Role In Cough Research Articles

Chapter 14 - Neural control of the lower airways: Role in cough and airway inflammatory disease

Airway function is under constant neurophysiological control, in order to maximize airflow and gas exchange and to protect the airways from aspiration, damage, and infection. There are multiple sensory nerve subtypes, whose disparate functions provide a wide array of sensory information into the CNS. Activation of these subtypes triggers specific reflexes, including cough and alterations in autonomic efferent control of airway smooth muscle, secretory cells, and vasculature. Importantly, every aspect of these reflex arcs can be impacted and altered by local inflammation caused by chronic lung disease such as asthma, bronchitis, and infections. Excessive and inappropriate activity in sensory and autonomic nerves within the airways is thought to contribute to the morbidity and symptoms associated with lung disease.

Comparative effects of capsaicin in chronic obstructive pulmonary disease and asthma (Review).

Chronic obstructive pulmonary disease (COPD) and asthma are chronic respiratory diseases with high prevalence and mortality that significantly alter the quality of life in affected patients. While the cellular and molecular mechanisms engaged in the development and evolution of these two conditions are different, COPD and asthma share a wide array of symptoms and clinical signs that may impede differential diagnosis. However, the distinct signaling pathways regulating cough and airway hyperresponsiveness employ the interaction of different cells, molecules, and receptors. Transient receptor potential cation channel subfamily V member 1 (TRPV1) plays a major role in cough and airway inflammation. Consequently, its agonist, capsaicin, is of substantial interest in exploring the cellular effects and regulatory pathways that mediate these respiratory conditions. Increasingly more studies emphasize the use of capsaicin for the inhalation cough challenge, yet the involvement of TRPV1 in cough, bronchoconstriction, and the initiation of inflammation has not been entirely revealed. This review outlines a comparative perspective on the effects of capsaicin and its receptor in the pathophysiology of COPD and asthma, underlying the complex entanglement of molecular signals that bridge the alteration of cellular function with the multitude of clinical effects.

Wall shear stress distribution in a compliant airway tree

The airflow in the bronchi applies a shear stress on the bronchial mucus, which can move the mucus. The air–mucus interaction plays an important role in cough and in chest physiotherapy (CP). The conditions under which it induces a displacement of the mucus are still unclear. Yet, the air–mucus interaction justifies common technics of CP used to help the draining of the mucus in prevalent diseases. Hence, the determination of the distribution of the shear stress in the lung is crucial for understanding the effects of these therapies and, potentially, improves their efficiency. We develop a mathematical model to study the distribution of the wall shear stress (WSS) induced by an air flow exiting an airway tree. This model accounts for the main physical processes that determine the WSS, more particularly the compliance of the airways, the air inertia, and the tree structure. We show that the WSS distribution in the tree depends on the dynamics of the airways deformation and on the air inertia. The WSS distribution in the tree exhibits a maximum whose amplitude and location depend on the amount of air flow and on the “tissue” pressure surrounding the airways. To characterize the behavior of the WSS at the tree bifurcations, we derive new analytical criteria related to the airway size reduction in the bifurcations. Our results suggest that a tuning of the airflow and of the tissue pressure during a CP maneuver might allow to control, at least partially, the air–mucus interaction in the lung.

A role for neurokinin 1 receptor expressing neurons in the paratrigeminal nucleus in bradykinin-evoked cough in guinea-pigs.

Airway projecting sensory neurons arising from the jugular vagal ganglia terminate centrally in the brainstem paratrigeminal nucleus, synapsing upon neurons expressing the neurokinin 1 receptor. This study aimed to assess the involvement of paratrigeminal neurokinin 1 receptor neurons in the regulation of cough, breathing and airway defensive responses. Lesioning neurokinin 1 receptor expressing paratrigeminal neurons significantly reduced cough evoked by inhaled bradykinin but not inhaled ATP or tracheal mechanical stimulation. The reduction in bradykinin-evoked cough was not accompanied by changes in baseline or evoked respiratory variables (e.g. frequency, volume or timing), animal avoidance behaviours or the laryngeal apnoea reflex. These findings warrant further investigations into targeting the jugular ganglia and paratrigeminal nucleus as a therapy for treating cough in disease. Jugular vagal ganglia sensory neurons innervate the large airways and are thought to mediate cough and associated perceptions of airway irritations to a range of chemical irritants. The central terminals of jugular sensory neurons lie within the brainstem paratrigeminal nucleus, where postsynaptic neurons can be differentiated based on the absence or presence of the neurokinin 1 (NK1) receptor. Therefore, in the present study, we set out to test the hypothesis that NK1 receptor expressing paratrigeminal neurons play a role in cough evoked by inhaled chemical irritants. To test this, we performed selective neurotoxin lesions of NK1 receptor expressing neurons in the paratrigeminal nucleus in guinea-pigs using substance P conjugated to saporin (SSP-SAP). Sham lesion control or SSP-SAP lesion guinea-pigs received nebulised challenges, with the pan-nociceptor stimulant bradykinin or the nodose ganglia specific stimulant adenosine 5'-triphosphate (ATP), in conscious whole-body plethysmography to study cough and associated behaviours. Laryngeal apnoea reflexes and cough evoked by mechanical stimulation of the trachea were additionally investigated in anaesthetised guinea-pigs. SSP-SAP significantly and selectively reduced the number of NK1 receptor expressing neurons in the paratrigeminal nucleus. This was associated with a significant reduction in bradykinin-evoked cough, but not ATP-evoked cough, mechanical cough or laryngeal apnoeic responses. These data provide further evidence for a role of jugular vagal pathways in cough, and additionally suggest an involvement of NK1 receptor expressing neurons in the paratrigeminal nucleus. Therefore, this neural pathway may provide novel therapeutic opportunities to treat conditions of chronic cough.

Treatment for Cough: Two Sides to the Story

The role of cough is of interest to speech-language pathologists (SLPs) for two seemingly contradictory reasons: chronic, excessive cough and insufficient cough. Evidence supports the role of the SLP in behavioral strategies for both the reduction and/or elimination of chronic cough, as well as the use of pulmonary exercise to realize improved airway clearance in individuals with a weak, insufficient cough. At both ends of this continuum, anchored at one end by too much coughing and the other end anchored by inadequate cough for airway clearance/pulmonary health, the SLP has an important role.

Effect of Aging on Cough and Swallowing Reflexes: Implications for Preventing Aspiration Pneumonia

The impairment of airway protective reflexes, i.e., swallowing and cough reflexes, is thought to be one of the major causes for aspiration pneumonia in older people. Restoration of cough and swallowing reflexes in the elderly is key to preventing aspiration pneumonia in the elderly. Although, the medical literature has asserted that cough and swallowing are controlled primarily by the brainstem, recent advances in human brain imaging has provided evidence that cortical and subcortical structures play critical roles in cough and swallowing control. Because of their nature, reflexive cough and swallowing activate both sensory and motor areas in the cortex. In both protective reflexes, the sensory component, including sensory cortex in reflexive circuits, seems to be more vulnerable to aging than the motor component, including the motor cortex. Therefore, the strategy to restore cough and swallowing reflexes should be focused on compensations of sensory components in these reflexive circuits. Remedies to enhance sensory nerve terminals and sensory cortical areas related to these reflexes might be useful to prevent aspiration pneumonia in the elderly.

Pharmacologic therapy for cough

Cough is the commonest symptom for which patients seek medical care and yet effective, well-tolerated cough medicines remain a significant unmet clinical need. The development of anti-tussive agents has probably been restricted by a number of factors; our understanding of the specific mechanisms evoking cough in different diseases and how this differs from the role of cough as a protective reflex is limited. Also well-validated tools for the assessment of cough have been lacking. These issues have not encouraged investment by the pharmaceutical industry and there have been no new licensed treatments for cough in more than 50 years. This article will use a mechanism-based approach to discuss the clinical evidence for the anti-tussive activity of currently available agents.

TRPV1 antagonists attenuate antigen-provoked cough in ovalbumin sensitized guinea pigs

We examined the molecular pharmacology and in vivo effects of a TRPV1 receptor antagonist, N-(4-Tertiarybutylphenyl)-4(3-cholorphyridin-2-yl)-tetrahydro-pyrazine1(2H) – carboxamide (BCTC) on the guinea pig TRPV1 cation channel. BCTC antagonized capsaicin-induced activation and PMA-mediated activation of guinea pig TRPV1 with IC50 values of 12.2 ± 5.2 nM, and 0.85 ± 0.10 nM, respectively. In addition, BCTC (100 nM) completely blocked the ability of heterologously expressed gpTRPV1 to respond to decreases in pH. Thus, BCTC is able to block polymodal activation of gpTRPV1. Furthermore, in nodose ganglia cells, capsaicin induced Ca2+ influx through TRPV1 channel was inhibited via BCTC in a concentration dependent manner. In in vivo studies capsaicin (10 – 300 μM) delivered by aerosol to the pulmonary system of non-sensitized guinea pigs produced an increase in cough frequency. In these studies, the tussigenic effects of capsaicin (300 μM) were blocked in a dose dependent fashion when BCTC (0.01–3.0 mg/kg, i.p.) was administered 30 minutes before challenge. The high dose of BCTC (3.0 mg/kg, i.p) produced a maximum inhibition of capsaicin-induced cough of 65%. We also studied the effects of BCTC (0.03 and 3.0) when administered 60 minutes before capsaicin. Under these conditions, BCTC (3.0 mg/kg, i.p) produced a maximum decrease in capsaicin-induced cough of 31%. In ovalbumin passively sensitized guinea pigs, we found that BCTC (1 and 3 mg/kg, i.p.) attenuated antigen ovalbumin (0.3%) cough responses by 27% and 60%, respectively. We conclude that TRPV1 channel activation may play role in cough mediated by antigen in sensitized guinea pigs. Our results supports increasing evidence that TRPV1 may play a role in the generation of the cough response.

Spontaneous fracture of the lower angle of scapula. Possible role of cough

We report a case of a fracture of the inferior angle of the scapula related to prolonged cough, without triggering trauma, sport, or occupational activity. Bone insufficiency was present in this patient. Stress fractures of the scapula are rare; the fatigue type is the most frequent, associated with sports or occupational activity. We do not find any published case report about scapula stress fracture related to cough, until rib fractures are frequent in this situation. Repetitive muscular activity of the serratus anterior and major rhomboid on the inferior angle of the scapula during cough may explain this avulsion fracture.

Effects of amlodipine, nifedipine GITS, and indomethacin on angiotensin-converting enzyme inhibitor-induced cough: A randomized, placebo-controlled, double-masked, crossover study

Prostaglandins (PGs) are thought to play a role in the genesis of cough induced by angiotensin-converting enzyme (ACE) inhibitors, whereas inhibition of PG synthesis can reduce or abolish the incidence of this side effect. Experimental and clinical data suggest that nifedipine, a dihydropyridine calcium channel blocker, can inhibit PG synthesis. Therefore, the aim of the present study was to determine whether treatment with amlodipine would also reduce cough induced by an ACE inhibitor and to compare the efficacy of amlodipine with that of indomethacin, a known inhibitor of PG synthesis. Thirty-three patients with hypertension who developed cough during chronic benazepril therapy were allocated randomly to receive slow-release nifedipine gastrointestinal therapeutic system (GITS) 30 mg once daily, amlodipine 5 mg once daily, indomethacin 50 mg twice daily, or placebo twice daily for 2 weeks. This was according to a double-masked, double-dummy, crossover, Latin square design. At the end of each phase, cough was assessed by means of a self-administered questionnaire with an ordinal 10-point visual analogue scale for rating daily cough intensity and frequency. Indomethacin eliminated or markedly reduced cough induced by the ACE inhibitor, whereas nifedipine GITS and amlodipine reduced it to a lesser degree. These findings suggest that PGs play a role in cough caused by ACE inhibitors and that a dihydropyridine calcium channel blocker can reduce the occurrence of this side effect.

Cough, its pathology and management

1. 1. Importance of cough as a symptom as viewed both from the health and economic standpoint is stressed. Pathology of the cough mechanism is simplified by describing the causes and effects of harmful and helpful coughs. Pathways of the cough reflexes are described. Tussal insufficiency and tussive syncope are discussed. 2. 2. Surgical intervention, physiotherapy and postoperative prevention of atelectasis are discussed with reference to cough. The role of cough in emphysema is described. Common colds, “air conditioning” and the lack of acclimatization of the respiratory mucous membrane as a cause of cough are discussed. 3. 3. Drug therapy including morphine and its derivatives is described. Bronchocatharsis and the use of such drugs as potassium iodide, ammonium chloride and others are described in detail. A few of the common combinations of cough remedies are listed. The use of antispasmodic drugs and gases, including the use of carbon dioxide, is enumerated. Positive-negative oxygen therapy in chronic pulmonary disease is reviewed and emphasized. Inhalations and aerosols are evaluated, and newer liquefying aerosol combinations are described. Oils and antihistaminic drugs are discussed. 4. 4. Radiation therapy and “teaching the patient” are discussed in detail.