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.
Chronic obstructive pulmonary disease (COPD) and asthma are two common respiratory diseases with distinct pathophysiology that share some clinical features such as cough, shortness of breath, and wheezing, making differential diagnosis an essential step in their management (
COPD is one of the most common causes of death, an important chronic morbidity, and is characterized by persistent respiratory symptoms and airflow limitation due to anomalies of the airways and/or alveolae caused by exposure to toxic particles or gases (
Capsaicin, the most pungent substance in chilli peppers, is an intensely studied molecule, with many applications in various diseases due to its anti-inflammatory and antitumoral properties (
Intensely studied in various conditions and on different experimental models, in the respiratory system, capsaicin has demonstrated great pleomorphism in its actions and is closely involved in triggering an abundance of signaling pathways, at times showing converse effects in pathological situations (
While capable of inducing direct effects, most of capsaicin's actions are mediated through its receptor, TRPV1. TRPV1 is a non-selective receptor that structurally belongs to the TRP family of ion channels. Besides capsaicin, it may be activated by different factors such as high temperature, acidity (pH <6.0), endocannabinoids, endogenous lipids, and other potential activators, such as numerous mediators of inflammation or various neurotransmitters (
TRPV1 may be activated by various ligands, including derivates of ployunsaturated fatty acids, oxytocin, neurotransmitters, chalcone derivatives, and cannabinoids (
The activation of TRPV1 has demonstrated a variety of effects (
TRPV1 may mediate cough (
Within the respiratory system, identical signaling pathways regulate the onset of cough, bronchoconstriction, and airway narrowing, while also enhancing the sensation of irritation as well as fluid secretion. Stimulation of airway neurons may have favorable or unfavorable effects. It was reported that it might contribute to airway protection, disposing of chemical irritants and pathogens that cause infections, while preserving and initiating tissue recovery and favoring the immune responses in murine models (
Inhaled capsaicin is the main agent for the measurement of cough reflex sensitivity because of a lack of side effects when properly administered, low price, and good correlation with the presence or absence of pathological cough. A review from 2005 that contained 122 published studies (1984-2005) on 4.833 subjects, including healthy subjects, patients with COPD, asthma, and other diagnoses, did not manage to isolate a single serious adverse effect of inhaled capsaicin in controlled conditions when using regulated concentrations (
Asthmatics without cough could not be differentiated from healthy individuals after the capsaicin cough challenge. Moreover, it was demonstrated that hyperresponsiveness of airways and cough were mediated through different neural pathways (
In an
Long-term respiratory effects after exposure to capsaicin aerosols were analyzed in several major studies. Two studies showed no difference between hot pepper workers and healthy individuals in regard to their pulmonary function (
Two decades of experience with capsaicin demonstrated that the capsaicin cough challenge is a safe investigation, and this procedure may prove to be an extremely important tool for future research.
The effects of capsaicin on mucus secretion in COPD and asthma were also investigated.
Dyspnea is a common respiratory symptom in both COPD and asthma, however, it has different attributes. In COPD, dyspnea is progressive and proportional to the airflow obstruction, while in asthma it appears simultaneously with the transitory bronchoconstriction (
Smoking is a major causative and aggravating factor in lung inflammation. However, acute and chronic infection, whether viral, bacterial, or fungal, may influence the prognosis of these patients and their response to treatment (
COPD is one of the leading causes of death and an important chronic morbidity featuring limitation of airflow, cough, mucus hypersecretion, and dyspnea. It is caused by long-term exposure to toxic particles or gases, usually tobacco smoke, and may sometimes affect patients with various genetic abnormalities or concurring respiratory diseases (
Inflammation is one of the fundamental characteristics of COPD. It accelerates the disease progression and it is not reversible. Inflammation in COPD is usually a consequence of smoking, which is a major factor in the pathogenesis of COPD. Most cigarette smokers have a chronic cough, which is usually present prior to the onset of airflow obstruction. Smoking induces airway inflammation causing an increase in the number of neutrophils, macrophages, and T lymphocytes (CD8+ and CD4+) (
Recent studies also revealed the role of TRPV1 in mediating the effects of cigarette smoke on the alveolar epithelial cells through the increase of inflammation, oxidative stress, and mitochondrial damage (
The expression of TRPV1 is related to the intensity of the inflammatory process induced by cigarette smoking (
In another study, human cells were exposed to cigarette smoking, and the expression of TRPV1 in pulmonary tissue was increased, as was the concentration of pro-inflammatory cytokines (
Stimulation of TRPV1 in COPD releases inflammatory neuropeptides which increase vascular permeability, cause extravasation of plasma proteins, bronchoconstriction, and amplify the concentration of mucus (
Interestingly,
Capsaicin stimulates TRPV1 with further release of pro-inflammatory cytokines in the airways. Activation of TRPV1 by capsaicin in patients with COPD stimulates the secretion of ILs, TNF-α, and prostaglandin E2 (PGE2) (
Studying the
A consensus was not yet reached regarding the overall effects of capsaicin in patients with airflow obstruction. A large cross-sectional study by Blanc
TRP channels have a protective role in physiological situations when the airways are not affected by pathological changes. In a disorder such as COPD, this role can be altered, and TRP channels may be responsible for the symptoms of COPD, especially cough and they may also participate in the inflammatory process identified in COPD (
Cough is usually the first symptom in patients with COPD. Cough may be sporadic and sometimes unproductive (
Several clinical studies using capsaicin aerosols have been developed for patients with cough and COPD. Capsaicin responsiveness and cough in COPD was researched in a study by Doherty
Asthma is a chronic, frequent, and treatable pulmonary disease characterized by respiratory symptoms, limitation of activity, and exacerbations that occasionally need urgent medical care, and can be a potentially lethal condition. The most common respiratory symptoms in asthma are wheezing, shortness of breath, cough, chest tightness, and variable expiratory airflow. The main risk factors that may aggravate asthma are viral infections, allergens, tobacco smoke, pollens, food, drugs, or exercise. Spirometry is required to set the diagnosis: FEV1 increases by 12% and a minimum of 200 ml of the baseline values post-bronchodilator (
Asthma is regarded as a typical Th2 disease, with increased immunoglobulin E (IgE) levels, airway inflammation, and the presence of numerous eosinophils. Usually, patients begin suffering from asthma in childhood. The allergens are inhaled and stimulate Th2-helper cell proliferation and the increase of IL-4, IL-5, and IL-13 levels (
TRPV1 may play important roles in the modulation of the pathogenic changes occurring in asthma (
These observations were demonstrated by studies on the same animal model showing that inhibition of the TRPV1 mRNA and protein expression using various antagonists including capsazepine caused an improvement in pulmonary function, decreased airway hyperresponsiveness, and reduced cytokine concentrations in aggravated asthma (
In an
In asthma, chronic inflammation is one of the fundamental features of the disease. Inflammation progresses when inflammatory cells interact with local cells to create a cascade of events that triggers and maintains chronic inflammation and causes clinical symptoms. The consequences of inflammation in asthma are bronchospasm, airways mucus secretion and edema, bronchoconstriction, and bronchial epithelial damage (
The role of capsaicin in the process of inflammation in asthma is unclear, as some studies cite pro-inflammatory properties of capsaicin, while other recent studies revealed its anti-inflammatory effects (
However, TRPV1 activation seems to play an important role in the inflammatory cascade of asthma, and pharmacological inhibition of TRPV1 leads to a reduction in IgE levels as well as an attenuation of airway inflammation in mice (
A study by Rehman
Cough is a frequent and important symptom that influences the quality of life in patients with asthma (
In a study performed
Previous findings showed an increase in the frequency of cough in patients with asthma after inhalation of capsaicin. This is an effect of the hyperresponsiveness that characterizes patients with asthma. The mechanism probably involves neuronal dysfunction. When capsaicin stimulates the TRPV1 receptor, inflammatory mediators are released with further increased stimulation of the nerve fibers. This process determines membrane depolarization and release of the inflammatory mediators which are in high concentration in asthmatic patients (
A study from 2019 comparing asthmatics and healthy controls showed no difference in the cough threshold after inhaled capsaicin between the two groups (
A study published in 2020 tested the effects of inhaled capsaicin on 385 chronic cough patients, revealing that the capsaicin cough challenge is a proper method for investigating patients with variable clinical factors in asthma (
However, in regard to therapeutic prognostic, cough sensitivity to capsaicin may hold an important role in predicting the response to bronchial thermoplasty when used for treating patients with severe asthma (
The intended finality of these findings is to improve the management of asthmatic cough. The use of the antimuscarinic bronchodilator Tiotropium has proved effective in controlling asthmatic cough in patients unresponsive to corticosteroids and long-acting β2 agonists, and it improved capsaicin cough reflex sensitivity, leading to the conclusion that its effects are mediated through sensory nerves, rather than effective bronchoconstrictors (
In summary, capsaicin demonstrates complex effects on cough and inflammation in COPD and asthma, either through direct TRPV1 activity or mediated by released factors, and these findings were summarized in
Capsaicin may exhibit a variety of clinical and paraclinical effects in COPD and asthma. Some are similar in both diseases, while others may be significantly different or opposite. In many cited studies, the frequency and intensity of cough are increased after capsaicin inhalation in COPD, while other authors report only an increase in the frequency of cough in asthmatic patients. The effects of capsaicin on inflammation in these two diseases are different. In COPD, several studies showed that capsaicin has pro-inflammatory effects, while, in asthma, the role of capsaicin in inflammation is unclear, as various studies showed conflicting results, citing pro-inflammatory as well as anti-inflammatory effects. Most authors revealed that the hyperresponsiveness to capsaicin is higher in smokers with airflow obstruction than non-smokers and smokers without airflow obstruction. Capsaicin appears to be a safe product as we failed to identify any studies showing an increase of dyspnea in COPD or asthma after capsaicin administration, when used in tolerable doses. Capsaicin may be a very promising, cost-effective, natural, and safe tool in expediting the diagnosis of COPD and asthma in the future, with increased accuracy in selected cases, especially due to its effects on cough and inflammation.
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MDD, CS, and CCa conceived and designed the review. CS and CCa have developed the methodology and scientific approach. Preliminary documentation, data selection and analysis, writing and editing of the original draft were performed by MDD, ASJ, CS, IAB, GDAP, AC, DOC, RSC, CCo, MN, and CCa. Content review and editing were performed by CS, AC, and CCa. Supervision was conducted by IAB, CCo, MN, and CCa. All authors have read and agreed to the published version of the manuscript.
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The authors declare no conflict of interest.
Comparative presentation of the most common cellular mechanisms involved in the development of the major symptoms and clinical elements of COPD and asthma. COPD, chronic obstructive pulmonary disease; TNF, tumor necrosis factor; PG, prostaglandin; SP, substance P; IL-13, interleukin-13.
Comparison of capsaicin effects on cough and inflammation in COPD and asthma.
Component | Effect | Study type | (Refs.) |
---|---|---|---|
COPD | |||
Cough | Increase in frequency | ( |
|
Increase in frequency | ( |
||
Increase in frequency | Trial | ( |
|
Rise of exacerbation incidence | ( |
||
Inflammation | Release of IL-1α, TNF-α and PGE2 | ( |
|
Release IL-8 and pro-inflammatory cytokines | ( |
||
Release IL-1β and IL-18 | |||
Maintain inflammation | ( |
||
Asthma | |||
Cough | Increase in frequency | ( |
|
Increase in frequency | ( |
||
Increase in frequency | Trial | ( |
|
Inflammation | Pro-inflammatory | ( |
|
Eosinophil infiltration | ( |
||
Pro- and anti-inflammatory | ( |
COPD, chronic obstructive pulmonary disease; TNF-α, tumor necrosis factor-α; PG, prostaglandin; IL, interleukin.