Elsevier

Medical Hypotheses

Volume 74, Issue 4, April 2010, Pages 661-664
Medical Hypotheses

Increased parasympathetic tone as the underlying cause of asthma: A hypothesis

https://doi.org/10.1016/j.mehy.2009.11.011Get rights and content

Summary

Asthma is a chronic inflammatory disease of airways that is characterized by increased responsiveness of the tracheo-bronchial tree to multiple number of stimuli. Immunological theory does not explain all features in asthma, for example hyper-reactivity of the airways. Neurogenic theory also fails to explain the pathogenesis of asthma comprehensively. Higher parasympathetic tone has been reported in asthmatics but has never been suggested as a major underlying cause of asthma. This article attempts to explain the occurrence of hyper-responsiveness, inflammatory/allergic reactions and broncho-constriction in asthma on a common basis of inherent higher parasympathetic tone in asthmatics. The higher background parasympathetic firing leads to increased nitric oxide (NO) production owing to its co-localization with acetylcholine (ACh) in inhibitory non-adrenergic and non-cholinergic (i-NANC) nerves. NO is a neurotransmitter of i-NANC system and it mediates bronchodilation. Increased NO release has been found to be responsible for hyper-responsiveness and increased inflammation in the airways. The authors suggest that an inherently higher background parasympathetic tone in concert with inflammation or a specific genetic background could modify the effects of NO on lung homeostasis in humans leading to increased susceptibility to an asthmatic state.

Introduction

Asthma is defined as “A chronic inflammatory disorder of the airways in which many cells play a role: particularly mast cells, eosinophils, and T lymphocytes. In susceptible persons, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night and in the early morning. These symptoms are usually associated with widespread but variable airflow limitation that is at least partly reversible, either spontaneously or with treatment” [1].

An important feature of asthma is an exaggerated broncho-constrictor response to a wide variety of stimuli. This airway hyper-responsiveness can be attributed in part to airway inflammatory response as airway markers of inflammation correlate with bronchial hyper-responsiveness but at the same time anti-inflammatory therapy, which reduced airway hyper-responsiveness, did not abolish it [2]. Thus, other factors in addition to inflammation may contribute to airway hyper-responsiveness.

Section snippets

Pathogenesis of asthma

Asthma is a complex disorder as various factors interact and influence its expression in patients. Factors that influence the risk of asthma could be host factors (which are primarily genetic) and environmental factors (like allergens, infections, occupational sensitizers, smoking, air Pollution, diet, etc.) that trigger asthma symptoms [1]. However, the mechanisms whereby they influence the development and expression of asthma are complex and interactive.

Airway narrowing is the final common

Evidences of increased parasympathetic tone in asthmatics

The parasympathetic nerves, innervating airways, are tonically active producing a stable, readily reversible baseline tone of the airway smooth muscles [13] which can be abolished by atropine or ipratropium bromide infusion [14], [15], which forms the basis of clinically observed improvement in asthmatic symptoms. Electrophysiological recordings from both preganglionic and post-ganglionic parasympathetic nerve fibres also confirm the existence of a persistent outflow of parasympathetic activity

Higher parasympathetic tone releases increased amounts of nitric oxide

The dysfunction in α, β and M2 receptors, although held responsible for increased background parasympathetic tone in several studies [26], [27], appears to be acquired secondarily rather than a primary defect [28], [29], [30].

Different frequencies of stimulation may have different profiles of secretion from parasympathetic nerves [31]. In general the “conventional” neurotransmitters, ACh and norepinephrine (NE), have greater quantities released at lower firing frequencies and the neuropeptides

Role of nitric oxide in airways

Nitric oxide (NO) is a ubiquitous intercellular messenger being synthesized from l-arginine by NO synthases (NOS) [34]. There are three isoforms of NOS; type I (neuronal), type II (inducible), and type III (endothelial). Among the three distinct NOS isoforms, NOS1 and NOS3 are constitutively active, exhibiting rapid responses to a small amount of NO, while NOS2 is constitutively expressed in the human airway epithelium and inflammatory cells (including macrophages) and is further up-regulated

Nitric oxide and inflammatory response

NO in the airways is also considered as a potent inflammatory factor and is thought to generate and perpetuate airway inflammation in asthmatic subjects [46] and elevated levels of NO in exhaled breath may reflect ongoing inflammation in airways [47], [48]. NO reacts rapidly with superoxide anions to form the potent cytotoxic species peroxynitrite anion which is potentially injurious to the airways [49], [50], [51]. NO may have effects on a myriad of cell functions and has been shown to damage

Higher parasympathetic tone as underlying cause: the hypothesis

The enhanced parasympathetic activity is an important factor in the pathogenesis of bronchial asthma. Kallenbach et al. demonstrated a definite relationship between the magnitude of respiratory sinus arrhythmia and the degree of bronchial hyper-reactivity in a group of asthmatic patients and suggested that the bronchial hyper-reactivity, a characteristic of asthma, may be related to enhanced parasympathetic nervous activity [56].

Yazar et al. suggested that asthma and irritable bowel syndrome

Implications

The susceptibility to asthma could become a recognizable trait, which can be evaluated with non-invasive electrophysiological studies of parasympathetic activity. Studies report a higher parasympathetic tone in asthmatics but none of the studies, till present; have been directed towards studying autonomic balance in subjects susceptible for asthma (having family history of allergic diseases). Well-designed prospective studies in this regard could clear the doubts regarding the pathogenesis of

Conclusions

Thus higher parasympathetic firing leading to increased NO production can describe neurogenic as well as immunologic events taking place in the pathogenesis of asthma. It is proposed that higher background parasympathetic tone in concert with inflammation or a specific genetic background could modify the effects of NO on lung homeostasis in human, giving rise to hyper-responsiveness and other features seen in asthma.

Conflicts of interest statement

None declared.

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