Airway Hyperresponsiveness In Asthma Research Articles

Airway Hyperresponsiveness: New Insights into the Pathogenesis

Airway hyperresponsiveness (AHR) is the most characteristic clinical feature of asthma. The pathogenesis of AHR in asthma is characterized by a variety of epithelial, microbial, and inflammatory triggers on one hand and abnormalities of effector structures in the airways such as smooth muscle cells, blood vessels, and nerves on the other hand. Obesity is increasingly recognized as an important additional factor in the diagnosis and the pathogenesis of AHR in asthma. It is important to note that structural changes in the asthmatic airway can persist in the absence of inflammation. This may be one reason for the observation that potent new antiinflammatory drugs for the treatment of asthma have only little impact on AHR. New therapeutic strategies are, therefore, needed to modulate structural and functional changes in the airways, especially in patients with treatment-resistant severe asthma.

Counterpoint: Alterations in airway smooth muscle phenotype do not cause airway hyperresponsiveness in asthma

We have been assigned the task of showing that “alterations in airway smooth muscle phenotype DO NOT cause the airways hyperresponsiveness of asthma.” In the following paragraphs we will briefly review the overwhelming lack of evidence that any fundamental change in the intrinsic properties of

Comments on Point:Counterpoint: Alterations in airway smooth muscle phenotype do/do not cause airway hyperresponsiveness in asthma

Comments on Point:Counterpoint: Alterations in airway smooth muscle phenotype do/do not cause airway hyperresponsiveness in asthma

Beyond the Immune System: The Role of Resident Cells in Asthma and COPD

Beyond the Immune System: The Role of Resident Cells in Asthma and COPD

Point:Counterpoint: Alterations in airway smooth muscle phenotype do/do not cause airway hyperresponsiveness in asthma

#### Summary. Airway hyperresponsiveness and obstruction are cardinal features of asthma. Compelling evidence now suggests that the key features of asthma in part are due to intrinsic differences in airway smooth muscle (ASM) function. Inflammatory mediators alter ASM phenotype, which directly

Functional consequences of human airway smooth muscle phenotype plasticity

Airway smooth muscle (ASM) phenotype plasticity, characterized by reversible switching between contractile and proliferative phenotypes, is considered to contribute to increased ASM mass and airway hyper-responsiveness in asthma. Further, increased expression of collagen I has been observed within the ASM bundle of asthmatics. Previously, we showed that exposure of intact bovine tracheal smooth muscle (BTSM) to collagen I induces a switch from a contractile to a hypocontractile, proliferative phenotype. However, the functional relevance of this finding for intact human ASM has not been established. We investigated the effects of exposure of human tracheal smooth muscle (HTSM) strips to monomeric collagen I and PDGF on contractile responses to methacholine and KCl. Expression of contractile proteins sm-α-actin and sm-MHC was assessed by Western blot analysis. The proliferation of HTSM cells was assessed by cell counting, measuring mitochondrial activity (Alamarblue conversion) and [(3) H]-thymidine incorporation. Proliferation of intact tissue slices was assessed by [(3) H]-thymidine incorporation. Culturing HTSM strips in the presence of collagen I or PDGF for 4 days reduced maximal contractile responses to methacholine or KCl and the expression of contractile proteins. Conversely, collagen I and PDGF increased proliferation of HTSM cells and proliferative responses in tissue slices. PDGF additively increased the proliferation of HTSM cells cultured on collagen I; this additive effect was not observed on contractility, contractile protein expression or proliferation of intact tissue. These findings indicate that collagen I and PDGF induce a functionally hypocontractile, proliferative phenotype of human ASM, which may contribute to airway remodelling in asthma.

Airway Hyperresponsiveness in Asthma: Mechanisms, Clinical Significance, and Treatment

Airway hyperresponsiveness (AHR) and airway inflammation are key pathophysiological features of asthma. Bronchial provocation tests (BPTs) are objective tests for AHR that are clinically useful to aid in the diagnosis of asthma in both adults and children. BPTs can be either “direct” or “indirect,” referring to the mechanism by which a stimulus mediates bronchoconstriction. Direct BPTs refer to the administration of pharmacological agonist (e.g., methacholine or histamine) that act on specific receptors on the airway smooth muscle. Airway inflammation and/or airway remodeling may be key determinants of the response to direct stimuli. Indirect BPTs are those in which the stimulus causes the release of mediators of bronchoconstriction from inflammatory cells (e.g., exercise, allergen, mannitol). Airway sensitivity to indirect stimuli is dependent upon the presence of inflammation (e.g., mast cells, eosinophils), which responds to treatment with inhaled corticosteroids (ICS). Thus, there is a stronger relationship between indices of steroid-sensitive inflammation (e.g., sputum eosinophils, fraction of exhaled nitric oxide) and airway sensitivity to indirect compared to direct stimuli. Regular treatment with ICS does not result in the complete inhibition of responsiveness to direct stimuli. AHR to indirect stimuli identifies individuals that are highly likely to have a clinical improvement with ICS therapy in association with an inhibition of airway sensitivity following weeks to months of treatment with ICS. To comprehend the clinical utility of direct or indirect stimuli in either diagnosis of asthma or monitoring of therapeutic intervention requires an understanding of the underlying pathophysiology of AHR and mechanisms of action of both stimuli.

New Omega-3 Derivatives Reduce Airway Inflammation and Prevent Rho-Kinase Activation in an Allergic Model of Asthma

Asthma is a chronic inflammatory airways disease characterized by early and late asthmatic reactions that are associated with infiltration and activation of inflammatory cells in the airways. Bronchial hyperresponsiveness to a variety of stimuli is part of the symptomology which include neurotransmitters and inflammatory mediators. Omega-3 fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are known to reduce inflammation in the lung. In the present study, we synthesized new omega-3 polyunsaturated fatty acid (n3-PUFA) derivatives, namely DHA monoglyceride (MAG-DHA) and EPA monoglyceride (MAG-EPA), and investigated their effects on lung inflammation and RhoA activation in an in vivo guinea pig model of allergic asthma. Histological analyses and leukocyte count in bronchoalveolar lavages revealed that oral MAG-DHA and MAG-EPA treatments led to less inflammatory cell recruitment in the lung of ovalbumine (OVA)-sensitized guinea pigs when compared to lung from control animals. Results also revealed a reduction in mucus production in OVA-sensitized animals treated with either MAG-DHA or MAG-EPA. Moreover, per os n-3 PUFA administrations prevented NF k B activation and COX2 over-expression in OVA-sensitized animals. Mechanical tension measurements revealed that oral MAG-DHA and MAG-EPA treatments prevented U-46619-induced bronchial hyperresponsiveness in OVA-sensitized guinea pigs. MAG-DHA and MAG-EPA also prevented U-46619-induced Ca 2+ hypersensitivity of bronchial smooth muscle through a decrease in RhoA activation. Together, these findings provide key evidences regarding the mode of action of MAG-DHA and MAG-EPA in the lung and point to new potential therapeutic strategies for modulating inflammation and airway hyperresponsiveness in asthma.

Is methacholine challenge sufficient to rule out bronchial hyperresponsiveness in patients with suspected asthma?

Bronchial provocation challenges may be useful for establishing a definitive diagnosis of asthma in individuals with compatible symptoms and normal pulmonary function test results. [1] National Asthma Education and Prevention ProgramExpert Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthma-summary report 2007. J Allergy Clin Immunol. 2007; 120: S94-S138 PubMed Google Scholar The methacholine challenge is the most commonly performed test. Because of the high sensitivity and negative predictive value of the methacholine challenge, a negative result practically excludes current asthma with reasonable certainty. [2] Cockcroft D.W. Direct challenge tests: airway hyperresponsiveness in asthma: its measurement and clinical significance. Chest. 2010; 138: 18S-24S Crossref PubMed Scopus (153) Google Scholar However, recent data show that challenges with indirect stimuli (eg, adenosine) associate better with airway inflammation [3] Manso L. Madero M.F. Ruiz-García M. Fernández-Nieto M. Sastre J. Comparison of bronchial hyperresponsiveness to methacholine and adenosine and airway inflammation markers in patients with suspected asthma. J Asthma. 2011; 48: 335-340 Crossref PubMed Scopus (12) Google Scholar and may be ideal for confirming bronchial hyperresponsiveness due to their high specificity.

The Pivotal Role of Airway Smooth Muscle in Asthma Pathophysiology

Asthma is characterized by the association of airway hyperresponsiveness (AHR), inflammation, and remodelling. The aim of the present article is to review the pivotal role of airway smooth muscle (ASM) in the pathophysiology of asthma. ASM is the main effector of AHR. The mechanisms of AHR in asthma may involve a larger release of contractile mediators and/or a lower release of relaxant mediators, an improved ASM cell excitation/contraction coupling, and/or an alteration in the contraction/load coupling. Beyond its contractile function, ASM is also involved in bronchial inflammation and remodelling. Whereas ASM is a target of the inflammatory process, it can also display proinflammatory and immunomodulatory functions, through its synthetic properties and the expression of a wide range of cell surface molecules. ASM remodelling represents a key feature of asthmatic bronchial remodelling. ASM also plays a role in promoting complementary airway structural alterations, in particular by its synthetic function.

Asthma diagnosis and treatment: Filling in the information gaps

Current approaches to the diagnosis and management of asthma are based on guideline recommendations, which have provided a framework for the efforts. Asthma, however, is emerging as a heterogeneous disease, and these features need to be considered in both the diagnosis and management of this disease in individual patients. These diverse or phenotypic features add complexity to the diagnosis of asthma, as well as attempts to achieve control with treatment. Although the diagnosis of asthma is often based on clinical information, it is important to pursue objective criteria as well, including an evaluation for reversibility of airflow obstruction and bronchial hyperresponsiveness, an area with new diagnostic approaches. Furthermore, there exist a number of treatment gaps (ie, exacerbations, step-down care, use of antibiotics, and severe disease) in which new direction is needed to improve care. Amajor morbidity in asthmatic patients occurs with exacerbations and in patients with severe disease. Novel approaches to treatment for these conditions will be an important advance to reduce the morbidity associated with asthma.

The effect of airway remodelling on airway hyper-responsiveness in asthma

The mechanisms of airway hyper-responsiveness are only partially understood and the contribution of airway remodelling is unknown. Airway remodelling can be assessed by measuring airway distensibility, which is reduced in asthma, even when lung function is normal. We hypothesised that airway remodelling contributes to airway hyper-responsiveness in asthma, independent of steroid-responsive airway inflammation. To determine the relationship between airway distensibility and airway responsiveness at baseline and after 12 weeks of inhaled corticosteroid therapy in a group of asthmatics with airway hyper-responsiveness. Nineteen doctor-diagnosed asthmatics had airway distensibility measured as the slope of the relationship between conductance and lung volume by the forced oscillation technique. Lung function, exhaled nitric oxide and methacholine challenge were also measured. Subjects had inhaled corticosteroid therapy for 12 weeks after which all measurements were repeated. At baseline, airway distensibility (mean, 95%CI) was 0.19(0.14-0.23) cm H(2)O(-1)s(-1), exhaled nitric oxide was 13.1(10.3-16.6)ppb and airway distensibility correlated with eNO (p=0.04) and disease duration (p=0.02) but not with airway responsiveness (p=0.46), FEV(1) (p=0.09) or age (p=0.23). After treatment, exhaled nitric oxide decreased (p=0.0002), FEV(1) improved (p=0.0001), airway responsiveness improved (p=0.0002), and there was a small improvement in airway distensibility but it did not normalise (p=0.05). Airway distensibility was not correlated with either exhaled nitric oxide (p=0.49) or airway responsiveness (p=0.20). Uncontrolled airway inflammation causes a small decrease in the distensibility of the airways of asthmatics with airway hyper-responsiveness. The lack of association between airway responsiveness and airway distensibility, both before and after 12 weeks ICS treatment, suggests that airway remodelling does not contribute to airway hyper-responsiveness in asthma.

Airway Smooth Muscle Responsiveness: The Origin of Airway Hyperresponsiveness in Asthma?

Airway Smooth Muscle Responsiveness: The Origin of Airway Hyperresponsiveness in Asthma?

Editorial from Editor-in-Chief [Hot topic:Airway Hyperresponsiveness in Asthma: Are We there Yet?

Editorial from Editor-in-Chief [Hot topic:Airway Hyperresponsiveness in Asthma: Are We there Yet?

CPAP as a novel treatment for bronchial asthma?

airway hyperresponsiveness in bronchial asthma is deemed to be sustained by airway wall inflammation, which ultimately triggers the airway smooth muscle (ASM) to contract. Yet the magnitude of the resulting airway narrowing in vivo depends on several factors, including the ASM mass, its

Kv7 Channels in Airway Smooth Muscle Cells as Targets for Asthma Therapy

Asthma is commonly associated with airway hyperresponsiveness (AHR) involving hypercontraction of airway smooth muscle cells (ASMCs). The mechanisms underlying this process are, however, not well understood. Here we test the hypothesis that bronchoconstrictor agonists suppress Kv7 potassium currents leading to ASMC contraction. We detected Kv7.1–7.5 mRNAs in guinea pig lung by RT‐PCR and Kv7.3–7.5 proteins by immunostaining of isolated ASMCs. Function of Kv7 channels was demonstrated in freshly isolated guinea pig ASMCs: currents measured by perforated patch whole cell voltage clamp displayed electrophysiological characteristics (slow voltage‐dependent non‐inactivating Kv currents with a very negative activation threshold (~−60mV) and a V0.5 ~ −31 mV) and pharmacological characteristics (enhancement by selective activators, suppression by selective blockers) of Kv7 currents. Bronchoconstrictor agonists methacholine (100 nM) and histamine (30 μM), significantly suppressed Kv7 currents and this effect was reversed by Kv7 channel activators. Our results provide the first evidence that Kv7 channels are present in ASMCs, that their activity is suppressed by bronchoconstrictor agonists, and that this effect can be reversed by Kv7 channel activators. Our findings reveal novel mechanisms for ASMC hypercontraction and identify a potential new therapeutic strategy for the treatment of AHR in asthma.

Multiscale mathematical models of airway constriction and disease

Loss of lung function in airway disease frequently involves many complex phenomena and interconnected underlying causes. In many conditions, such as asthmatic airway hyper-responsiveness, hypothesised underlying causes span multiple spatial scales. In cases like this, it is insufficient to take a reductionist approach, wherein each subsystem (at a given spatial scale) is considered in isolation and then the whole is taken to be merely the sum of the parts; this is because there can be significant and important interactions and synergies between spatial scales. Experimentally this can manifest as, for example, significant differences between behaviour in isolated tissue and that seen in vivo, while from a modelling perspective, it necessitates multiscale modelling approaches. Because it is precisely in these complex environs that models have the greatest potential to improve understanding of underlying behaviours, these multiscale models are of particular importance. This paper reviews several examples of multiscale models from the most important models in the literature, with a particular emphasis on those concerned with airway hyper-responsiveness and airway constriction.

Peripheral lung mechanics in asthma: Exploring the outer limits

Asthma is a disease characterized by airways hyperresponsiveness (AHR), which is traditionally thought to involve the large, central airways. However, there is increasing evidence of the importance of peripheral airway involvement in asthma as well. Our group has developed particular expertise in measuring peripheral lung mechanics in both humans and mice. This presentation will review data on lung mechanics in subjects with asthma obtained by both classical means and uniquely through the wedged bronchoscope, as well as relevant experiments in mice. Our findings reveal that the lung periphery is hyperresponsive to stimuli in asthmatic subjects, with evidence of airway closure. We also show that the overall impedance of the lung is determined by a combination of peripheral airway narrowing and central airway shunting that occurs in both normal and asthmatic subjects. Experiments in mice have revealed the importance of airway closure in contributing to the phenomenon of AHR. Based on the effects of fibrin on lung mechanics, fibrin may contribute to airway closure via inactivation of surfactant. Another mechanism contributing to AHR is the heterogeneity of airway narrowing. We have explored this in humans by combining the forced oscillation technique with computerized tomography imaging of the lung, and demonstrated that heterogeneity is common to both normal and asthmatic subjects. Further experiments are ongoing and planned in both mice and humans to elucidate the role of fibrin, surfactant and heterogeneous airway narrowing and closure in contributing to AHR in asthma.

The laminin β1-competing peptide YIGSR induces a hypercontractile, hypoproliferative airway smooth muscle phenotype in an animal model of allergic asthma

BackgroundFibroproliferative airway remodelling, including increased airway smooth muscle (ASM) mass and contractility, contributes to airway hyperresponsiveness in asthma. In vitro studies have shown that maturation of ASM cells to a (hyper)contractile phenotype is dependent on laminin, which can be inhibited by the laminin-competing peptide Tyr-Ile-Gly-Ser-Arg (YIGSR). The role of laminins in ASM remodelling in chronic asthma in vivo, however, has not yet been established.MethodsUsing an established guinea pig model of allergic asthma, we investigated the effects of topical treatment of the airways with YIGSR on features of airway remodelling induced by repeated allergen challenge, including ASM hyperplasia and hypercontractility, inflammation and fibrosis. Human ASM cells were used to investigate the direct effects of YIGSR on ASM proliferation in vitro.ResultsTopical administration of YIGSR attenuated allergen-induced ASM hyperplasia and pulmonary expression of the proliferative marker proliferating cell nuclear antigen (PCNA). Treatment with YIGSR also increased both the expression of sm-MHC and ASM contractility in saline- and allergen-challenged animals; this suggests that treatment with the laminin-competing peptide YIGSR mimics rather than inhibits laminin function in vivo. In addition, treatment with YIGSR increased allergen-induced fibrosis and submucosal eosinophilia. Immobilized YIGSR concentration-dependently reduced PDGF-induced proliferation of cultured ASM to a similar extent as laminin-coated culture plates. Notably, the effects of both immobilized YIGSR and laminin were antagonized by soluble YIGSR.ConclusionThese results indicate that the laminin-competing peptide YIGSR promotes a contractile, hypoproliferative ASM phenotype in vivo, an effect that appears to be linked to the microenvironment in which the cells are exposed to the peptide.

A multiscale, spatially distributed model of asthmatic airway hyper-responsiveness

We present a multiscale, spatially distributed model of lung and airway behaviour with the goal of furthering the understanding of airway hyper-responsiveness and asthma. The model provides an initial computational framework for linking events at the cellular and molecular levels, such as Ca 2+ and crossbridge dynamics, to events at the level of the entire organ. At the organ level, parenchymal tissue is modelled using a continuum approach as a compressible, hyperelastic material in three dimensions, with expansion and recoil of lung tissue due to tidal breathing. The governing equations of finite elasticity deformation are solved using a finite element method. The airway tree is embedded in this tissue, where each airway is modelled with its own airway wall, smooth muscle and surrounding parenchyma. The tissue model is then linked to models of the crossbridge mechanics and their control by Ca 2+ dynamics, thus providing a link to molecular and cellular mechanisms in airway smooth muscle cells. By incorporating and coupling the models at these scales, we obtain a detailed, computational multiscale model incorporating important physiological phenomena associated with asthma.