The effects of repeated allergen challenge on airway smooth muscle structural and molecular remodeling in a rat model of allergic asthma

2009 ◽  
Vol 297 (4) ◽  
pp. L698-L705 ◽  
Author(s):  
Isabelle Labonté ◽  
Muhannad Hassan ◽  
Paul-André Risse ◽  
Kimitake Tsuchiya ◽  
Michel Laviolette ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Ex Vivo ◽  
Mrna Level ◽  
Allergen Challenge ◽  
Airway Responsiveness ◽  
Brown Norway ◽  
Contractile Phenotype ◽  
The Relationship

The effects of remodeling of airway smooth muscle (SM) by hyperplasia on airway SM contractility in vivo are poorly explored. The aim of this study was to investigate the relationship between allergen-induced airway SM hyperplasia and its contractile phenotype. Brown Norway rats were sensitized with ovalbumin (OVA) or saline on day 0 and then either OVA-challenged once on day 14 and killed 24 h later or OVA-challenged 3 times (on days 14, 19, and 24) and killed 2 or 7 days later. Changes in SM mass, expression of total myosin, SM myosin heavy chain fast isoform (SM-B) and myosin light chain kinase (MLCK), tracheal contractions ex vivo, and airway responsiveness to methacholine (MCh) in vivo were assessed. One day after a single OVA challenge, the number of SM cells positive for PCNA was greater than for control animals, whereas the SM mass, contractile phenotype, and tracheal contractility were unchanged. Two days after three challenges, SM mass and PCNA immunoreactive cells were increased (3- and 10-fold, respectively; P < 0.05), but airway responsiveness to MCh was unaffected. Lower expression in total myosin, SM-B, and MLCK was observed at the mRNA level ( P < 0.05), and total myosin and MLCK expression were lower at the protein level ( P < 0.05) after normalization for SM mass. Normalized tracheal SM force generation was also significantly lower 2 days after repeated challenges ( P < 0.05). Seven days after repeated challenges, features of remodeling were restored toward control levels. Allergen-induced hyperplasia of SM cells was associated with a loss of contractile phenotype, which was offset by the increase in mass.

scholarly journals Repeated allergen inhalations induce DNA synthesis in airway smooth muscle and epithelial cells in vivo

1998 ◽  
Vol 274 (3) ◽  
pp. L417-L424 ◽  
Author(s):  
Reynold A. Panettieri ◽  
Richard K. Murray ◽  
Andrew J. Eszterhas ◽  
Gulsevil Bilgen ◽  
James G. Martin
Keyword(s):  
Smooth Muscle ◽  
Epithelial Cells ◽  
Basement Membrane ◽  
Dna Synthesis ◽  
Airway Smooth Muscle ◽  
Allergen Challenge ◽  
Brown Norway ◽  
Small Airways ◽  
Airway Epithelial

Airway smooth muscle (ASM) mass appears to be increased in the bronchi of patients with chronic severe asthma. Although the precise mechanisms that induce these changes are unknown, increases in ASM mass are caused, in part, by ASM cell proliferation. After allergen challenge in rats, it has been possible to demonstrate an increase in ASM mass by morphometric techniques. To examine whether hyperplasia is involved in ASM cell growth in vivo, we investigated whether repeated allergen challenges in sensitized Brown Norway rats stimulated DNA synthesis in airway epithelial and ASM cells. Animals that were actively sensitized to ovalbumin (OA) received either three aerosolized OA or saline challenges at 5-day intervals. DNA synthesis was measured by indirect immunohistochemical techniques with an anti-bromodeoxyuridine (BrdU) antibody. OA inhalations increased ASM mass as determined by morphometry and also induced DNA synthesis in both airway epithelial and ASM cells in the airways of sensitized animals compared with saline-challenged control animals. ASM mass was increased in large- and medium-sized airways but not in small airways. However, the number of BrdU-positive ASM cells normalized to basement membrane length was also greater in the large- and medium-sized airways compared with that in the small airways. When the number of BrdU-positive epithelial cells was normalized to basement membrane length, there was no difference among airway sizes and the number of BrdU-positive epithelial cells. These data suggest that DNA synthesis is induced in both airway epithelial and ASM cells after inhalational antigen challenge.

Airway smooth muscle tone increases airway responsiveness in healthy young adults

2017 ◽  
Vol 312 (3) ◽  
pp. L348-L357 ◽  
Author(s):  
Morgan Gazzola ◽  
Katherine Lortie ◽  
Cyndi Henry ◽  
Samuel Mailhot-Larouche ◽  
David G. Chapman ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Muscle Tone ◽  
Airway Responsiveness ◽  
High Dose ◽  
Forced Oscillation Technique ◽  
Single High Dose ◽  
Healthy Humans

Force adaptation, a process whereby sustained spasmogenic activation (viz., tone) of airway smooth muscle (ASM) increases its contractile capacity, has been reported in isolated ASM tissues in vitro, as well as in mice in vivo. The objective of the present study was to assess the effect of tone on airway responsiveness in humans. Ten healthy volunteers underwent methacholine challenge on two occasions. One challenge consisted of six serial doses of saline followed by a single high dose of methacholine. The other consisted of six low doses of methacholine 5 min apart followed by a higher dose. The cumulative dose was identical for both challenges. After both methacholine challenges, subjects took a deep inspiration (DI) to total lung capacity as another way to probe ASM mechanics. Responses to methacholine and the DI were measured using a multifrequency forced oscillation technique. Compared with a single high dose, the challenge preceded by tone led to an elevated response measured by respiratory system resistance (Rrs) and reactance at 5 Hz. However, there was no difference in the increase in Rrs at 19 Hz, suggesting a predominant effect on smaller airways. Increased tone also reduced the efficacy of DI, measured by an attenuated maximal dilation during the DI and an increased renarrowing post-DI. We conclude that ASM tone increases small airway responsiveness to inhaled methacholine and reduces the effectiveness of DI in healthy humans. This suggests that force adaptation may contribute to airway hyperresponsiveness and the reduced bronchodilatory effect of DI in asthma.

Sites of allergic airway smooth muscle remodeling and hyperresponsiveness are not associated in the rat

2010 ◽  
Vol 109 (4) ◽  
pp. 1170-1178 ◽  
Author(s):  
Sana Siddiqui ◽  
Taisuke Jo ◽  
Meiyo Tamaoka ◽  
Karim H. Shalaby ◽  
Heberto Ghezzo ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Goblet Cell ◽  
Allergen Challenge ◽  
Brown Norway ◽  
Small Airways ◽  
Cell Hyperplasia ◽  
Goblet Cell Hyperplasia ◽  
Wall Area ◽  
Large Airway

The cause-and-effect relationship between airway smooth muscle (ASM) remodeling and airway hyperresponsiveness (AHR) following allergen challenge is not well established. Using a rat model of allergen-induced ASM remodeling we explored the relationship between the site of ASM remodeling and AHR. Brown Norway rats, sensitized and challenged (3 times at 5-day intervals) with ovalbumin, were intranasally administered 0.1 mg/kg budesonide 24 and 1 h before challenge. Airway responses to aerosolized methacholine were assessed 48 h or 1 wk after three challenges. Airways were stained and analyzed for total airway wall area, area of smooth muscle-specific α-actin, and goblet cell hyperplasia, and the constant-phase model was used to resolve the changes in respiratory system mechanics into large airway and peripheral lung responses. After three ovalbumin challenges, there was a significant increase in ASM area and in the total wall area in all sized airways as well as an increase in goblet cells in the central airways. Budesonide inhibited ASM growth and central airway goblet cell hyperplasia following ovalbumin challenges. Budesonide also inhibited small but not large airway total wall area. AHR was attributable to excessive responses of the small airways, whereas responsiveness of the large airways was unchanged. Budesonide did not inhibit AHR after repeated challenge. We conclude that ASM remodeling induced by repeated allergen challenges involves the entire bronchial tree, whereas AHR reflects alterations in the lung periphery. Prevention of ASM remodeling by corticosteroid does not abrogate AHR.

scholarly journals Molecular Mechanisms for the Mechanical Modulation of Airway Responsiveness

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Wenwu Zhang ◽  
Susan J. Gunst
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Actin Polymerization ◽  
Molecular Mechanisms ◽  
Airway Responsiveness ◽  
Small Gtpase ◽  
Cortical Actin

The smooth muscle of the airways is exposed to continuously changing mechanical forces during normal breathing. The mechanical oscillations that occur during breathing have profound effects on airway tone and airway responsiveness both in experimental animals and humans in vivo and in isolated airway tissues in vitro. Experimental evidence suggests that alterations in the contractile and mechanical properties of airway smooth muscle tissues caused by mechanical perturbations result from adaptive changes in the organization of the cytoskeletal architecture of the smooth muscle cell. The cytoskeleton is a dynamic structure that undergoes rapid reorganization in response to external mechanical and pharmacologic stimuli. Contractile stimulation initiates the assembly of cytoskeletal/extracellular matrix adhesion complex proteins into large macromolecular signaling complexes (adhesomes) that undergo activation to mediate the polymerization and reorganization of a submembranous network of actin filaments at the cortex of the cell. Cortical actin polymerization is catalyzed by Neuronal-Wiskott–Aldrich syndrome protein (N-WASP) and the Arp2/3 complex, which are activated by pathways regulated by paxillin and the small GTPase, cdc42. These processes create a strong and rigid cytoskeletal framework that may serve to strengthen the membrane for the transmission of force generated by the contractile apparatus to the extracellular matrix, and to enable the adaptation of smooth muscle cells to mechanical stresses. This model for the regulation of airway smooth muscle function can provide novel perspectives to explain the normal physiologic behavior of the airways and pathophysiologic properties of the airways in asthma.

Human and rat airway smooth muscle responsiveness after ozone exposure in vitro

1996 ◽  
Vol 271 (4) ◽  
pp. L631-L636 ◽  
Author(s):  
E. Roux ◽  
C. Guibert ◽  
H. Crevel ◽  
J. P. Savineau ◽  
R. Marthan
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Dose Response ◽  
Ex Vivo ◽  
Airway Responsiveness ◽  
Ozone Exposure ◽  
Maximal Response ◽  
The Right ◽  
Rat Trachea

We previously reported that NO2 and acrolein administered ex vivo to the lung altered the subsequent responsiveness of airway smooth muscle. The aim of this study was to determine the dose-response relationship for O3 in both human isolated bronchi and rat tracheae and to investigate the mechanisms underlying O3-induced airway responsiveness. Exposure to 1 ppm O3 for 15 min significantly increased the maximal response to carbachol of rat tracheal rings to 149.6 +/- 5.4% of the reference response to acetylcholine (ACh) compared with that of unexposed rings (131.3 +/- 2.4%, n = 6, P < 0.05). The change in maximal airway responsiveness to carbachol, when plotted against the product of exposure concentration and exposure time to O3, a surrogate for the dose, formed a bell-shaped curve. The peak of this dose-response curve was shifted to the right for human bronchi (50 ppm x min, n = 5) compared with that of rat tracheae (15 ppm x min, n = 6). In the rat trachea, responses to KCl were not altered by O3, whereas those to 5-hydroxytryptamine hydrochloride (5-HT) were significantly increased. Finally, in the absence of external Ca2+, O3 exposure still potentiated the maximal response to carbachol from 73.6 +/- 13.9 to 137.0 +/- 6.0% and that to 5-HT from 21.5 +/- 5.5 to 38.7 +/- 2.2% of the reference ACh response. These results indicate that O3 alters the subsequent in vitro airway responsiveness depending on 1) the dose, 2) the nature of the agonist, and 3) the species investigated. Because in vitro exposure to O3 increases responses to agonists that release intracellular Ca2+ and since this effect is maintained in Ca(2+)-free solution, the mechanism of O3-induced increase in airway smooth muscle responsiveness is likely to involve an enhancement in intracellular Ca2+ release.

scholarly journals A novel GABAA receptor ligand MIDD0301 with limited blood-brain barrier penetration relaxes airway smooth muscle ex vivo and in vivo

2019 ◽  
Vol 316 (2) ◽  
pp. L385-L390 ◽  
Author(s):  
Gene T. Yocum ◽  
Jose F. Perez-Zoghbi ◽  
Jennifer Danielsson ◽  
Aisha S. Kuforiji ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Ex Vivo ◽  
Drug Candidate ◽  
Organ Bath ◽  
Forced Oscillation Technique ◽  
Gaba A ◽  
Peripheral Airways ◽  
Trace Concentrations

Airway smooth muscle (ASM) cells express GABA A receptors (GABAARs), and previous reports have demonstrated that GABAAR activators relax ASM. However, given the activity of GABAARs in central nervous system inhibitory neurotransmission, concern exists that these activators may lead to undesirable sedation. MIDD0301 is a novel imidazobenzodiazepine and positive allosteric modulator of the GABAAR with limited brain distribution, thus eliminating the potential for sedation. Here, we demonstrate that MIDD0301 relaxes histamine-contracted guinea pig ( P < 0.05, n = 6–9) and human ( P < 0.05, n = 6–10) tracheal smooth muscle ex vivo in organ bath experiments, dilates mouse peripheral airways ex vivo in precision-cut lung-slice experiments ( P < 0.001, n = 16 airways from three mice), and alleviates bronchoconstriction in vivo in mice, as assessed by the forced-oscillation technique ( P < 0.05, n = 6 mice). Only trace concentrations of the compound were detected in the brains of mice after inhalation of nebulized 5 mM MIDD0301. Given its favorable pharmacokinetic properties and demonstrated ability to relax ASM in a number of clinically relevant experimental paradigms, MIDD0301 is a promising drug candidate for bronchoconstrictive diseases, such as asthma.

Allergen-induced airway hyperresponsiveness in Brown-Norway rat: role of parasympathetic mechanisms

1993 ◽  
Vol 75 (1) ◽  
pp. 279-284 ◽  
Author(s):  
W. Elwood ◽  
T. Sakamoto ◽  
P. J. Barnes ◽  
K. F. Chung
Keyword(s):  
Airway Hyperresponsiveness ◽  
Allergen Challenge ◽  
Electrical Field Stimulation ◽  
Airway Responsiveness ◽  
Brown Norway ◽  
Field Stimulation ◽  
Electrical Field ◽  
Norway Rat

Enhanced parasympathetic mechanisms may contribute to airway hyperresponsiveness. The present study examined whether the in vivo increase in airway responsiveness seen 18–24 h after either a single or chronic aerosolized allergen challenge protocol in actively sensitized Brown-Norway rats was due to altered parasympathetic mechanisms. The roles of central and reflex vagal mechanisms were studied by performing bilateral cervical vagotomy before measurement of airway responsiveness. Bilateral vagotomy failed to reduce the increase in airway responsiveness after either a single or chronic allergen challenge. The roles of increased neural release of acetylcholine (ACh) and increased end organ responsiveness were studied in vitro. The isometric responses of tracheal and bronchial strips to both electrical field stimulation and exogenously applied ACh from rats exposed both to single and chronic allergen challenges were compared with those from saline-exposed rats. The responses to electrical field stimulation and to exogenous ACh were not significantly enhanced 18–24 h after either protocol. We conclude that the airway hyperresponsiveness observed in this allergic rat model is not mediated through an enhancement of parasympathetic mechanisms.

scholarly journals Attenuation of airway smooth muscle contractility via flavonol-mediated inhibition of phospholipase-Cβ

2016 ◽  
Vol 310 (8) ◽  
pp. L747-L758 ◽  
Author(s):  
Amy Brown ◽  
Jennifer Danielsson ◽  
Elizabeth A. Townsend ◽  
Yi Zhang ◽  
Jose F. Perez-Zoghbi ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Inositol Phosphates ◽  
Ex Vivo ◽  
Treatment Options ◽  
Smooth Muscle Contractility ◽  
Phosphodiesterase 4 ◽  
Naturally Occurring ◽  
Pharmacological Method

Enhanced contractility of airway smooth muscle (ASM) is a major pathophysiological characteristic of asthma. Expanding the therapeutic armamentarium beyond β-agonists that target ASM hypercontractility would substantially improve treatment options. Recent studies have identified naturally occurring phytochemicals as candidates for acute ASM relaxation. Several flavonoids were evaluated for their ability to acutely relax human and murine ASM ex vivo and murine airways in vivo and were evaluated for their ability to inhibit procontractile signaling pathways in human ASM (hASM) cells. Two members of the flavonol subfamily, galangin and fisetin, significantly relaxed acetylcholine-precontracted murine tracheal rings ex vivo ( n = 4 and n = 5, respectively, P < 0.001). Galangin and fisetin also relaxed acetylcholine-precontracted hASM strips ex vivo ( n = 6–8, P < 0.001). Functional respiratory in vivo murine studies demonstrated that inhaled galangin attenuated the increase in lung resistance induced by inhaled methacholine ( n = 6, P < 0.01). Both flavonols, galangin and fisetin, significantly inhibited purified phosphodiesterase-4 (PDE4) ( n = 7, P < 0.05; n = 7, P < 0.05, respectively), and PLCβ enzymes ( n = 6, P < 0.001 and n = 6, P < 0.001, respectively) attenuated procontractile Gq agonists' increase in intracellular calcium ( n = 11, P < 0.001), acetylcholine-induced increases in inositol phosphates, and CPI-17 phosphorylation ( n = 9, P < 0.01) in hASM cells. The prorelaxant effect retained in these structurally similar flavonols provides a novel pharmacological method for dual inhibition of PLCβ and PDE4 and therefore may serve as a potential treatment option for acute ASM constriction.

scholarly journals Effects of Zileuton on Airway Smooth Muscle Remodeling after Repeated Allergen Challenge in Brown Norway Rats

Respiration ◽  
2013 ◽  
Vol 86 (5) ◽  
pp. 421-429 ◽  
Author(s):  
Wei-Ji Chen ◽  
Shwu-Fang Liaw ◽  
Ching-Chi Lin ◽  
Mei-Wei Lin ◽  
Feng-Ting Chang
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Allergen Challenge ◽  
Brown Norway ◽  
Norway Rats ◽  
Muscle Remodeling

scholarly journals Pathophysiological regulation of lung function by the free fatty acid receptor FFA4

2020 ◽  
Vol 12 (557) ◽  
pp. eaaw9009 ◽  
Author(s):  
Rudi Prihandoko ◽  
Davinder Kaur ◽  
Coen H. Wiegman ◽  
Elisa Alvarez-Curto ◽  
Chantal Donovan ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Ex Vivo ◽  
Smooth Muscle Relaxation ◽  
Chronic Obstructive ◽  
Prostaglandin E ◽  
Omega 3 ◽  
Airway Diseases

Increased prevalence of inflammatory airway diseases including asthma and chronic obstructive pulmonary disease (COPD) together with inadequate disease control by current frontline treatments means that there is a need to define therapeutic targets for these conditions. Here, we investigate a member of the G protein–coupled receptor family, FFA4, that responds to free circulating fatty acids including dietary omega-3 fatty acids found in fish oils. We show that FFA4, although usually associated with metabolic responses linked with food intake, is expressed in the lung where it is coupled to Gq/11 signaling. Activation of FFA4 by drug-like agonists produced relaxation of murine airway smooth muscle mediated at least in part by the release of the prostaglandin E2 (PGE2) that subsequently acts on EP2 prostanoid receptors. In normal mice, activation of FFA4 resulted in a decrease in lung resistance. In acute and chronic ozone models of pollution-mediated inflammation and house dust mite and cigarette smoke–induced inflammatory disease, FFA4 agonists acted to reduce airway resistance, a response that was absent in mice lacking expression of FFA4. The expression profile of FFA4 in human lung was similar to that observed in mice, and the response to FFA4/FFA1 agonists similarly mediated human airway smooth muscle relaxation ex vivo. Our study provides evidence that pharmacological targeting of lung FFA4, and possibly combined activation of FFA4 and FFA1, has in vivo efficacy and might have therapeutic value in the treatment of bronchoconstriction associated with inflammatory airway diseases such as asthma and COPD.

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