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

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.

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1998.274.3.l417 ◽

1998 ◽

Vol 274 (3) ◽

pp. L417-L424 ◽

Cited By ~ 16

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.

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The modulation of large airway smooth muscle phenotype and effects of epidermal growth factor receptor inhibition in the repeatedly allergen-challenged rat

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00047.2012 ◽

2013 ◽

Vol 304 (12) ◽

pp. L853-L862 ◽

Cited By ~ 14

Author(s):

S. Siddiqui ◽

M. Novali ◽

K. Tsuchiya ◽

N. Hirota ◽

B. J. Geller ◽

...

Keyword(s):

Gene Expression ◽

Epidermal Growth Factor Receptor ◽

Smooth Muscle ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Airway Smooth Muscle ◽

Growth Factor Receptor ◽

Brown Norway ◽

Large Airway ◽

Epidermal Growth

Allergen challenges induce airway hyperresponsiveness (AHR) and increased airway smooth muscle (ASM) mass in the sensitized rat. Whether the remodeled ASM changes its phenotype is uncertain. We examined, in sensitized Brown Norway rats, the effects of multiple ovalbumin (Ova) challenges on ASM remodeling and phenotype and the role of the epidermal growth factor receptor (EGFR) in these processes. Rats were sensitized with Ova and challenged three times at 5-day intervals with phosphate-buffered saline or Ova and pretreated with the EGFR inhibitor AG-1478 (5 mg/kg) or its vehicle dimethyl sulfoxide. Ova challenges increased ASM mass in all-sized airways and in large airway mRNA expression of smooth muscle myosin heavy chain (sm-MHC), assessed by laser capture. Myosin light chain kinase and the fast myosin isoform SM-B mRNA expressions were not affected. Ova induced AHR to methacholine, and, based on the constant-phase model, this was largely attributable to the small airways and lung derecruitment at 48 h that recovered by 1 wk. The EGFR ligands amphiregulin and heparin-binding epidermal growth factor (HB-EGF) were increased in bronchoalveolar lavage fluid at 48 h after Ova exposure. AG-1478 inhibited AHR and prevented ASM growth. Epithelial gene expression of EGFR, HB-EGF, matrix metalloproteinase (MMP)-9, Gro-α, and transforming growth factor-β was unaffected by Ova challenges. We conclude that EGFR drives remodeling of ASM, which results from repeated Ova challenge. Furthermore, the latter results in excessive small airway and, to a lesser degree, large airway narrowing to methacholine, and large airway gene expression of contractile protein is conserved.

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00142.2009 ◽

2009 ◽

Vol 297 (4) ◽

pp. L698-L705 ◽

Cited By ~ 31

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.

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

Respiration ◽

10.1159/000353427 ◽

2013 ◽

Vol 86 (5) ◽

pp. 421-429 ◽

Cited By ~ 3

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

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A Time Course Study on the Development of Allergen-induced Nasal Airway Remodeling in a Rat Model

American Journal of Rhinology and Allergy ◽

10.2500/ajra.2012.26.3823 ◽

2012 ◽

Vol 26 (6) ◽

pp. 421-427

Author(s):

Young-Jun Chung ◽

Hyo Yeol Kim ◽

Seung-Kyu Chung ◽

Hun-Jong Dhong

Keyword(s):

Goblet Cell ◽

Airway Remodeling ◽

Tissue Inhibitor Of Metalloproteinase ◽

Eosinophil Infiltration ◽

Brown Norway ◽

Control Group ◽

Nasal Airway ◽

Submucosal Gland ◽

Cell Hyperplasia ◽

Goblet Cell Hyperplasia

Background Only a few studies have investigated the airway remodeling process in allergic rhinitis (AR), and the results reported are conflicting. We established an allergen-induced nasal remodeling model for AR using brown Norway rats and investigated time-dependent histological changes and the reversibility of the epithelial and subepithelial changes. Methods Ovalbumin (OVA)-sensitized rats were exposed to OVA daily and then assigned to one of five groups depending on the duration of the challenge. Groups I, II, III, and IV rats were exposed for 1, 4, 8, and 12 weeks, respectively. Group V rats were exposed for 12 weeks and then protected from challenge for 4 weeks. Matched control rats were exposed to saline. Histological parameters of the nasal mucosa such as epithelial and subepithelial thickness, goblet cell hyperplasia, eosinophil infiltration, submucosal gland hypertrophy, and expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were compared between groups. Results Repeated challenges for 12 weeks resulted in the characteristic features of nasal airway remodeling. All parameters except epithelial thickness increased markedly. Goblet cell hyperplasia and eosinophil infiltration decreased to control group levels after cessation of challenge for 4 weeks. Subepithelial changes such as subepithelial thickening, submucosal gland hypertrophy, and increased expression of MMP-9 and TIMP-1 were still observed after 4 weeks without challenge. Conclusion Our results indicate that prolonged OVA challenge can induce nasal remodeling. Epithelial changes were minimal or absent after cessation of the challenge, but subepithelial changes were resistant to reversal.

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