Airway hyperresponsiveness (AHR) is one of the hallmarks of asthma, which is defined as a chronic inflammatory disorder of the airways associated with reversible airway obstruction and increased sensitivity and reactivity of the airways to various stimuli. AHR is a key feature of asthma diagnosis and severity, and it is also a target for asthma treatment. However, the exact mechanisms underlying AHR are still not fully understood, and they involve a complex interplay of inflammatory, neural, mechanical and genetic factors.
Inflammation and AHR
It is widely accepted that inflammation plays a major role in the pathogenesis of asthma and AHR. Inflammation causes airway edema, mucus hypersecretion, plasma leakage and infiltration of inflammatory cells such as eosinophils, mast cells, T cells and macrophages. These cells release various mediators such as histamine, leukotrienes, cytokines and chemokines that can directly or indirectly affect the airway smooth muscle (ASM) tone and contractility. Inflammation also induces structural changes in the airway wall, such as fibrosis, smooth muscle hypertrophy/hyperplasia and epithelial damage, which can alter the mechanical properties of the airways and contribute to AHR.
However, inflammation alone cannot fully explain the development and persistence of AHR in asthma. There is not always a clear correlation between the degree of inflammation and the level of AHR in asthmatic patients. Moreover, some anti-inflammatory treatments such as corticosteroids can reduce inflammation but not AHR in some cases. Therefore, other factors besides inflammation must be involved in the regulation of AHR.
Neural and Mechanical Factors
The ASM tone is also modulated by neural mechanisms that can either increase or decrease the ASM contraction. The sympathetic nervous system releases noradrenaline that binds to beta-2 adrenergic receptors on the ASM and causes relaxation. The parasympathetic nervous system releases acetylcholine that binds to muscarinic receptors on the ASM and causes contraction. The balance between these two systems determines the baseline ASM tone and reactivity.
In addition, there are sensory nerves that innervate the airways and can sense mechanical or chemical stimuli. These nerves can trigger reflexes that affect the ASM tone or secretion of mucus or inflammatory mediators. For example, the cough reflex is mediated by sensory nerves that detect irritants in the airways and activate motor nerves that cause ASM contraction and expiratory muscle activation.
The mechanical properties of the airways also influence the ASM tone and reactivity. The airways are surrounded by elastic tissues that provide a passive recoil force that opposes the ASM contraction. The airway diameter also affects the ASM length-tension relationship, which determines how much force the ASM can generate at a given length. The lung volume also affects the transmural pressure gradient across the airway wall, which determines how much force is needed to overcome the external pressure on the airways.
These mechanical factors can modulate the AHR in asthma by changing the load on the ASM or altering its sensitivity to stimuli. For example, deep inspiration can stretch the ASM and reduce its contractility, thus attenuating AHR. Conversely, shallow breathing or bronchoconstriction can shorten the ASM and increase its contractility, thus enhancing AHR.
Asthma and AHR are also influenced by genetic factors that can affect various aspects of the disease such as susceptibility, severity, phenotype and response to treatment. Several genes have been identified that are associated with asthma or AHR in different populations. Some of these genes encode for proteins involved in inflammation, such as cytokines, chemokines, receptors or enzymes. Others encode for proteins involved in neural or mechanical regulation of ASM tone, such as receptors, ion channels or cytoskeletal components.
One example of a gene that has been linked to asthma and AHR is DENND1B, which encodes for a protein involved in endocytosis and vesicle trafficking. Mutations in this gene have been shown to increase the risk of developing asthma and AHR in children. According to KnowYourAsthma.com, these mutations lead to overproduction of cytokines that subsequently drive an oversensitive response in asthma patients.
Airway hyperresponsiveness in asthma is a complex and multifactorial phenomenon that results from an interaction between inflammatory, neural, mechanical and genetic factors. Understanding these factors can help to improve the diagnosis, treatment and prevention of asthma and AHR.