, for example asthma and chronic bronchitis.
-
effects of the cysteinyl leukotriene receptor antagonists pranlukast and zafirlukast on tracheal Mucus Secretion in ovalbumin sensitized guinea pigs in vitro
British Journal of Pharmacology, 1998Co-Authors: Yuchih Liu, Aamir M Khawaja, Duncan F. RogersAbstract: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.
Jae Young Choi - One of the best experts on this subject based on the ideXlab platform.
-
protease activated receptor 2 mediates Mucus Secretion in the airway submucosal gland
PLOS ONE, 2012Co-Authors: Hyunjae Lee, Yumi Yang, Dong Min Shin, Kyubo Kim, Jooheon Yoon, Hyung Ju Cho, Jae Young ChoiAbstract:Protease-activated receptor 2 (PAR2), a G protein-coupled receptor expressed in airway epithelia and smooth muscle, plays an important role in airway inflammation. In this study, we demonstrated that activation of PAR2 induces Mucus Secretion from the human airway gland and examined the underlying mechanism using the porcine and murine airway glands. The mucosa with underlying submucosal glands were dissected from the cartilage of tissues, pinned with the mucosal side up at the gas/bath solution interface of a physiological chamber, and covered with oil so that Secretions from individual glands could be visualized as spherical bubbles in the oil. Secretion rates were determined by optical monitoring of the bubble diameter. The Ca2+-sensitive dye Fura2-AM was used to determine intracellular Ca2+ concentration ([Ca2+]i) by means of spectrofluorometry. Stimulation of human tracheal mucosa with PAR2-activating peptide (PAR2-AP) elevated intracellular Ca2+ and induced glandular Secretion equal to approximately 30% of the carbachol response in the human airway. Porcine gland tissue was more sensitive to PAR2-AP, and this response was dependent on Ca2+ and anion Secretion. When the mouse trachea were exposed to PAR2-AP, large amounts of Secretion were observed in both wild type and ΔF508 cystic fibrosis transmembrane conductance regulator mutant mice but there is no Secretion from PAR-2 knock out mice. In conclusion, PAR2-AP is an agonist for Mucus Secretion from the airway gland that is Ca2+-dependent and cystic fibrosis transmembrane conductance regulator-independent.
-
properties of substance p stimulated Mucus Secretion from porcine tracheal submucosal glands
American Journal of Physiology-lung Cellular and Molecular Physiology, 2011Co-Authors: Monal Khansaheb, Mauri E Krouse, Jae Young Choi, Yumi Yang, Jeffrey J WineAbstract:Human and pig airway submucosal glands secrete Mucus in response to substance P (SubP), but in pig tracheal glands the response to SubP is >10-fold greater than in humans and shares features with c...
-
synergistic airway gland Mucus Secretion in response to vasoactive intestinal peptide and carbachol is lost in cystic fibrosis
Journal of Clinical Investigation, 2007Co-Authors: Jae Young Choi, Mauri E Krouse, Juan P Ianowski, Nam Soo Joo, Robert C Robbins, John W Hanrahan, Jeffrey J WineAbstract:Cystic fibrosis (CF) is caused by dysfunction of the CF transmembrane conductance regulator (CFTR), an anion channel whose dysfunction leads to chronic bacterial and fungal airway infections via a pathophysiological cascade that is incompletely understood. Airway glands, which produce most airway Mucus, do so in response to both acetylcholine (ACh) and vasoactive intestinal peptide (VIP). CF glands fail to secrete Mucus in response to VIP, but do so in response to ACh. Because vagal cholinergic pathways still elicit strong gland Mucus Secretion in CF subjects, it is unclear whether VIP-stimulated, CFTR-dependent gland Secretion participates in innate defense. It was recently hypothesized that airway intrinsic neurons, which express abundant VIP and ACh, are normally active and stimulate low-level gland Mucus Secretion that is a component of innate mucosal defenses. Here we show that low levels of VIP and ACh produced significant Mucus Secretion in human glands via strong synergistic interactions; synergy was lost in glands of CF patients. VIP/ACh synergy also existed in pig glands, where it was CFTR dependent, mediated by both Cl(-) and HCO(3) (-), and clotrimazole sensitive. Loss of "housekeeping" gland Mucus Secretion in CF, in combination with demonstrated defects in surface epithelia, may play a role in the vulnerability of CF airways to bacterial infections.
Mahmoud A O Dawood - One of the best experts on this subject based on the ideXlab platform.
-
physiological response blood chemistry profile and Mucus Secretion of red sea bream pagrus major fed diets supplemented with lactobacillus rhamnosus under low salinity stress
Fish Physiology and Biochemistry, 2017Co-Authors: Mahmoud A O Dawood, Shunsuke Koshio, Manabu Ishikawa, Mabrouk Elsabagh, Saichiro Yokoyama, Weilong Wang, Zhang Yukun, Adissin OlivierAbstract:Environmental stressors caused by inadequate aquaculture management strategies suppress the immune response of fish and make them more susceptible to diseases. Therefore, efforts have been made to relieve stress in fish by using various functional feed additives in the diet, including probiotics. The present work evaluates the effects of Lactobacillus rhamnosus (LR) on physiological stress response, blood chemistry and Mucus Secretion of red sea bream (Pagrus major) under low salinity stress. Fish were fed four diets supplemented with LR at [0 (LR0), 1 × 102 (LR1), 1 × 104 (LR2) and 1 × 106 (LR3) cells g−1] for 56 days. Before stress, blood cortisol, urea nitrogen (BUN) and total bilirubin (T-BIL) showed no significant difference (P > 0.05), whereas plasma glucose and triglyceride (TG) of fish-fed LR2 and LR3 diets were significantly lower (P 0.05). In addition, the fish that received LR-supplemented diets showed significantly higher tolerance against low salinity stress than the fish-fed LR-free diet (P < 0.05). The physiological status and the detected immune responses, including total plasma protein and Mucus myeloperoxidase activity in red sea bream, will provide a more comprehensive outlook of the effects of probiotics to relieve stress in fish.
-
immune responses and stress resistance in red sea bream pagrus major after oral administration of heat killed lactobacillus plantarum and vitamin c
Fish & Shellfish Immunology, 2016Co-Authors: Mahmoud A O Dawood, Shunsuke Koshio, Manabu Ishikawa, Saichiro YokoyamaAbstract:The present study evaluated the interactive benefits of dietary administration of heat-killed Lactobacillus plantarum (LP) and vitamin C (VC) on the growth, oxidative status and immune response of red sea bream (Pagrus major). A diet without LP and VC supplements was employed as a control diet. Four other test diets with 0 or 1 g LP kg(-1) combined with 0.5 or 1 g VC kg(-1) (2 × 2 factorial design) were fed to red sea bream (2 ± 0.01 g) for 56 days. A significant interaction was found between LP and VC on final body weight (FNW), weight gain (WG), hematocrit (HCT), serum bactericidal (BA) and lysozyme (LZY) activities, Mucus LZY and peroxidase (PA) activities, nitro blue tetrazolium (NBT), catalase, Mucus Secretion and tolerance against low salinity stress test (LT50) (P < 0.05). In addition, FNW, WG, specific growth rate, feed and protein efficiency ratio, serum (BA, LZY, PA and NBT), Mucus (LZY and PA), superoxide dismutase, malondialdehyde and Mucus Secretion were significantly affected by either LP or VC (P < 0.05). Furthermore, only LP was a significant factor on survival, plasma total cholesterol, Mucus BA and alternative complement pathway (P < 0.05). However, VC supplementation affected on HCT and LT50. Interestingly, fish fed with both LP at 1 g kg(-1) diet with VC at 0.5 or 1 g kg(-1) diet showed higher growth, humoral and mucosal immune responses, anti-oxidative status, Mucus Secretion and LT50 as well as decreased plasma, triglyceride and total cholesterol levels than the fish fed control diet (P < 0.05). These results demonstrated that dietary LP and VC had a significant interaction for red sea bream with the capability of improving growth performance and enhancing stress resistance by immunomodulation.
-
effects of dietary supplementation of lactobacillus rhamnosus or and lactococcus lactis on the growth gut microbiota and immune responses of red sea bream pagrus major
Fish & Shellfish Immunology, 2016Co-Authors: Mahmoud A O Dawood, Shunsuke Koshio, Manabu Ishikawa, Saichiro Yokoyama, Mohammed El F Basuini, Md Sakhawat Hossain, Truong H Nhu, Serge DossouAbstract:Pagrus major fingerlings (3·29 ± 0·02 g) were fed with basal diet (control) supplemented with Lactobacillus rhamnosus (LR), Lactococcus lactis (LL), and L. rhamnosus + L. lactis (LR + LL) at 10(6) cell g(-1) feed for 56 days. Feeding a mixture of LR and LL significantly increased feed utilization (FER and PER), intestine lactic acid bacteria (LAB) count, plasma total protein, alternative complement pathway (ACP), peroxidase, and Mucus Secretion compared with the other groups (P < 0.05). Serum lysozyme activity (LZY) significantly increased in LR + LL when compared with the control group. Additionally, fish fed the LR + LL diet showed a higher growth performance (Fn wt, WG, and SGR) and protein digestibility than the groups fed an individual LR or the control diet. Superoxide dismutase (SOD) significantly increased in LR and LR + LL groups when compared with the other groups. Moreover, the fish fed LR or LL had better improvement (P < 0.05) in growth, feed utilization, body protein and lipid contents, digestibility coefficients (dry matter, protein, and lipid), protease activity, total intestine and LAB counts, hematocrit, total plasma protein, biological antioxidant potential, ACP, serum and Mucus LZY and bactericidal activities, peroxidase, SOD, and Mucus Secretion than the control group. Interestingly, fish fed diets with LR + LL showed significantly lower total cholesterol and triglycerides when compared with the other groups (P < 0.05). These data strongly suggest that a mixture of LR and LL probiotics may serve as a healthy immunostimulating feed additive in red sea bream aquaculture.
Jeffrey J Wine - One of the best experts on this subject based on the ideXlab platform.
-
properties of substance p stimulated Mucus Secretion from porcine tracheal submucosal glands
American Journal of Physiology-lung Cellular and Molecular Physiology, 2011Co-Authors: Monal Khansaheb, Mauri E Krouse, Jae Young Choi, Yumi Yang, Jeffrey J WineAbstract:Human and pig airway submucosal glands secrete Mucus in response to substance P (SubP), but in pig tracheal glands the response to SubP is >10-fold greater than in humans and shares features with c...
-
Mucus Secretion from individual submucosal glands of the ferret trachea
American Journal of Physiology-lung Cellular and Molecular Physiology, 2010Co-Authors: Jeffrey J WineAbstract:Mucus Secretion from individual tracheal glands in adult ferrets was studied with time-lapse optical imaging of Mucus droplets under an oil layer. Density of functional glands (determined by respon...
-
synergistic airway gland Mucus Secretion in response to vasoactive intestinal peptide and carbachol is lost in cystic fibrosis
Journal of Clinical Investigation, 2007Co-Authors: Jae Young Choi, Mauri E Krouse, Juan P Ianowski, Nam Soo Joo, Robert C Robbins, John W Hanrahan, Jeffrey J WineAbstract:Cystic fibrosis (CF) is caused by dysfunction of the CF transmembrane conductance regulator (CFTR), an anion channel whose dysfunction leads to chronic bacterial and fungal airway infections via a pathophysiological cascade that is incompletely understood. Airway glands, which produce most airway Mucus, do so in response to both acetylcholine (ACh) and vasoactive intestinal peptide (VIP). CF glands fail to secrete Mucus in response to VIP, but do so in response to ACh. Because vagal cholinergic pathways still elicit strong gland Mucus Secretion in CF subjects, it is unclear whether VIP-stimulated, CFTR-dependent gland Secretion participates in innate defense. It was recently hypothesized that airway intrinsic neurons, which express abundant VIP and ACh, are normally active and stimulate low-level gland Mucus Secretion that is a component of innate mucosal defenses. Here we show that low levels of VIP and ACh produced significant Mucus Secretion in human glands via strong synergistic interactions; synergy was lost in glands of CF patients. VIP/ACh synergy also existed in pig glands, where it was CFTR dependent, mediated by both Cl(-) and HCO(3) (-), and clotrimazole sensitive. Loss of "housekeeping" gland Mucus Secretion in CF, in combination with demonstrated defects in surface epithelia, may play a role in the vulnerability of CF airways to bacterial infections.
-
optical method for quantifying rates of Mucus Secretion from single submucosal glands
American Journal of Physiology-lung Cellular and Molecular Physiology, 2001Co-Authors: Jin V Wu, Mauri E Krouse, Yamil Saenz, Jeffrey J WineAbstract:We describe an optical method to quantify single- gland Secretion. Isolated tracheal mucosa were mounted at the air-Krebs interface and coated with oil. Gland Secretions formed spherical bubbles th...
-
hco3 transport in relation to Mucus Secretion from submucosal glands
Journal of the Pancreas, 2001Co-Authors: Mauri E Krouse, Jin V Wu, Sujatha Jayaraman, Yamil Saenz, Jeffrey J WineAbstract:The role of HCO3 - transport in relation to fluid Secretion by submucosal glands is being studied in sheep, pigs, cats and humans. Optical methods have been developed to measure Secretion rates of Mucus volume from single glands with sufficient temporal resolution to detect differences in minute-by-minute Secretion rates among glands. The ionic composition and viscoelastic properties of the uncontaminated gland Mucus are measured with a combination of ratiometric fluorescent indicators, ion-selective microelectrodes, FRAP, and a miniaturized, magnetic force viscometer. Sheep glands secreted basally at low rates, showed small, transient responses to alpha- and beta-adrenergic agonists, and large responses to a cholinergic agonist, carbachol. Peak rates and temporal patterns of responses to carbachol differed markedly among glands. To assess the contribution of HCO3 - transport to gland Secretion, we either inhibited Na+ /K+ /2Clcotransporter (NKCC) with bumetanide or replaced HCO3 - with HEPES and gassed with O2. Bumetanide caused a small, non-significant inhibition of basal Secretion, but removal of HCO3 - /CO2 significantly reduced basal Secretion almost by half. Both bumetanide and removal of HCO3 - /CO2 reduced carbacholstimulated Secretion significantly, with HCO3 - removal having the larger effect: a reduction to 33% of control (P<0.01). The remaining secretory response to carbachol was nearly eliminated by bumetanide. Sheep Mucus pH measured with ion selective electrodes was about 0.4 log more acidic than the bath. In humans, we observed the same pattern of responses to agonists and antagonists as in sheep, and observed a Mucus pH of 7.0 using 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF). We hypothesize that HCO3 - transport is important in the formation of Mucus Secretion, but that most HCO3 - is scavenged before the final Mucus appears at the duct opening.
Aamir M Khawaja - One of the best experts on this subject based on the ideXlab platform.
-
effect of the long acting tachykinin nk1 receptor antagonist men 11467 on tracheal Mucus Secretion in allergic ferrets
British Journal of Pharmacology, 2001Co-Authors: Safina Khan, Yuchih Liu, Aamir M Khawaja, Stefano Manzini, Duncan F. RogersAbstract:We investigated the effect of MEN 11467 ((1R,2S)-2-N[1(H)indol-3-yl-carbonyl]-1-N-{Nα(p-tolylacetyl)-Nα(methyl)-D-3-(2-naphthyl)alanyl}diaminocyclohexane) on tachykinin-induced Mucus Secretion in ferret trachea in vitro and determined its effect on Secretion by tracheae from allergic ferrets in response to allergen challenge. Repeated administration of [Sar9,Met(O2)11]-substance P ([Sar9]SP, 1 μM) maintained Mucus output above control values for at least 1.75 h. MEN 11467 inhibited Secretion in a concentration-dependent manner with maximal inhibition at 10 μM and an approximate IC50 of 0.3 μM. Inhibition by MEN 11467 (0.1 – 10 μM) was maintained, to varying degree, for at least 1.75 h after washout in the continued presence of [Sar9]SP. In electrically stimulated tracheae, tachykininergic neural Secretion was virtually abolished by 1 μM MEN 11467. In tracheae from ovalbumin-sensitised animals, repeated administration of ovalbumin maintained Mucus output above controls for 1.5 h. MEN 11467 inhibited ovalbumin-induced Secretion in a concentration-dependent manner, with complete inhibition at 1 μM. Inhibition by MEN 11467 (1 and 10 μM) was maintained, to varying degree, after drug washout for the 1.5 h of ovalbumin stimulation. MEN 11467 1 μM did not affect Secretion induced by either acetylcholine or histamine, whereas 10 μM MEN 11467 did inhibit agonist-induced Secretion. We conclude that, in ferret trachea in vitro, MEN 11467 at concentrations of 0.1 – 1 μM is a long acting and selective inhibitor of tachykininergic-induced Mucus Secretion, and may have therapeutic potential for bronchial hyperSecretion associated with allergic conditions, for example in asthma. Keywords: Airway, allergy, asthma, mucin, Mucus, MEN 11467, respiratory tract, sensitisation, tachykinin receptor, tachykinin receptor antagonist Introduction Mucus Secretion is a vital component of airway homeostasis, providing the ‘front-line' barrier to inhaled irritants. The rate of Secretion is controlled by both humoral and neuronal mechanisms. In mammalian airways, the dominant neural control is cholinergic (Rogers, 2000a). Adrenergic neural mechanisms contribute little to control, particularly in human airways. Capsaicin-sensitive ‘sensory-efferent' nerves also control Secretion, although their relative contribution varies with species (Rogers, 2000a). Asthma and chronic obstructive pulmonary disease (COPD) are two severe respiratory conditions that are associated with airway Mucus hyperSecretion (Liu et al., 1998a; Rogers, 2000b). In both conditions, abnormalities in neural control are implicated in pathophysiology. Consequently, investigation of the neural control of airway Secretion is linked to design of therapeutic drugs for bronchial Mucus hyperSecretion. Preclinical test systems have, therefore, been developed to assess compounds with potential to inhibit neurogenic Secretion. One such system is the in vitro ferret trachea. Neurogenic Secretion in ferret trachea is mediated via cholinergic nerves and capsaicin-sensitive ‘sensory-efferent' nerves (Rogers, 2000a). Tachykinin receptor agonist studies (Geppetti et al., 1993; Meini et al., 1993) and tachykinin receptor antagonist studies using a range of peptide and non-peptide compounds (Ramarine et al., 1994; Khawaja et al., 1999) show that the sensory-efferent secretory response is mediated exclusively via tachykinin NK1 receptors. Thus, Mucus Secretion from the in vitro ferret trachea is a useful experimental system for investigating drugs acting at tachykinin NK1 receptors. Allergy is one component of asthma. Consequently, antigen-sensitized animals are commonly employed as models of allergic asthma (Chung, 1995). In guinea-pigs, the later-phase of antigen-induced tracheal plasma exudation is mediated via tachykinin interaction with tachykinin NK1 receptors (Bertrand et al., 1993a). The involvement of tachykininergic pathways in antigen-induced airway Mucus Secretion is not reported. In the present study, we used the pseudopeptide tachykinin NK1 receptor antagonist, MEN 11467 ((1R,2S)-2-N[1(H)indol-3-yl-carbonyl]-1-N-{Nα(p-tolylacetyl)-Nα (methyl)-D-3-(2-naphthyl) alanyl}diaminocyclohexane) (Cirillo et al., 1998), to study tachykininergic involvement in antigen-induced Mucus Secretion in ferret trachea in vitro. We used this antagonist because its long duration of action was required if antigen-induced neurogenic secretory responses were late in onset (Bertrand et al., 1993a). Firstly, we determined the inhibitory profile and duration of action of MEN 11467 against Secretion induced by the selective tachykinin NK1 receptor agonist [Sar9,Met(O2)11]-substance P ([Sar9]SP). Secondly, we examined inhibition by MEN 11467 of electrically stimulated tissue in the presence of adrenoceptor and cholinoceptor blockade (i.e. tachykininergic neural Secretion). Thirdly, we assessed the inhibitory profile and duration of action of MEN 11467 in tracheae from ovalbumin-sensitised animals challenged with ovalbumin (‘allergic' Secretion). Finally, the selectivity of MEN 11467 for tachykininergic-induced Mucus Secretion was assessed using acetylcholine and histamine to induce Secretion. We used 35SO4 as a Mucus marker because it localises to secretory structures and is released upon stimulation (Gashi et al., 1987), and the released material has a molecular weight and buoyant density characteristic of a Mucus glycoprotein (Davies et al., 1990).
-
effect of non peptide tachykinin nk1 receptor antagonists on non adrenergic non cholinergic neurogenic Mucus Secretion in ferret trachea
European Journal of Pharmacology, 1999Co-Authors: Aamir M Khawaja, Yuchih Liu, Duncan F. RogersAbstract:Abstract We investigated, in ferret trachea in vitro, the binding characteristics and the inhibition of non-adrenergic, non-cholinergic (NANC) neural Mucus Secretion of four tachykinin receptor antagonists: the non-peptide tachykinin NK 1 receptor antagonists CGP 49823 ((2 R ,4 S )-2-benzyl-1-(3,5-dimethylbenzoyl)-4-(quinolin-μ-ylmethyl amino) piperidine), CGP 55000 ((2 R ,4 S )-2-benzyl-1-(3,5-bistrifluoromethyl-benzoyl)-4-(quinolinyl-methylamino)piperidine) and CP 99,994 ((+)-(2 S ,3 S )-3-methoxybenzyl amino)-2-phenylpiperidine), and the peptide tachykinin NK 2 receptor antagonist MEN 10,627 (cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2β–5β)). CGP 49823, CGP 55000 and CP 99,994 concentration-dependently displaced [ 125 I]Bolton–Hunter substance P binding in tracheal membranes with Hill coefficients not different from unity and IC 50 values of 1.4, 1.7 and 1.3 nM, respectively. In contrast, MEN 10,627 displaced binding according to a two-site model, with IC 50 s of 0.2 nM and 1.3 μM. Electrical stimulation of tracheal segments with adrenoceptor and cholinoceptor blockade increased output of the Mucus marker 35 SO 4 by 59% above baseline (representing the NANC neural secretory response). CGP 49823, CGP 55000 or CP 99,994 concentration-dependently inhibited NANC neural Secretion with IC 50 values of 30, 8 and 120 nM, respectively. In contrast, MEN 10,627 (3 μM) did not inhibit Secretion. The NK 1 antagonists, but not the NK 2 antagonist, inhibited [Sar 9 ]substance P-induced Secretion, while none of the antagonists affected acetylcholine-induced Secretion. We conclude that NANC neural Secretion in ferret trachea in vitro is a useful test system for tachykinin NK 1 receptor antagonists with therapeutic potential in conditions of the airways in which tachykininergic mechanisms and Mucus hyperSecretion are implicated in pathophysiology, for example asthma and chronic bronchitis.
-
effects of the cysteinyl leukotriene receptor antagonists pranlukast and zafirlukast on tracheal Mucus Secretion in ovalbumin sensitized guinea pigs in vitro
British Journal of Pharmacology, 1998Co-Authors: Yuchih Liu, Aamir M Khawaja, Duncan F. RogersAbstract: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.