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At least 19 recordsLinked to original sources
PubMed2003

Airway hyperresponsiveness.

Airway hyperresponsiveness is a characteristic feature of asthma and consists of an increased sensitivity of the airways to an inhaled constrictor agonist, a steeper slope of the dose-response curve, and a greater maximal response to the agonist. Measurements of airway responsiveness are useful in making a diagnosis of asthma, particularly in patients who have symptoms that are consistent with asthma and who have no evidence of airflow obstruction. These tests can be performed quickly, safely, and reproducibly. Certain inhaled stimuli, such as environmental allergens, increase airway inflammation and enhance airway hyperresponsiveness. These changes in airway hyperresponsiveness are of much smaller magnitude than those seen when asthmatic patients with persistent airway hyperresponsiveness are compared to healthy subjects. They are, however, similar to changes occurring in asthmatic patients that are associated with worsening asthma control. The mechanisms of the transient allergen-induced airway hyperresponsiveness are not likely to fully explain the underlying mechanisms of the persistent airway hyperresponsiveness in asthmatic patients.

Asthma↗
PubMed2005

Pharmacological targeting of anaphylatoxin receptors during the effector phase of allergic asthma suppresses airway hyperresponsiveness and airway inflammation.

Airway hyperresponsiveness and airway inflammation are hallmarks of allergic asthma, the etiology of which is crucially linked to the presence of Th2 cytokines. A role for the complement anaphylatoxins C3a and C5a in allergic asthma was suggested, as deficiencies of the C3a receptor (C3aR) and of complement factor C5 modulate airway hyperresponsiveness, airway inflammation, and Th2 cytokine levels. However, such models do not allow differentiation of effects on the sensitization phase and the effector phase of the allergic response, respectively. In this study, we determined the role of the anaphylatoxins on the effector phase of asthma by pharmacological targeting of the anaphylatoxin receptors. C3aR and C5a receptor (C5aR) signaling was blocked using the nonpeptidic C3aR antagonist SB290157 and the neutralizing C5aR mAb 20/70 in a murine model of Aspergillus fumigatus extract induced pulmonary allergy. Airway hyperresponsiveness was substantially improved after C5aR blockade but not after C3aR blockade. Airway inflammation was significantly reduced in mice treated with the C3aR antagonist or the anti-C5aR mAb, as demonstrated by reduced numbers of neutrophils and eosinophils in bronchoalveolar lavage fluid. Of note, C5aR but not C3aR inhibition reduced lymphocyte numbers in bronchoalveolar lavage fluid. Cytokine levels of IL-5 and IL-13 in bronchoalveolar lavage fluid were not altered by C3aR or C5aR blockade. However, blockade of both anaphylatoxin receptors markedly reduced IL-4 levels. These data suggest an important and exclusive role for C5aR signaling on the development of airway hyperresponsiveness during pulmonary allergen challenge, whereas both anaphylatoxins contribute to airway inflammation and IL-4 production.

Animals↗
PubMedDate not supplied

The smooth muscle and airway hyperresponsiveness.

Airway hyperresponsiveness, excessive airway narrowing caused by stimuli that normally elicit limited or no response, is one of the cardinal features of asthma. The length-dependence of smooth muscle contractility has been recognized for decades, and it forms an essential foundation for many aspects of the physiological regulation of airway contractility in vivo. This review summarizes the structural and functional alterations of airway smooth muscle in asthma and chronic obstructive pulmonary disease, that underlie pathophysiological conditions of airway hyperresponsiveness.

Airway Resistance↗
PubMed2003

Possible mechanisms of influence of esophageal acid on airway hyperresponsiveness.

Airway hyperresponsiveness is among the defining phenomena in asthma. In this article, 3 mechanisms are reviewed to explain how gastroesophageal reflux (GER) may influence airway hyperresponsiveness. First, microaspiration may cause not only direct tissue injury, but may also trigger vagal reflexes. Second, acid infusion of the esophagus in a dog model and in humans has been shown to result in vagally mediated reflexes leading to bronchoconstriction. These reflexes have been studied using immunohistochemical techniques. Third, neuroinflammatory reflexes have been found to play a role in airway responses through the release of tachykinins, including substance P and neurokinin A. Combined, these 3 mechanisms may lead to an increase in vagal efferent impulses that can cause or augment airway hyperresponsiveness. Studies indicate that there is an increase in airway responsiveness in asthma patients who have documented GER. Further, based on the reported number of reflux episodes occurring during 24-hour pH monitoring, airway hyperresponsiveness to methacholine challenge tends to increase as GER worsens.

Animals↗
PubMed2006

Mechanisms of airway hyperresponsiveness.

Airway hyperresponsiveness (AHR) to direct (histamine and methacholine) and indirect (exercise, cold air, hyperventilation, AMP) challenges is a universal and defining feature of asthma. One component of AHR is transient or inducible and occurs after allergen exposure, for example, and improves occasionally rapidly after inhaled corticosteroids or environmental control. This transient airway hyperresponsiveness is more marked to the indirect stimuli. There are convincing data linking this component of AHR to airway inflammation; however, the precise mechanisms linking airway inflammation and hyperresponsiveness of the airway smooth muscle are not clear. The other component of AHR is more persistent and is relatively refractory to environmental control and inhaled corticosteroids. This is likely secondary to structural airway changes, which are collectively referred to as airway remodeling, and which are a result of the chronic (rather than the acute) effects of airway inflammation. This persistent AHR is best reflected by airway hyperresponsiveness to direct stimuli such as methacholine. The mechanisms are also uncertain, but reduced airway caliber, increased airway wall thickness, increased airway smooth muscle mass, and perhaps contractility likely all play a role.

Asthma↗
PubMed1991

Inflammation and cell-cell interactions in airway hyperresponsiveness.

Airway hyperresponsiveness results from the conversion of normally reactive airways to a state of augmented responsiveness to constrictor stimuli. Although the mechanism accounting for the induction of airway hyperresponsiveness remains elusive, recent investigations have suggested that inflammation may be a sine qua non for human asthma. Numerous experimental models have demonstrated the necessity of circulating granulocytes as mediators of augmented bronchoconstriction during immune challenge. It is not known how granulocytes are targeted for selective migration to the conducting airways of the lung during hyperresponsive states; however, recent evidence implicates the upregulation of granulocyte adhesion molecules on both the endothelial and epithelial surfaces of the airway. There is evidence that during migration diapedesis, granulocytes interact with epithelial and endothelial cells to produce regionally secreted mediators that upregulate the responsiveness of adjacent airway smooth muscle and/or cause lumenal edema, thus augmenting the effect of constrictor stimuli. Most evidence suggests that the eosinophil is the most important granulocyte in these responses and that eosinophilic infiltration and activation may account for the unique, spasmodic, and cyclic nature of hyperreactive airways. The molecular biology of the eosinophil granule proteins has characterized four distinct substances, each of which exerts potential cytotoxic effects on airway epithelium by different mechanism. In addition, at least one of these proteins, the major basic protein, appears to cause direct, noncytotoxic stimulation of epithelial secretion that upregulates nonspecifically the response of airway smooth muscle to contractile stimuli. The recognition of inflammation as the essential component to airway hyperresponsiveness provides a fresh approach to a difficult problem and suggests a host of novel therapies for human asthma.

Amino Acid Sequence↗
PubMed2006

Mice lacking the VIP gene show airway hyperresponsiveness and airway inflammation, partially reversible by VIP.

The mechanisms leading to asthma, and those guarding against it, are yet to be fully defined. The neuropeptide VIP is a cotransmitter, together with nitric oxide (NO), of airway relaxation, and a modulator of immune and inflammatory responses. NO-storing molecules in the lung were recently shown to modulate airway reactivity and were proposed to have a protective role against the disease. We report here that mice with targeted deletion of the VIP gene spontaneously exhibit airway hyperresponsiveness to the cholinergic agonist methacholine as well as peribronchiolar and perivascular cellular infiltrates and increased levels of inflammatory cytokines in bronchoalveolar lavage fluid. Immunologic sensitization and challenge with ovalbumin generally enhanced the airway hyperresponsiveness and airway inflammation in all mice. Intraperitoneal administration of VIP over a 2-wk period in knockout mice virtually eliminated the airway hyperresponsiveness and reduced the airway inflammation in previously sensitized and challenged mice. The findings suggest that 1) VIP may be an important component of endogenous anti-asthma mechanisms, 2) deficiency of the VIP gene may predispose to asthma pathogenesis, and 3) treatment with VIP or a suitable agonist may offer potentially effective replacement therapy for this disease.

Animals↗
PubMed2000

Effects of once daily dosing with inhaled budesonide on airway hyperresponsiveness and airway inflammation following repeated low-dose allergen challenge in atopic asthmatics.

BACKGROUND: Repeated low-dose allergen challenge increases airway hyperresponsiveness and sputum eosinophils in atopic asthmatics. Inhaled corticosteroids attenuate the airway responses to high-dose allergen challenge, but have not been evaluated against repeated low dose challenge. OBJECTIVE: This study evaluates the effects of once daily treatments of two doses of inhaled budesonide on airway responses to repeated low-dose allergen challenge. METHODS: Eight atopic asthmatics with a dual airway responses to inhaled allergen were recruited into a randomized, double-blind crossover, placebo-controlled study. In the mornings of four consecutive days (day 1-day 4), subjects inhaled budesonide 100 microg, 400 microg, or placebo, 30 min before inhaling a concentration of allergen causing a 5% early fall in FEV1. Airway hyperresponsiveness to methacholine and sputum eosinophils were measured at baseline, on the afternoon of day 2, day 4, and 24 h after the last challenge. There was a 1-week washout between each of the three treatment periods. RESULTS: The repeated low-dose allergen challenge induced increases in the percentage sputum eosinophils from 2.0 +/- 0.7% at baseline to 16.6 +/- 7.1% on day 4 (P = 0.002), and this effect was reduced by once daily budesonide 100 microg to 5.6 +/- 1.8% (P = 0. 01) and by once daily budesonide 400 microg to 3.1 +/- 0.9% (P = 0. 004). Also, the allergen-induced methacholine airway hyperresponsiveness which occurred by day 4 (P = 0.03) of the repeated low dose challenge was inhibited by budesonide 400 microg (P = 0.017). CONCLUSION: Both budesonide 100 microg and 400 microg inhaled once daily significantly reduces allergen-induced sputum eosinophilia after repeated low dose challenge; however, only the higher dose also attenuates the allergen-induced airway hyperresponsiveness.

Adult↗
PubMed1996

[Airway hyperresponsiveness and airway mucosal permeability].

The relationship between airway mucosal permeability and airway hyperresponsiveness was examined with tachykinins, their selective antagonists, and superoxide dismutase in male Hartley guinea pigs. In animals with ozone-induced airway inflammation, airway hyperresponsiveness and mucosal permeability increased concurrently but there was a time lag before the increase in airway vascular permeability. To study the role of tachykinins in the increases in mucosal permeability and in hyperresponsiveness, we used a neurokinin-receptor antagonist, CP-96345, and a neurokinin-2 receptor antagonist, SR-48968. CP-96345 had no significant effect, but SR-48968 reduced the increase in airway mucosal permeability; their effects on airway hyperresponsiveness were the opposite of their effects on airway permeability. Tachykinins themselves, both substance P and neurokinin A, significantly increased airway mucosal permeability. Superoxide dismutase, a scavenger enzyme of superoxide, reduced the ozone-induced airway hyperresponsiveness. These data suggest that the factors causing airway hyperresponsiveness differ from those that influence mucosal permeability, but it is possible that these pathophysiologic conditions are caused by the same substances or processes.

Animals↗
PubMed2003

Physiopathology of airway hyperresponsiveness.

Airway hyperresponsiveness (AHR), the tendency of the airways to narrow too much and too easily in response to various stimuli, is a universal feature of asthma, although it is not exclusive to this disease. Airway responsiveness shows a unimodal distribution in the general population and might vary with time, increasing after exposure to allergens, industrial substances, or infectious agents in predisposed individuals, or decreasing for variable time periods after environmental or pharmacologic interventions. Airway inflammation and structural airway changes can lead to this heightened airway response, but the mechanisms by which they modify airway function are still unclear. They might be associated with increased contractile properties of the airways--from an increase in contractile elements, a change in smooth muscle mechanical properties, or a reduction of forces opposing bronchoconstriction, such as reduced airway-parenchymal interdependence. Other factors, such as neurohumoral influences and "geometric factors" (eg, airway caliber), can modulate the degree of AHR.

Asthma↗
PubMed2001

[Measurement of airway hyperresponsiveness].

Airway hyperresponsiveness (AHR) refers to an abnormal increase in airway responses, such as airflow limitation, to nonselective stimuli that are divided into direct (acting directly on the effector organs) and indirect (mediated via inflammatory or neuronal cells). The mechanisms of AHR in asthma have received much attention but remain uncertain. Well-standardized methods for measuring AHR represent important tools for the diagnosis and monitoring of asthma. The measurement of AHR is generally based on the dose-response curve that is obtained after exposure to a stimulus (usually inhalation of increasing doses of aerosolized mediator) followed by the assessment of lung function. Indirect challenges, as well as direct challenges, may provide useful information on the multiple pathways leading to AHR, towards improvements in the management of asthma.

Asthma↗
PubMed2006

Do biophysical properties of the airway smooth muscle in culture predict airway hyperresponsiveness?

Airway hyperresponsiveness is a cardinal feature of asthma but remains largely unexplained. In asthma, the key end-effector of acute airway narrowing is the airway smooth muscle (ASM) cell. Here we report novel biophysical properties of the ASM cell isolated from the relatively hyporesponsive Lewis rat versus the relatively hyperresponsive Fisher rat. We focused upon the ability of the cytoskeleton (CSK) of the ASM cell to stiffen, to generate contractile forces, and to remodel. We used optical magnetic twisting cytometry to measure cell stiffness and traction microscopy to measure contractile forces. To measure remodeling dynamics, we quantified spontaneous nanoscale motions of a microbead tightly anchored to the CSK. In response to a panel of contractile and relaxing agonists, Fisher ASM cells showed greater stiffening, bigger contractile forces, and faster CSK remodeling; they also exhibited higher effective temperature of the CSK matrix. These physical differences measured at the level of the single cell in vitro were consistent with strain-related differences in airway responsiveness in vivo. As such, comprehensive biophysical characterizations of CSK dynamics at the level of the cell in culture may provide novel perspectives on the ASM and its contributions to the excessive airway narrowing in asthma.

Adenosine Triphosphate↗
PubMed2002

Effect of intranasal administration of CV-11974, a type 1 angiotensin II receptor antagonist, on airway hyperresponsiveness and airway inflammation induced by antigen inhalation in guinea pigs.

BACKGROUND: Angiotensin II is a putative mediator in asthma, but the effect of topical administration of type 1 angiotensin II (AT1) receptor antagonists on allergic airway reactions is not known. OBJECTIVE: To investigate the effect of intranasal administration of CV-11974, an AT1 receptor antagonist, and of PD123319, a type 2 angiotensin II (AT2) receptor antagonist, on antigen-induced airway reactions in guinea pigs. METHODS: Thirty minutes after intranasal topical administration of CV-11974 (0.1 or 1.0 mg/ml) or PD123319 (10 mg/ml) into the airways, the animals were given an antigen challenge. Airway hyperresponsiveness and bronchoalveolar lavage fluid were analyzed 24 h after the antigen challenge. RESULTS: Although these compounds did not inhibit antigen-induced early-phase bronchoconstriction or late-phase airway eosinophilia, intranasal administration of CV-11974 (but not PD123319) inhibited antigen-induced airway hyperresponsiveness in a dose-dependent manner 24 h after the antigen challenge. CONCLUSION: Intranasal administration of an AT1 receptor antagonist reduces antigen-induced airway hyperresponsiveness.

Administration, Inhalation↗
PubMed1991

Asthma and airway hyperresponsiveness.

Airway hyperresponsiveness to a large number of stimuli is a characteristic of asthma in humans. Various components of the tracheobronchial tree might contribute to this characteristic, such as smooth muscle, the bronchial epithelium, various neurohumoral mechanisms, and the mechanical linkages between the lung parenchyma and the airways. The degree of responsiveness can be further increased by a series of stimuli associated with inflammation in the periphery of the lung. Such stimuli actually induce an asthmatic state or heighten the vulnerability of asthmatics, making them more prone to overt attacks in response to minor stimuli that would ordinarily be well tolerated. Depending upon the inciting stimulus, different cells and mediators may be playing a role in producing and perpetuating the inflammatory state and producing further increases in responsiveness.

Asthma↗
PubMed2005

Single-nucleotide polymorphisms of the KCNS3 gene are significantly associated with airway hyperresponsiveness.

Airway hyperresponsiveness (AHR) is one of the major clinical symptoms and intermediate phenotypes of asthma. A recent genome-wide search for asthma quantitative trait loci has revealed a significant linkage signal between a p-terminal region of chromosome 2 and AHR. Thus, the gene encoding the potassium voltage-gated channel delayed-rectifier protein S3 (KCNS3) in this region is considered a positional candidate for asthma. We have evaluated a total of 12 single-nucleotide polymorphisms (SNPs) of the KCNS3 gene in a validation panel of 48 lymphoblastoid cell line DNA samples of Chinese origin. Three SNPs were found to be polymorphic and were tested. Two independent sets (an initial screening set and a replication set) of cases and controls from the original linkage study sample were collected. In the initial screening set, two SNPs (rs1031771 and rs1031772) showed suggestive association and were further confirmed by the replication set. In combined single-SNP analysis, the rs1031771 G allele (odds ratio=1.42, P=0.006) and rs1031772 T allele (odds ratio=1.40, P=0.018) were associated with a significantly higher risk of AHR. Haplotype analysis also detected significant association (P=0.006). Our findings suggest that SNPs located at the 3' downstream region of KCNS3 have a significant role in the etiology of AHR.

Adult↗
PubMed2005

Interacting genetic loci cause airway hyperresponsiveness.

Airway hyperresponsiveness (AHR) is a key physiological component of asthma, and the genetic basis of this complex trait has remained elusive. We created recombinant congenic mice with increased naive AHR by serially backcrossing A/J mice (which have elevated naive AHR) with C57BL/6J mice and selecting for mice with an elevated naive AHR phenotype. The seventh backcross-generation hyperresponsive mice retained A/J loci in three regions. Quantitative trait linkage (QTL) analysis of 123 unselected N8 progeny demonstrated that the AHR phenotype was not associated with any single locus but was significantly associated with an interaction of loci on chromosomes 2 and 6. These findings were confirmed in an independent analysis of chromosome substitution strain mice. The identification of genomic regions containing loci causally associated with AHR and the demonstration that this trait requires their interaction have important implications for the dissection of the genetic etiology of asthma in humans.

Animals↗
PubMed1990

Acute exposure to cigarette smoke induces airway hyperresponsiveness without airway inflammation in guinea pigs. Dose-response characteristics.

We examined whether acute exposure to a low dose of cigarette smoke causes an increase in airway responsiveness in guinea pigs and whether the changes in airway responsiveness are accompanied by increased vascular permeability or neutrophil influx in the trachea. Animals were divided into four groups: groups exposed to 5, 10, or 20 puffs of cigarette smoke and a control group. Airway responsiveness was assessed by measuring specific airway resistance (SRaw) as a function of increasing concentration of inhaled methacholine (Mch) aerosol immediately, 5 h, and 24 h after exposure. In parallel studies, tracheal vascular permeability was quantified by measuring the tracheal extravasation of intravenously administered Evans blue dye, and neutrophil influx into the tracheal mucosa was quantified by counting cells within whole mounts of tracheas that were stained with Giemsa. Exposure to 5 puffs of cigarette smoke caused no changes in airway responsiveness. Exposure to 10 puffs induced airway hyperresponsiveness only immediately after exposure. Exposure to 20 puffs induced airway hyperresponsiveness not only immediately but also 5 h after exposure. There was a significant correlation between the dose (puffs) of cigarette smoke and increase in airway responsiveness immediately after exposure (r = 0.77; p less than 0.001). The tracheal extravasation of intravenously administered Evans blue dye and the number of neutrophils in the tracheal mucosa did not differ significantly from the corresponding control values at any time or in any exposed group. Furthermore, none of these changes was observed in the airways distal to the trachea of any animal immediately after exposure to 20 puffs of cigarette smoke.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1993

Isbufylline, a new xanthine derivative, inhibits airway hyperresponsiveness and airway inflammation in guinea pigs.

The pharmacological actions of the new xanthine, isbufylline, were evaluated in several models of airway hyperresponsiveness and airway inflammation in guinea pigs. At a dose (106 mumol kg-1 i.p.) providing complete protection against acetylcholine aerosol-induced dyspnea in the guinea pig, isbufylline inhibited platelet activating factor (PAF)- and antigen-induced eosinophil infiltration into bronchoalveolar lavage fluid 24 h after challenge of normal and actively immunized guinea pigs, respectively. In addition, this dose of isbufylline also inhibited capsaicin-induced extravasation of protein into bronchoalveolar lavage fluid. Isbufylline, 4.2 mumol kg-1 i.v., significantly inhibited PAF-induced bronchial hyper-responsiveness to i.v. histamine, without exerting evident bronchodilator activity. On the other hand the bronchodilator, salbutamol, at a dose (10.4 mumol kg-1 i.p.) shown to be equieffective to isbufylline (106 mumol kg-1 i.p.) for blocking acetylcholine aerosol-induced dyspnea, had no protective action against PAF- or antigen-induced eosinophil recruitment in bronchoalveolar lavage fluid, or against capsaicin-induced plasma protein extravasation. Furthermore, salbutamol (3.5 mumol kg-1) significantly potentiated allergen-induced cell infiltration and PAF-induced bronchial hyperresponsiveness. The results suggest that isbufylline can exert significant anti-inflammatory actions in guinea pig airways, in addition to its bronchodilator activity. These pharmacological activities are not shared by the beta 2-adrenoceptor agonist, salbutamol.

1-Methyl-3-isobutylxanthine↗