Structural basis for exaggerated airway narrowingThis article is one of a selection of papers published in the Special Issue on Recent Advances in Asthma Research.

2007 ◽  
Vol 85 (7) ◽  
pp. 653-658 ◽  
Author(s):  
Peter D. Paré ◽  
Brent E. McParland ◽  
Chun Y. Seow
Keyword(s):  
Airway Hyperresponsiveness ◽  
Structural Changes ◽  
Airway Remodeling ◽  
Structural Basis ◽  
Airway Wall ◽  
Special Issue ◽  
Airway Narrowing ◽  
Quantitative Changes ◽  
Or Organization ◽  
Selection Of

Airway hyperresponsiveness, particularly the ability of airways to narrow excessively in response to stimuli that normally cause little airway narrowing in nonasthmatic subjects, is a characteristic feature of asthma and the basis of its symptoms. Although airway hyperresponsiveness may be partly the result of alterations in the contractile phenotype of the airway smooth muscle, there is evidence that it may also be caused by structural changes in the airway wall, collectively termed airway remodeling. Airway remodeling is defined as changes in composition, quantity, and (or) organization of cellular and molecular constituents of the airway wall. Airway wall remodeling that occurs in asthma can result in functional alterations because of quantitative changes in airway wall compartments, and (or) because of changes in the biochemical composition or material properties of the various constituents of the airway wall. This brief review summarizes the quantitative changes in the dimensions and organization of the airway wall compartments that have been described and explains how structural alterations may lead to the exaggerated airway narrowing.

scholarly journals Mechanisms of Remodeling in Asthmatic Airways

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Adrian Shifren ◽  
Chad Witt ◽  
Chandrika Christie ◽  
Mario Castro
Keyword(s):  
Airway Hyperresponsiveness ◽  
Structural Changes ◽  
Airway Remodeling ◽  
Airflow Obstruction ◽  
Asthma Treatment ◽  
Airway Wall ◽  
Lung Function Decline ◽  
Airway Wall Thickness ◽  
Asthma Patients ◽  
Reversible Airflow Obstruction

Asthma is a chronic inflammatory airway disorder characterized by airway hyperresponsiveness and reversible airflow obstruction. Subgroups of asthma patients develop airflow obstruction that is irreversible or only partially reversible and experience an accelerated rate of lung function decline. The structural changes in the airways of these patients are referred to as airway remodeling. All elements of the airway wall are involved, and remodeled airway wall thickness is substantially increased compared to normal control airways. Airway remodeling is thought to contribute to the subphenotypes of irreversible airflow obstruction and airway hyperresponsiveness, and it has been associated with increased disease severity. Reversal of remodeling is therefore of paramount therapeutic importance, and mechanisms responsible for airway remodeling are feasible therapeutic targets for asthma treatment. This paper will focus on our current understanding of the mechanisms of airway remodeling in asthma and potential targets for future intervention.

scholarly journals Decreased airway narrowing and smooth muscle contraction in hyperresponsive pigs

2002 ◽  
Vol 93 (4) ◽  
pp. 1296-1300 ◽  
Author(s):  
Debra J. Turner ◽  
Peter B. Noble ◽  
Matthew P. Lucas ◽  
Howard W. Mitchell
Keyword(s):  
Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Porcine Model ◽  
Smooth Muscle Contraction ◽  
Airway Wall ◽  
Muscle Contractility ◽  
Smooth Muscle Contractility ◽  
Airway Narrowing

Increased smooth muscle contractility or reduced smooth muscle mechanical loads could account for the excessive airway narrowing and hyperresponsiveness seen in asthma. These mechanisms were investigated by using an allergen-induced porcine model of airway hyperresponsiveness. Airway narrowing to electric field stimulation was measured in isolated bronchial segments, over a range of transmural pressures (0–20 cmH2O). Contractile responses to ACh were measured in bronchial segments and in isolated tracheal smooth muscle strips isolated from control and test (ovalbumin sensitized and challenged) pigs. Test airways narrowed less than controls ( P < 0.0001). Test pigs showed reduced contractility to ACh, both in isolated bronchi ( P < 0.01) and smooth muscle strips ( P < 0.01). Thus isolated airways from pigs exhibiting airway hyperresponsiveness in vivo are hyporesponsive in vitro. The decreased narrowing in bronchi from hyperresponsive pigs may be related to decreased smooth muscle contractility. These data suggest that mechanisms external to the airway wall may be important to the hyperresponsive nature of sensitized lungs.

scholarly journals Repeated airway constrictions in mice do not alter respiratory function

2018 ◽  
Vol 124 (6) ◽  
pp. 1483-1490 ◽  
Author(s):  
Samuel Mailhot-Larouche ◽  
Louis Deschênes ◽  
Morgan Gazzola ◽  
Katherine Lortie ◽  
Cyndi Henry ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Respiratory System ◽  
Structural Changes ◽  
Respiratory Mechanics ◽  
Airway Remodeling ◽  
Structural Components ◽  
Airway Wall ◽  
Cell Hyperplasia ◽  
Shed Light

It is suggested that the frequent strain the airways undergo in asthma because of repeated airway smooth muscle (ASM)-mediated constrictions contributes to airway wall remodeling. However, the effects of repeated constrictions on airway remodeling, as well as the ensuing impact of this presumptive remodeling on respiratory mechanics, have never been investigated in subjects without asthma. In this study, we set out to determine whether repeated constrictions lead to features that are reminiscent of asthma in mice without asthma. BALB/c mice were subjected to a 30-min constriction elicited by aerosolized methacholine every other day over 6 wk. Forty-eight hours after the last constriction, the mechanics of the respiratory system was evaluated at baseline and in response to incremental doses of nebulized methacholine with the flexiVent. The whole-lung lavages, the tracheas, and the lungs were also collected to evaluate inflammation, the contractile capacity of ASM, and the structural components of the airway wall, respectively. The resistance and the compliance of the respiratory system, as well as the Newtonian resistance and the resistive and elastic properties of the lung tissue, were not affected by repeated constrictions, both at baseline and in response to methacholine. All the other examined features also remained unaltered, except the number of goblet cells in the epithelium and the number of macrophages in the whole-lung lavages, which both increased with repeated constrictions. This study demonstrates that, despite causing goblet cell hyperplasia and a mild macrophagic inflammation, repeated constrictions with methacholine do not lead to structural changes that adversely impact the physiology. NEW & NOTEWORTHY Repeated airway constrictions led to signs of remodeling that are typically observed in asthma, which neither altered respiratory mechanics nor the contractile capacity of airway smooth muscle. These findings shed light on a debate between those claiming that constrictions induce remodeling and those convinced that methacholine challenges are harmless. Insofar as our results with mice relate to humans, the findings indicate that repeated challenges with methacholine can be performed safely.

scholarly journals Advances and Challenges of Antibody Therapeutics for Severe Bronchial Asthma

2021 ◽  
Vol 23 (1) ◽  
pp. 83
Author(s):  
Yuko Abe ◽  
Yasuhiko Suga ◽  
Kiyoharu Fukushima ◽  
Hayase Ohata ◽  
Takayuki Niitsu ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Severe Asthma ◽  
Airway Hyperresponsiveness ◽  
Airway Remodeling ◽  
Disease Process ◽  
Antibody Treatment ◽  
Airway Narrowing ◽  
Antibody Therapeutics ◽  
Phenotype Classification ◽  
Major Factors

Asthma is a disease that consists of three main components: airway inflammation, airway hyperresponsiveness, and airway remodeling. Persistent airway inflammation leads to the destruction and degeneration of normal airway tissues, resulting in thickening of the airway wall, decreased reversibility, and increased airway hyperresponsiveness. The progression of irreversible airway narrowing and the associated increase in airway hyperresponsiveness are major factors in severe asthma. This has led to the identification of effective pharmacological targets and the recognition of several biomarkers that enable a more personalized approach to asthma. However, the efficacies of current antibody therapeutics and biomarkers are still unsatisfactory in clinical practice. The establishment of an ideal phenotype classification that will predict the response of antibody treatment is urgently needed. Here, we review recent advancements in antibody therapeutics and novel findings related to the disease process for severe asthma.

scholarly journals Heterogeneity of airway wall dimensions in humans: a critical determinant of lung function in asthmatics and nonasthmatics

2017 ◽  
Vol 312 (3) ◽  
pp. L425-L431 ◽  
Author(s):  
Christopher D. Pascoe ◽  
Chun Y. Seow ◽  
Tillie L. Hackett ◽  
Peter D. Paré ◽  
Graham M. Donovan
Keyword(s):  
Airway Remodeling ◽  
Airflow Obstruction ◽  
Small Airways ◽  
Airway Wall ◽  
Critical Determinant ◽  
Mean Values ◽  
Airway Narrowing ◽  
Wall Area ◽  
First Time ◽  
Fixed Airflow Obstruction

Airway remodeling, a key feature of asthma, alters every layer of the airway wall but most strikingly the airway smooth muscle (ASM) layer. Airway remodeling in asthmatics contributes to fixed airflow obstruction and can amplify airway narrowing caused by ASM activation. Previous modeling studies have shown that the increase in ASM mass has the largest effect on increasing maximal airway narrowing. Simulated heterogeneity in the dimensions and properties of the airway wall can further amplify airway narrowing. Using measurements made on histological sections from donor lungs, we show for the first time that there is profound heterogeneity of ASM area and wall area in both nonasthmatics and asthmatics. Using a mathematical model, we found that this heterogeneity, together with changes in the mean values, contributes to an increased baseline resistance and elastance in asthmatics as well as a leftward shift in the responsiveness of the airways to a simulated agonist in both nonasthmatics and asthmatics. The ability of heterogeneous wall dimensions to shift the dose-response curve is largely due to an increased susceptibility for the small airways to close. This research confirms that heterogeneity of airway wall dimensions can contribute to exaggerated airway narrowing and provides an actual assessment of the magnitude of these effects.

scholarly journals Lung parenchymal shear modulus, airway wall remodeling, and bronchial hyperresponsiveness

1997 ◽  
Vol 83 (1) ◽  
pp. 140-147 ◽  
Author(s):  
Rodney K. Lambert ◽  
Peter D. Paré
Keyword(s):  
Smooth Muscle ◽  
Shear Modulus ◽  
Airway Remodeling ◽  
Bronchial Hyperresponsiveness ◽  
Lung Parenchyma ◽  
Wall Thickening ◽  
Forced Expiration ◽  
Airway Wall ◽  
Airway Narrowing ◽  
Muscle Shortening

Lambert, Rodney K., and Peter D. Paré. Lung parenchymal shear modulus, airway wall remodeling, and bronchial hyperresponsiveness. J. Appl. Physiol.83(1): 140–147, 1997.—When airways narrow, either through the action of smooth muscle shortening or during forced expiration, the lung parenchyma is locally distorted and provides an increased peribronchial stress that resists the narrowing. Although this interdependence has been well studied, the quantitative significance of airway remodeling to interdependence has not been elucidated. We have used an improved computational model of the bronchial response to smooth muscle agonists to investigate the relationships between airway narrowing (as indicated by airway resistance), parenchymal shear modulus, adventitial thickening, and inner wall thickening at lung recoil pressures of 4, 5, and 8 cmH2O. We have found that, at low recoil pressures, decreases in parenchymal shear modulus have a significant effect that is comparable to that of moderate thickening of the airway wall. At higher lung recoil pressures, the effect is negligible.

Remodelling and Inflammation in Bronchial Asthma

2003 ◽  
Vol 1 (1) ◽  
pp. 9-12 ◽  
Author(s):  
G. Riccioni ◽  
N. D'Orazio ◽  
R. Della Vecchia ◽  
T. Iezzi ◽  
C. Di Ilio
Keyword(s):  
Airway Inflammation ◽  
Bronchial Asthma ◽  
Structural Changes ◽  
Bronchial Hyperresponsiveness ◽  
Lymphocytic Infiltration ◽  
Smooth Muscle Contraction ◽  
Airway Remodelling ◽  
Airway Wall ◽  
Airway Narrowing ◽  
Abnormal Accumulation

Chronic stable asthma is characterized by inflammation of the airway wall, with abnormal accumulation of basophils, eosinophils, lymphocytes, mast cells, macrophages, dendritic cells and myofibroblasts. The airway inflammation is not confined to severe asthma, but is also found in mild and moderate asthma. This inflammation results in a peculiar type of lymphocytic infiltration whereby Th2 lymphocytes secrete cytokines that orchestrate cellular inflammation and promote airway hyperresponsiveness. The term “airway remodelling” in bronchial asthma refers to structural changes that occurr in conjunction with, or because of, chronic airway inflammation. Airway remodelling results in alterations in the airway epithelium, lamina propria, and submucosa, leading to thickening of airway wall. The consequences of airway remodelling in asthma include incompletely reversible airway narrowing, bronchial hyperresponsiveness (BHR), smooth muscle contraction, airway edema, and mucus hypersecretion which may predispose persons with asthma to exacerbations and even death from airway obstruction.

Airway wall remodeling: friend or foe?

2003 ◽  
Vol 95 (1) ◽  
pp. 426-434 ◽  
Author(s):  
Brent E. McParland ◽  
Peter T. Macklem ◽  
Peter D. Paré
Keyword(s):  
Airway Hyperresponsiveness ◽  
Protective Effects ◽  
Airway Wall ◽  
Short Term ◽  
Airway Narrowing ◽  
Asthmatic Patients ◽  
Short Term Exposure ◽  
Inflammatory Stimuli

Airway wall remodeling is well documented for asthmatic airways and is believed to result from chronic and/or short-term exposure to inflammatory stimuli. Airway wall remodeling can contribute to airway narrowing as well as to the airway hyperresponsiveness, which is a characteristic abnormality in asthma. However, the potential for airway narrowing could be much worse if it were not for some of the protective effects of remodeling that may help to limit airway narrowing in asthmatic patients. This minireview discusses the evidence for airway wall remodeling and its effects, friend and/or foe, on airway narrowing in asthmatic patients.

scholarly journals Immunologic and Non-Immunologic Mechanisms Leading to Airway Remodeling in Asthma

2020 ◽  
Vol 21 (3) ◽  
pp. 757 ◽  
Author(s):  
Lei Fang ◽  
Qinzhu Sun ◽  
Michael Roth
Keyword(s):  
Allergic Asthma ◽  
Immune Cells ◽  
Structural Changes ◽  
Airway Remodeling ◽  
Airway Wall ◽  
Epigenetic Events ◽  
Wide Range ◽  
Direct Binding ◽  
Tissue Cells ◽  
Definition Of

Asthma increases worldwide without any definite reason and patient numbers double every 10 years. Drugs used for asthma therapy relax the muscles and reduce inflammation, but none of them inhibited airway wall remodeling in clinical studies. Airway wall remodeling can either be induced through pro-inflammatory cytokines released by immune cells, or direct binding of IgE to smooth muscle cells, or non-immunological stimuli. Increasing evidence suggests that airway wall remodeling is initiated early in life by epigenetic events that lead to cell type specific pathologies, and modulate the interaction between epithelial and sub-epithelial cells. Animal models are only available for remodeling in allergic asthma, but none for non-allergic asthma. In human asthma, the mechanisms leading to airway wall remodeling are not well understood. In order to improve the understanding of this asthma pathology, the definition of “remodeling” needs to be better specified as it summarizes a wide range of tissue structural changes. Second, it needs to be assessed if specific remodeling patterns occur in specific asthma pheno- or endo-types. Third, the interaction of the immune cells with tissue forming cells needs to be assessed in both directions; e.g., do immune cells always stimulate tissue cells or are inflamed tissue cells calling immune cells to the rescue? This review aims to provide an overview on immunologic and non-immunologic mechanisms controlling airway wall remodeling in asthma.

Smooth muscle molecular mechanics in airway hyperresponsiveness and asthmaThis paper is one of a selection of papers published in this Special Issue, entitled the Young Investigators' Forum.

2007 ◽  
Vol 85 (1) ◽  
pp. 133-140 ◽  
Author(s):  
Fulvio R. Gil ◽  
Anne-Marie Lauzon
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Airway Remodeling ◽  
Force Production ◽  
Muscle Length ◽  
Protective Role ◽  
Respiratory Disorder ◽  
Airway Narrowing ◽  
Muscle Plasticity

Asthma is a respiratory disorder characterized by airway inflammation and hyperresponsiveness associated with reversible airway obstruction. The relative contributions of airway hyperresponsiveness and inflammation are still debated, but ultimately, airway narrowing mediated by airway smooth muscle contraction is the final pathway to asthma. Considerable effort has been devoted towards identifying the factors that lead to the airway smooth muscle hypercontractility observed in asthma, and this will be the focus of this review. Airway remodeling has been observed in severe and fatal asthma. However, it is unclear whether remodeling plays a protective role or worsens airway responsiveness. Smooth muscle plasticity is a mechanism likely implicated in asthma, whereby contractile filament rearrangements lead to maximal force production, independent of muscle length. Increased smooth muscle rate of shortening via altered signaling pathways or altered contractile protein expression has been demonstrated in asthma and in numerous models of airway hyperresponsiveness. Increased rate of shortening is implicated in counteracting the relaxing effect of tidal breathing and deep inspirations, thereby creating a contracted airway smooth muscle steady-state. Further studies are therefore required to understand the numerous mechanisms leading to the airway hyperresponsiveness observed in asthma as well as their multiple interactions.

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