Mechanisms Of Bronchial Hyperresponsiveness Research Articles

A new mechanism of bronchial hyperresponsiveness revealed by murine Th9 cell-transferred asthma model

Bronchial asthma is a complex disease involving various inflammatory cells and tissue constituent cells. The spread of inhaled corticosteroids is changing asthma into a controllable disease, though the existence of intractable patients implies new mechanisms for the development and deterioration of asthma. Based on the difference in the pathological condition (phenotypes) and molecular mechanism (endotypes), subdivision of disease understanding is recently progressing. Accordingly, various T cell subsets other than Th2 cells, which have been considered to play a major role for many years, are being implicated in the pathogenesis of asthma. Therefore, we aimed to deepen the understanding of the complex mechanisms of intractable asthma by reviewing the characteristics of allergic inflammation mediated by each T cell subset and the trend of therapeutic strategies targeting their representative functional molecules. Among them, recently identified Th9 cells were reported to induce asthma-like eosinophilic inflammation with bronchial hyperresponsiveness (BHR). These phenotypes resemble to Th2 cells-mediated airway inflammation, though we found that Th9 but not Th2 cell-dependent asthma model develops eosinophil-independent and steroid-resistant BHR. Here, we would like to introduce our recent findings and an approach to elucidate a new mechanism of BHR, based on antigen-specific T cell subset-transferred mouse models we have established.

Airway responsiveness in an allergic rabbit model

Background Animal models of allergy and bronchial hyperresponsiveness (BHR) are useful in researching pulmonary diseases and evaluating drug effects on the airways. Neonatally immunised rabbits exhibit several features of asthma as adults, including early and late airway responses following antigen challenge, oedema and inflammatory cell infiltration into the lung, BHR to inhaled histamine and methacholine (compared with naïve rabbits) and exacerbations of BHR following antigen challenge. Therefore this model can be used to investigate the underlying mechanisms of BHR and for the preclinical evaluation of new drugs for the treatment of asthma. Aim To describe the characteristics of airway responses in a rabbit model of allergic inflammation and to evaluate the relationship between skin test reactivity to antigen, airway inflammation and BHR. Methods New Zealand White rabbits were neonatally immunised against Alternaria tenius. At 3 months of age, airway responsiveness was measured to aerosolised histamine, methacholine or allergen. Bronchoalveolar lavage (BAL) was performed and cell counts recorded. Direct skin tests were performed to assess skin reactivity to allergen and passive cutaneous anaphylaxis (PCA) tests were performed to determine titres of circulating IgE. Results In a population of allergic rabbits, allergen challenge induced a significant bronchoconstriction, airway inflammation and BHR. Skin test responsiveness to allergen did not correlate with various indices of pulmonary mechanics e.g. baseline sensitivity to methacholine and histamine, or allergen-induced BHR. In contrast, skin test responsiveness did predict airway inflammation as assessed by measurements of eosinophil recruitment to the lung. Conclusion The allergic rabbit is a useful model to further our understanding of allergic diseases. Recording lung function using a minimally invasive procedure allows repeated measurements to be made in rabbits longitudinally, and each animal may thus be used as its own control. Our observations do not support the use of skin responsiveness to allergen as a predictor of airway sensitivity as we observed no correlation between skin sensitivity and airway responsiveness to inhaled histamine, methacholine or allergen. However, skin reactivity did predict airway inflammation as assessed by measurements of eosinophil recruitment to the lung. Our results also further highlight the likely dissociation between airway inflammation and BHR.

The effects of natural pollen exposure on inflammatory cytokines and their relationship with nonspecific bronchial hyperresponsiveness in seasonal allergic rhinitis

The exact mechanism of bronchial hyperresponsiveness (BHR) is not clear in allergic rhinitis (AR); an increase of BHR in pollen season suggests that natural pollen exposure causes airway inflammation in seasonal AR (SAR). This study was designed to investigate the effects of natural pollen exposure on inflammatory cytokines and their relationship with BHR. Sixty-six SAR patients with grass pollen sensitivity and 26 nonallergic rhinitis (NAR) patients were included. Peripheral blood samples for cytokine levels were taken and a nonspecific bronchial provocation test was performed during pollen season between May and August. The same measurements were repeated off-season between November and February. These measurements were done in NAR patients once. During the pollen season, SAR patients had significantly more increased levels of IL-13 than NAR patients (11.45 +/- 12.54 versus 5.19 +/- 4.02; p = 0.005). Blood eosinophil numbers were higher in those patients with BHR during pollen season than those without BHR (399.0 +/- 255.8 versus 278.9 +/- 193.2 mm(-3); p = 0.046). Blood eosinophil numbers during off-season were not different in those with and without BHR (respectively, 261.4 +/- 202.3 mm(-3) versus 205.9 +/- 116.9 mm(-3); p = 0.53). IL-10 levels were higher in the patients without BHR (n = 28) than those patients with BHR (n = 22) during off-season (8.12 +/- 13.1 versus 3.28 +/- 0.37; p = 0.04). Having higher levels of IL-10 than threshold value was more frequent in SAR patients without BHR than those patients with BHR during off-season (7/28 versus 1/22; chi(2) = 4.34; p = 0.04). IL-10 has a role in the continuation of BHR during off-season in SAR patients.

Bronchial hyperresponsiveness to acetylcholine during acute pulmonary congestion in guinea pigs

To understand the precise mechanism of bronchial hyperresponsiveness in patients with congestive heart failure, we studied the effect of mild pulmonary congestion on bronchial responsiveness to inhaled acetylcholine (ACh) in guinea pigs. We induced mild pulmonary congestion by inflation of a balloon placed in the left atrium, and maintained the left atrial pressure (Pla) at 10 mmHg for 30 minutes with continuous monitoring of lung resistance (RL) and dynamic compliance (Cdyn). Furthermore, we determined the provocative concentration of ACh producing 100% increase in RL (PC100-ACh), before and during balloon inflation. In animals with propranolol pretreatment, but not in animals without propranolol pretreatment, mild pulmonary congestion caused slight increase in RL (N.S.) and significant decrease in Cdyn (p less than 0.01) and PC 100-ACh (p less than 0.01). Cutting of bilateral vagal nerves partially inhibited the decrease of PC100-ACh, but pretreatment with either phenoxybenzamine, indomethacin, AA-861 or OKY-046 had not effect. These results suggest that blockade of beta-adrenergic receptors and the vagal reflex, but not of alpha-adrenergic receptors or arachidonates, contributes to bronchial hyperresponsiveness during acute pulmonary congestion.

Asthma and Chitinases

Asthma is a complex and heterogeneous syndrome in which the airway mucosa is abnormal and inflamed. Although its causes are unknown, there are strong clues: it runs in families, and many, but by no means all, patients with asthma have signs and symptoms of IgE responses to common allergens. Asthma has an incomplete association with the phenomenon of nonspecific bronchial hyperresponsiveness to a variety of stimuli. The mechanism of bronchial hyperresponsiveness is itself mysterious. A childhood in an environment rich in microbes protects against the development of asthma in many parts of the world.In this issue of the Journal . . .

Endothelin-1 in exhaled breath condensate of stable and unstable asthma patients

Endothelins are proinflammatory, profibrotic, broncho- and vasoconstrictive peptides, which play an important role in the development of airway inflammation and remodeling in asthma. The study was undertaken to evaluate the endothelin-1 (ET-1) levels in exhaled breath condensate (EBC) of asthmatics with different degree in asthma severity. EBC was collected from 31 patients with allergic asthma (11 with steroid-naïve mild asthma, 10 with ICS-treated, stable mild-to-moderate asthma, 10 with ICS-treated unstable, severe asthma) and 7 healthy volunteers. In the three groups of asthmatics, ET-1 concentrations in EBC were significantly higher than in healthy volunteers. ET-1 levels were significantly higher in patients with unstable asthma than in the two groups with stable disease. There was a significant correlation between ET-1 levels and FENO in the three groups of asthmatics and between ET-1 and blood eosinophil counts in the group of patients with unstable asthma. Measurements of ET-1 in EBC may provide another useful diagnostic tool for detecting and monitoring inflammation in patients with asthma.

A study of the association between exercise-induced wheeze and exercise versus methacholine-induced bronchoconstriction in adolescents.

Among asthmatics, exercise-induced wheeze (EIW) is a frequent symptom, and 40-77% of asthmatics demonstrate exercise-induced bronchoconstriction (EIB). In the North-Trøndelag population-based survey of 8,571 adolescents (YOUNG-HUNT), 26% reported wheeze during the previous 12 months (current wheeze). Of those subjects, 50% reported EIW. The aim of the present study was to investigate the association between EIW and EIB in randomly selected adolescents with EIW as the only or predominant asthma-like symptom, and to relate our findings to results from methacholine bronchoprovocation tests (MT) and measurements of exhaled nitric oxide (ENO). Sixty-three subjects with current wheeze induced by exercise, but not by allergen exposure, were investigated using a treadmill exercise test (ET) and measurements of ENO. Fifty-eight subjects completed a MT on a separate study day. EIB was defined as a fall of >or= 10% in the forced expiratory volume in 1 second (FEV1) after exercise (DeltaFEV1%ex). Twenty-one subjects (33%) had EIB and 33 (57%) had a positive MT. The degree of reported dyspnea during the ET was not correlated to the DeltaFEV1%ex. The correlation between EIB and methacholine-induced bronchoconstriction (MIB) was poor, and the DeltaFEV1%ex was more pronounced in smokers than in non-smokers. Moreover, ENO was not increased in subjects with positive vs. negative ET. Hence, EIW, when reported as the only or predominant asthma-like symptom, was linked to EIB in only one-third of the patients. We conclude that EIW is a poor predictor of EIB in epidemiological studies. The poor correlation between EIB and MIB indicates that these two tests measure different mechanisms of bronchial hyper-responsiveness.

Mechanisms of bronchial hyperresponsiveness: the interaction of endothelin-1 and other cytokines.

Bronchial hyperresponsiveness (BHR) is a fundamental characteristic of asthma and has become part of a more recent definition of asthma. Data show a close link between bronchial hyperresponsiveness (both transient and persistent) and airway inflammation. Airway inflammation is orchestrated by a complex network of cytokines. It has been considered that endothelin-1 is involved in bronchoconstriction and airway structural remodelling and has several pro-inflammatory properties of potential relevance to asthma. We focus on endothelin-1, its activities and interaction with other cytokines in the pathogenesis of asthma.

Difference in Airway Reactivity in Children With Atopic vs Nonatopic Asthma

To examine the difference in the mechanisms of bronchial hyperresponsiveness (BHR) in nonatopic asthma and in atopic asthma, we studied bronchial reactivity against nonspecific stimuli in children with atopic asthma and nonatopic asthma. Fourteen children with nonatopic asthma, 24 children with atopic asthma, and 20 age-matched controls participated in this study. Inhalation challenge was performed by administering progressively doubling doses of methacholine with a continuous inhalation provocation method. The speed of bronchoconstriction to methacholine (Sm) and the speed of reversal of bronchoconstriction to methacholine after inhalation of a beta2-agonist (r-Sm), which was considered to represent the effect of the beta2-agonist, were calculated from the dose-response curve. The value of Sm was higher in the nonatopic asthma group than in the atopic asthma group and the control group. The value of r-Sm was also higher in the nonatopic asthma group than in the atopic asthma group, but did not differ from that in the control group. These results indicate that bronchial reactivity against methacholine and the beta2-agonist was greater in nonatopic asthma than in atopic asthma, and that the mechanism of BHR in children with nonatopic asthma may differ from that in children with atopic asthma.

Cromoglycate and Nedocromil: Influence on Airway Reactivity

Although basic mechanisms of bronchial hyper-responsiveness (BHR) are still incompletely understood, inflammation of airways is likely to play a fundamental role in modulating BHR in patients with asthma. The involvement of several inflammatory cells (eosinophils, mast cells, lymphocytes, neutrophils, macrophages and platelets) and of bioactive mediators secreted by these cells in the pathogenesis of asthma is well documented. Sodium cromoglycate and nedocromil sodium are two pharmacological agents which have anti-allergic and anti-inflammatory properties. Their clinical effectiveness in mild to moderate asthma, and the capacity to reduce BHR under different natural and experimental conditions, make them valuable drugs for maintenance therapy in patients with asthma.

Lung Rejection and Bronchial Hyperresponsiveness to Methacholine and Ultrasonically Nebulized Distilled Water in Heart-Lung Transplantation Patients

Acute denervation of the lungs occurs after heart-lung transplantation (HLT), affecting both afferent and efferent nerves below the tracheal anastomosis. After surgery, the carina and main bronchi are perfused by mediastinal collaterals derived from the coronary arteries, and the intrapulmonary airways by retrograde blood flow from pulmonary artery collaterals. During acute rejection, the lungs are subjected to inflammation, particularly perivascular lymphocytic infiltrates. Rejection can be diagnosed by transbronchial biopsy (TBB). We report the bronchial responses to inhaled methacholine and ultrasonically nebulized distilled water (USNDW) in 16 HLT patients 2 wk to 43 months after surgery, relating them to the lung histopathology from concurrent TBB. Methacholine bronchial hyperresponsiveness was common, but it was not associated with airway epithelial or submucosal inflammation or perivascular lymphocytic infiltration. Six patients had a modest response to USNDW (fall in FEV1 greater than 10%). The responsiveness to USNDW was not associated with enhanced methacholine responsiveness or epithelial and mucosal inflammation. However, it was more commonly seen in patients with lung rejection and perivascular infiltrates. Methacholine hyperresponsiveness in HLT patients could therefore reflect denervation hypersensitivity of airway smooth muscle muscarinic receptors. The modest response to USNDW in some patients cannot be a result of a vagal reflex but could reflect a pathologic vascular response associated with lung rejection. These observations offer insight into the possible mechanisms of bronchial hyperresponsiveness in disease.

The Changing Face of Asthma

Asthma may affect 5 to 10 per cent of the population, yet remains underdiagnosed and undertreated. It is probably the only common treatable condition whose prevalence and severity is increasing [1,2] and there is evidence from several countries that mortality has risen, despite advances in therapy [3,4]. In New Zealand the problem has reached epidemic proportions and asthma is now one of the commonest causes of death in young people [5]. Even in the United States, which was unaffected by the epidemic of asthma deaths in the 1960s, there are now indications that the mortality from asthma may be rising [6]. These alarming statistics should encourage greater effort to be put into elucidating the pathogenesis of asthma. Several advances have recently been made in elucidating the mechanisms of asthma and this should eventually lead to more effective treatment. Bronchial hyperresponsiveness, an exaggerated bronchoconstrictor response to many different stimuli, is a key feature of asthma, and relates more closely to the severity of asthma and the frequency of symptoms than does resting lung function [7]. To determine the cause of asthma it is necessary to understand the mechanisms of bronchial hyperresponsiveness, and effective control of asthma symptoms implies a reduction in bronchial responsiveness. Increased bronchial responsiveness follows exposure to allergens, upper respiratory tract infection, and certain industrial chemicals. There is now considerable experimental evidence that induced hyperresponsiveness in animals is associated with inflammation of the airways [8]. Histopathological studies from asthmatic patients who have died during asthma attacks show marked inflammation in the airways, with infiltration of inflammatory cells, particularly eosinophils, disruption of airway epithelium and plugging of the airway lumen by viscous mucus [9]. Similar, but less severe, pathological changes have also been described in bronchial biopsies from asthmatics with relatively mild disease [10] and this supports the experimental evidence that airway inflammation may underly bronchial hyperresponsiveness. Bronchial microvascular leakage is also a typical feature, leading to oedema of the submucosa and extravasation of plasma which may be linked to bronchial hyperresponsiveness [11]. The previously held view that asthma could be explained by release of mast cell mediators which cause bronchospasm must now be modified. It now seems likely that several different cells are involved in the pathogenesis of asthma, and that these cells produce a variety of mediators which interact in a complex way to produce a number of pathological effects which, together, contribute to bronchial hypeiTesponsiveness and the clinical features of asthma. Recent advances have been made by recognition of the different cells and inflammatory mediators participating in asthma, and of the neural mechanisms which may contribute to or modify these inflammatory events.