A physiological model of the human cough reflex : investigations of the afferent pathway and antitussive studies

Cough is a common symptom of respiratory disease. Assessmentof antitussives has relied mainly on animal studies and clinical trials inwhich recording of natural cough is difficult. This thesis describes the useof ultrasonically nebulized distilled water (UNOW) to induce cough in man.Investigation of the chemosensitivity of this response identified thatextremes of pH, a chloride concentration below 75mmol/l, but not changesin osmolarity induce cough which reflects afferent rapidly adaptingrecep~or sensitivity in animal studies. Inhaled beta-adrenergic andanticholinergic bronchodilators, which inhibit cough in asthma, markedlyreduced UNOW-induced cough in both healthy and asthmatic volunteers.Bronchoconstriction with inhaled leukotriene 04, which constricts bothasthmatic and non-asthmatic airways, also caused coughing. Inhibition ofbronchoconstriction either specifically or non-specifically resulted ininhibition of cough. Nedocromil sodium and the diuretic, frusemide, butnot the commonly prescribed opiate, codeine, exhibited antitussiveactivity. Cough was also induced by inhalation of the C-fibre stimulants,capsaicin and prostaglandin E2 (PGE2), which was characterised bystudies of adaptation, cross-adaptation and antitussives. UNOW andPGE2, but not capsaicin, exhibited rapid adaptation of cough. Crossadaptation,however, did not occur suggesting distinct mechanisms ofcough mediation. Nedocromil inhibited capsaicin-induced cough but notPGE2-induced cough, while fenoterol did not affect either challenge.Oxitropium, which inhibited UNOW-induced cough, did not reduce coughassociated with upper respiratory tract infection.Cough can be induced by a variety of inhaled stimuli. These canidentify differences in response which may signal a number of pathwaysleading to cough. Antitussive activity may also be specific to individualchallenges. This diversity in response reflects the complex neurologicalorganisation of cough and may be related to pathological causes of cough

Exercise induced bronchoconstriction in athletes: influence of airway dehydration on bronchial hyper-responsiveness, epithelial injury and mast cell activation

This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University LondonExercise-induced bronchoconstriction (EIB) is the most common chronic medical condition affecting elite athletes; our understanding of the condition remains however incomplete. The over-arching aim of this thesis was therefore to investigate the underlying mechanisms of EIB in athletes. More specifically, via induced and inhibited bronchoconstriction, the influence of airway dehydration on bronchial hyper-responsiveness, epithelial injury and inflammatory mediator release was investigated. The results of our first experiment suggest that mild, whole-body dehydration does not affect the severity of EIB in athletes; however, signs of small airway dysfunction were noticed post-dehydration. The clinical and functional relevance of these findings are yet to be evaluated.Our next two experiments showed that administration of a single, therapeutic dose of the inhaled 32-agonist terbutaline before bronchial provocation challenge with dry air I) reduced the severity of bronchoconstriction by 54% in athletes, ii) attenuated the rise in urinary CC16 (a marker of airway epithelial injury), and iii) inhibited the release of the mast-cell derived broncho-constrictive mediator prostaglandin (PG)Dz. These results suggest that local airway dehydration and mast cell activation have a key role in hyperpnoea-induced epithelial injury and bronchoconstriction in athletes. In our final study, using a newly developed mass spectrometry platform, we identified for the first time that exercise provocation is not solely associated with the release of potent broncho-constrictive mediators, such as PGD2 and thromboxane, but also with the release of the broncho-protective mediators PGE2 and PGI2. These results of naturally occurring broncho-protective agents in response to exercise open exciting new opportunities for drug development for ElB

Bronchoprovocation studies to define mechanisms in asthma and airway inflammation

Bronchial provocations with a variety of stimuli have been widely used over the past 70 years in both asthma research as well as in daily clinical praxis in order to aid the physician to establish the asthma diagnosis. In research, the bronchoprovocation model represents an excellent tool to better understand asthma pathophysiology, and to assess the effects of different interventions and new investigational therapies. Most of the currently approved asthma therapeutic options have shown efficacy in previous studies using the bronchoprovocation setting. In the current thesis, a range of bronchial provocations was performed prior to and after treatment with pharmacological interventions with different mode of actions. Responses were measured in the airways in the form of induced bronchoconstriction and airway inflammation (sputum cell counts), as well as in other matrices (skin, blood, urine). For the first time, it was shown that treatment with the combination of budesonide-formoterol (bud/form) in a single inhaler taken three to four times per week provided the same magnitude of protection against exercise-induced bronchoconstriction (EIB) as to regular treatment with a low dose of budesonide. Moreover, subjects who received monotherapy with the short acting β2 agonist (SABA) terbutaline had no protection against EIB over time. These results question the place of SABA monotherapy in asthma treatment even for subjects with mild asthma. It is recommended to replace SABA monotherapy with intermittent use of bud/form, which can also be an alternative option to regular treatment with low dose inhaled corticosteroids (ICS). Furthermore, using an allergen bronchoprovocation model, it was demonstrated that treatment with the second-generation anti-IgE monoclonal antibody QGE031 (ligelizumab) elicited an inhibition of the early allergic response (EAR) that was three times greater than what was achieved by the currently approved anti-IgE treatment with omalizumab. In addition, the data showed that there were important differences in the allergen response in the airways compared to the skin during QGE031 therapy; the highest dose of QGE031 consistently supressed allergen induced skin test responses that persisted six weeks after the last dose was given, while there was a variable effect on the airway response that did not last six weeks after the last dose. These results elucidate the complexity of the IgE pathway and the different kinetics and tissue responses to anti-IgE therapy. Finally, this thesis answered some important questions about the role of cysteinyl leukotrienes (CysLTs) and in particular leukotriene E4 (LTE4) in asthma. The data showed that treatment with the potent CysLT1 receptor antagonist montelukast completely abolished the bronchoconstriction elicited by LTE4 inhalation in subjects with mild asthma. Urine was collected during the LTE4 provocations for analysis of lipid mediator excretion, which led to the serendipitous discovery of increased urinary excretion of metabolites of prostaglandin (PG) D2, as well as other lipid mediators after LTE4 inhalation. These novel findings add a new dimension, namely that LTE4, in addition to a direct bronchoconstrictive action, can also activate both the mast cell as well as other cells to produce secondary responses that can amplify or modify its primary effect. Thus, this thesis demonstrates that carefully planned and conducted studies using bronchial provocations in combination with various pharmacological interventions, can elucidate important mechanisms in asthma pathogenesis and reveal potential new targets for treatmen

Airway inflammation in asthma : from concept to the clinic

Three aspects of airway inflammation in asthma were investigated in this thesis: proof of concept, monitoring and management. In chapter 2 is shown that IL-5 is mainly effective in the circulation. In chapter 3 is shown that steroids improve airway hyperresponsiveness, sputum eosinophils, and NO. The changes were not related. This suggests that these markers may provide different information when monitoring anti-inflammatory treatment in asthma. In chapter 4 is shown that alpha-2-macroglobulin is an appropriate marker for measuring microvascular leakage in sputum. This "dual induction" model may used when testing the antiexudative effect of drugs. Chapter 5 demonstrated that the annual decline in FEV1 is related with CD8+ cells. This suggests that inflammatory phenotypes in asthma may have prognostic relevance. In chapter 6 is shown that PEF-variability provides information about asthma severity. Therefore, the current guidelines for the treatment of asthma can be improved by including PEF-variability. In chapter 7 is shown that anti-IgE improves PEF, diminishes allergen responses and is paralleled by a reduction in eosinophils in biopsies and sputum and a decline in IgE+ cells. This suggests that the clinical benefits of anti-IgE in asthma may be explained by a decrease in eosinophilic inflammation and IgE bearing cells.LEI Universiteit LeidenStichting Longziekten Research GlaxoSmithKline BV AstraZeneca BV Stichting Astma BestrijdingPathogenese en behandeling van astm

Respiratory Control: Central and Peripheral Mechanisms

Understanding of the respiratory control system has been greatly improved by technological and methodological advances. This volume integrates results from many perspectives, brings together diverse approaches to the investigations, and represents important additions to the field of neural control of breathing. Topics include membrane properties of respiratory neurons, in vitro studies of respiratory control, chemical neuroanatomy, central integration of respiratory afferents, modulation of respiratory pattern by peripheral afferents, respiratory chemoreception, development of respiratory control, behavioral control of breathing, and human ventilatory control. Forty-seven experts in the field report research and discuss novel issues facing future investigations in this collection of papers from an international conference of nearly two hundred leading scientists held in October 1990. This research is of vital importance to respiratory physiologists and those in neurosciences and neurobiology who work with integrative sensory and motor systems and is pertinent to both basic and clinical investigations. Respiratory Control is destined to be widely cited because of the strength of the contributors and the dearth of similar works. The four editors are affiliated with the University of Kentucky: Dexter F. Speck is associate professor of physiology and biophysics, Michael S. Dekin is assistant professor of biological sciences, W. Robert Revelette is research scientist of physiology and biophysics, and Donald T. Frazier is professor and chairman of physiology and biophysics. Experts in the field report current research and discuss novel issues facing future investigations. —SciTech Book Newshttps://uknowledge.uky.edu/upk_biology/1002/thumbnail.jp

Towards restoring the physiological protection against airway narrowing in asthma : take a deep breath!

Asthma is characterized by chronic airway inflammation and airway hyperresponsiveness. Deep inspirations affect airway narrowing and may therefore play a role in airway hyperresponsiveness in asthma. The studies described in this thesis were all directed at further elucidating the (patho)physiological mechanism underlying deep inspiration-induced bronchodilation or to restoring this protective mechanism in asthma. We showed that deep inspiration-induced bronchodilation is reduced in asthma and that this reduction is related to increased numbers of CD4+ lymphocytes in the bronchial submucosa and to increased numbers of mast cells in airway smooth muscle bundles in bronchial biopsies. In addition, impaired deep inspiration-induced bronchodilation is related to lower expression of several smooth muscle proteins (calponin, desmin, and MLCK) in bronchial biopsies, whereas lung function and airway hyperresponsiveness wa s related to higher expression of alpha-SM-actin, desmin and elastin. Further, pulmonary congestion had no influence on airway responses to deep inspiration as measured in patients with mitral valve disease. A course of high-dose corticosteroid treatment increased bronchodilation following deep inspiration in patients with asthma, whereas treatment with tiotropium for 21 days had no effect on airway responses to deep inspiration. Positive-pressure inflation of the lungs reduced airway narrowing, even in patients who showed no airway dilation following an active deep inspiration.Nederlands Astma Fonds, Boehringer IngelheimUBL - phd migration 201