Inflammatory Cells and Mediators in Bronchial Asthma

Devendra K. Agrawal, Robert G. Townley

• Publisher: CRC Press
• Year: 2020
• eBook ISBN: 9781000142068
• Edition: 1
• Topic: Medicina
• Subtopic: Inmunología

Inflammatory Cells and Mediators in Bronchial Asthma provides reviews and summaries regarding state-of-the-art articles that examine the role of various inflammatory cells and their mediators in the pathogenesis of asthma. Topics include pharmacological and biochemical regulation of the airways; involvement of key inflammatory cells and the release and effect of their mediators in airway function; and the characteristics of receptors for leukotriene B4, C4, and D4, adenosine, platelet-activating factor, sensory and inflammatory peptides, and the effect of various anti-asthmatic drugs on airway inflammation. Physicians, allergists, immunologists, and pulmonary disease research scientists will find this book to be an invaluable reference resource.

Chapter 1

PHARMACOLOGICAL AND BIOCHEMICAL CHANGES IN AIRWAY SMOOTH MUSCLE IN RELATION TO BRONCHIAL HYPERRESPONSIVENESS

Herman Meurs and Johan Zaagsma

TABLE OF CONTENTS

I. Introduction

II. Stimulus-Response Coupling in Airway Smooth Muscle

III. Bronchial Hyperresponsiveness and Human Airway Smooth Muscle Changes

A. Pharmacological Studies

1. Nonasthmatic Patients

2. Asthmatic Patients

B. Biochemical Studies

IV. Mechanisms of Altered Airway Smooth Muscle Responsiveness

A. Inflammation and Bronchial Hyperresponsiveness

B. Allergic Mechanisms

1. Bronchial Hyperresponsiveness In Vivo

2. Contractile Responses In Vitro

3. ß-Adrenoceptor Function In Vitro

a. Animal Studies

b. Human Blood Cell Studies

c. Role of Cross-Talk Between Phosphoinositide Metabolism and ß-Adrenoceptor System in Airway Smooth Muscle

C. Infections

1. Viral Infections

2. Bacterial Infections

D. Airway Irritants

E. ß-Agonist Drugs

V. Conclusions

Acknowledgments

References

I. INTRODUCTION

Bronchial hyperresponsiveness to physical, chemical, and pharmacological stimuli (such as mist, cold air, SO₂, histamine, and methacholine) is a common characteristic of patients with asthma and chronic obstructive pulmonary disease (COPD).^1–5 There is a close correlation between the degree of bronchial responsiveness to histamine or methacholine and the severity of asthmatic symptoms,⁵ and bronchial hyperresponsiveness is regarded as a risk factor for the development of chronic airflow obstruction.⁶ Patients with asthma and those with COPD have quantitatively and qualitatively different responses to inhaled stimuli,^2–4 which suggests that there may be differences in the pathogenic mechanisms of hyperresponsiveness in the different groups. The mechanisms that cause either type of hyperresponsiveness are, not clear, however. Family⁷ and twin⁸ studies have provided some evidence that genetic factors may play a role in the development of bronchial hyperresponsiveness. However, it is obvious that environmental factors, such as exposure to allergens,^9,10 viral infections,¹¹ and airway irritants (ozone,¹² toluene diisocyanate,¹³ cigarette smoke¹⁴), may greatly influence this responsiveness, presumably by inflammation of the airways.^15,16

Since the bronchial response to inhaled stimuli depends on a variety of biophysical and biochemical events, it is reasonable to expect that hyperresponsiveness can be produced by abnormalities at a number of different levels. The rapid time course of the airway narrowing observed during challenge tests, as well as the rapid response to bronchodilators, suggest that the abnormal responses are related to smooth muscle shortening. In the first instance, smooth muscle shortening is determined by the delivery of agonists via the airways, from cells surrounding the muscle, from the circulating blood, or from nerve endings. Second, the amount of shortening is determined by the stimulus-response coupling in the muscle, the smooth muscle length-tension characteristics, and the relationship between the amount of airway smooth muscle and the load that the muscle has to overcome during the shortening process. Finally, the effect that airway smooth muscle shortening will have on the airway caliber depends on geometric factors such as thickness of the mucosa and the presence of secretions in the airway lumen.¹⁷ Thus, abnormalities that may be involved in bronchial hyperreactivity are abnormalities in the neurogenic,¹⁸ humoral,¹⁹ or paracrine²⁰ control of airway smooth muscle function, physical alterations in the airways (such as epithelial damage,^20,21 reduced elastic recoil,¹⁷ or reduced airway caliber,¹⁷ and, finally, pharmacological, biochemical, and biophysical alterations in the smooth muscle itself.^17,22–25

Due to a number of practical and technical limitations, very little is known about airway smooth muscle alterations in relation to bronchial hyperresponsiveness. Measurements of human airway smooth muscle tone in vivo are indirect because they employ techniques that measure changes in indices of airway diameter, such as maximal expiratory flow rates and airway resistance. However, airway narrowing in response to a given stimulus depends not only on airway smooth muscle activation, but also on several other factors, as indicated above. In addition, the deep inspiration preceding measurements of maximal expiratory flow rate can abolish a preexisting airway narrowing, while airway resistance measurements are largely insensitive to narrowing of peripheral airways.¹⁷ Therefore, in vitro studies on isolated tissue are obviously indicated for the investigation of airway smooth muscle abnormalities in relation to bronchial hyperresponsiveness.

On the other hand, human airway smooth muscle studies in vitro are hampered by the scarce supply of appropriate tissue. Lung tissue is usually obtained from surgery for lung cancer. Although during the last few years this has lead to a reasonable amount of information on the pharmacology of airway smooth muscle from patients with COPD,²⁶ pharmacological information on the group of relatively young asthmatic patients by this procedure is only slowly accumulating. In addition, a number of methodological difficulties are met in the in vitro studies, such as tissue heterogeneity, which is most pronounced in parenchymal strips,²⁷ and the uncertainty about the most appropriate method of assessing in vitro smooth muscle function. Thus, most studies have measured smooth muscle function under conditions of isometric tension. However, in vivo airway narrowing involves shortening of muscle, and it is possible that an assessment of isotonic shortening of smooth muscle was more relevant to the in vivo conditions, although the differences between both methods appear to be small.²⁸ In addition, because length-tension characteristics of airway smooth muscle in vivo are unknown, it is unclear what are the most appropriate length-tension conditions to use in vitro.

Another important aspect of the in vitro studies is the expression of the pharmacological responses in terms of sensitivity (pD₂) and maximal response. The in vivo airway dose-response curves for bronchoconstricting stimuli in mild asthmatic patients are characterized both by a leftward shift and by an increased maximal response.²⁹ This suggests that both alterations in the sensitivity of the smooth muscle for contractile and relaxant agonists (for instance, by a change in affinity of the receptors) and the maximal response to these agonists (for example, due to post-receptor changes in the stimulus-response coupling) may be involved. However, due to technical problems in assessing reproducible maximal responses,³⁰ most in vitro studies have focused on the sensitivity of the airway smooth muscle to the different agonists, which precludes drawing conclusions about the maximal ...

Table of contents

• Cover
• Title Page
• Copyright Page
• Dedication
• Series Page
• Table of Contents
• Series Preface
• Preface
• The Editors
• Contributors
• 1. Pharmacological and Biochemical Changes in Airway Smooth Muscle in Relation to Bronchial Hyperresponsiveness
• 2. Calcium Homeostatic Pumps in Asthma
• 3. Mast Cell Mediators and Their Effect on Airway Smooth Muscle
• 4. Effect of Neutrophils on Airway Smooth Muscle Responsiveness
• 5. Macrophages and Their Potential Role in Hyperreactive Airways Disease
• 6. Role of Platelets in Altered Airway Responsiveness
• 7. Eosinophils in Airway Hyperresponsiveness
• 8. The Autacoid Functions of Adenosine in Asthma
• 9. Leukotriene Receptors in the Airways
• 10. Platelet-Activating Factor Receptors in the Airways
• 11. Sensory and Inflammatory Peptide Receptors in Airways
• 12. The Airway and Vasoactive Intestinal Peptide Autoantibodies and Receptors
• 13. The Effect of Antiasthmatic Drugs on Airway Hyperresponsiveness and Inflammation
• Index