Physiological and pathophysiological down-regulation of cough

Abstract

Recent clinical studies have emphasized the up-regulation (sensitization) of cough in pathological conditions of the airways. However there are also many situations where voluntary and reflex cough can be down-regulated. These include: (1) chemical stimulation of breathing by hypercapnia or hypoxia or both, establishing that cough sensitivity can be inversely related to drive to breathing; (2) voluntary inhibition of cough, probably similar in mechanism to the depression of cough that can be induced by hypnosis and other branches of alternative medicine; (3) the placebo effect of many antitussive treatments; (4) sleep; (5) general anaesthesia; (6) central nervous disorders such as coma, stroke, Parkinson's disease and several other conditions where the defect in the protective reflexes may lead to aspiration pneumonia; (7) increased activity in various afferent inputs from viscera in the thorax and abdomen; (8) a number of bronchopulmonary clinical disorders. The list is long, but regrettably the nervous mechanisms of these down-regulations have been little studied. In addition there are a number of situations, such as exercise, coitus, talking and singing which, while important to coughing humans, have been not investigated in relation to cough. Most of the studies have been with experimental animals, and their extension to human research is desirable. In view of the importance of cough and other defensive reflexes in maintaining human well-being, far more research is needed. The field is wide-open.

Introduction

Until a few years ago, cough was regarded as a rather stereotyped response to physical and chemical irritant stimuli in the larynx and lower respiratory tract. Its enhancement in airway diseases was considered as an excitatory reaction to the presence of various chemical and physical stimulants released by disease processes. Our understanding of cough has recently been transformed by two main approaches: an increased understanding of the complex sensory mechanisms of nervous sensory receptors in the airway walls that induce cough, and the discovery that the cough reflex strongly exhibits plasticity, induced physiologically or pathologically, at sensory receptor, afferent ganglion and central nervous levels. These major advances in our understanding of increased sensitivity of cough have been abundantly reviewed (e.g. Widdicombe, 1996a, Widdicombe, 1996b, Korpas and Widdicombe, 2002, Chung et al., 2003, Chung and Widdicombe, 2004) and will not be considered further here.

The importance of sensitization of cough in disease is obvious, but its obverse has been neglected. If cough can be sensitized it can also, at least in theory, be desensitized. This review deals with how cough can be down-regulated. There is a brief review of the topic (Fontana and Widdicombe, 2004). If the arguments for down-regulation are convincing, then not only might they tell us about the pathophysiological mechanisms of cough, but they should point to possible therapeutic approaches. There is an analogy with hyper-reactivity of airway smooth muscle. If many in the population are hyper-reactive, an approximately similar number should be hyporeactive; these subjects have been little studied but their investigation might have much scientific interest and prognostic value.

Cough is defined as a deep inspiration followed by a forced expiration initially against a closed glottis, after which the glottis opens and the expulsive phase of cough occurs. It can be induced primarily from the laryngo-pharyngeal region and the tracheobronchial tree. It is not the same as the expiration reflex which consists of isolated expiratory efforts caused by irritation of the vocal folds (Korpas and Tomori, 1979, Korpas and Jakus, 2000, Nishino, 2000, Nishino, 2002) or the trachea (Widdicombe, 1954, Nishino and Honda, 1986, Nishino et al., 1996), or as the glottal closure reflex caused by the same laryngeal stimuli. All three reflexes are part of the defensive reflex system of the respiratory tract, and all three show striking differences in their regulation. A cough bout or attack may consist of a cough followed by expiratory efforts; conversely, when the larynx is stimulated the response may be an expiratory effort followed by coughs. While this review will concentrate on the cough reflex, the other reflexes, especially the expiration reflex, will be considered where relevant since they all play a major part in defending the lower airways and lungs. Cough is a complex motor act, and its different components, cough frequency, cough effort (intensity), and the balance between inspiratory and expiratory components show different regulatory processes which are often neglected (Fontana et al., 1998, Fontana et al., 1999, Fontana et al., 2002). Induction of cough is also associated with respiratory sensation and the ‘urge-to-cough’, and these parts of the cough mechanism will also be considered.

The sensitivity of the cough reflex varies with age and gender. Fetuses and the newborn, especially if premature, have a weak or even absent cough and laryngeal expiration reflexes; the apnoeic and glottal closure reflexes are strong, however (Lee et al., 1977, Javorka et al., 1980, Javorka et al., 1985, Boggs and Bartlett, 1982, Davies et al., 1989, Thach, 2001). Similarly in old age the cough reflex decreases in strength (Newnham and Hamilton, 1997). Females have a more sensitive and stronger cough response to inhaled irritants than do males (Kastelik et al., 2002, Nieto et al., 2003, Dicpinigaitis et al., 2001). Since these are not examples of down-regulation they will not be considered further, although they should be borne in mind; taking account of them may lessen the scatter of results, the bugbear of cough investigations.

The most obvious way to down-regulate cough is to give antitussive drugs, on which there is an enormous literature; while obviously relevant to the subject of this review, for reasons of space they will not be considered further here.

Table 1 summarizes the main ways, established or postulated, that cough can be down-regulated.