Combination therapy with relaxin and methylprednisolone augments the effects of either treatment alone in inhibiting subepithelial fibrosis in an experimental model of allergic airways disease

Simon G Royce, Amelia Sedjahtera, Chrishan S Samuel, Mimi LK Tang

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Abstract

Although corticosteroids demonstrate potent effects in the control of airway inflammation in asthma, many patients continue to experience symptoms and airway hyperresponsiveness despite optimal treatment with these agents, likely due to progressive airway remodeling. Identifying novel therapies that can target airway remodeling and/or airway reactivity may improve symptom control in these patients. We have previously demonstrated that the anti-fibrotic hormone relaxin can reverse airway remodeling (epithelial thickening and subepithelial fibrosis) and airway hyperresponsiveness in a murine model of allergic airways disease. In this current study, we compared the effects of relaxin to a corticosteroid (methyl prednisolone) on airway remodeling and airway hyperresponsiveness when administered independently or in combination in the mouse allergic airways disease model. Six-to-eight week old female mice were sensitized and challenged to ovalbumin over a 9 week period and treated with methylprednisolone, relaxin, a combination of both treatments, or vehicle controls. Methylprednisolone was administered i.p. on the same day as nebulization for 6 weeks; while recombinant human relaxin-2 was administered via s.c. implanted osmotic mini-pumps from weeks 9-11. Relaxin or methylprednisolone alone were both able to significantly decrease subepithelial thickness and total lung collagen deposition; while relaxin but not methylprednisolone significantly decreased epithelial thickness and airway hyperresponsiveness. Additionally, combination therapy with corticosteroid and relaxin more effectively reduced subepithelial collagen thickness than either therapy alone. These findings demonstrate that relaxin can modulate a broader range of airway remodelling changes and airway hyperresponsiveness than methylprednisolone and the combination of both treatments offers enhanced control of subepithelial fibrosis.
Original languageEnglish
Pages (from-to)41 - 51
Number of pages11
JournalClinical Science
Volume124
Issue number1
DOIs
Publication statusPublished - 2013

Cite this

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title = "Combination therapy with relaxin and methylprednisolone augments the effects of either treatment alone in inhibiting subepithelial fibrosis in an experimental model of allergic airways disease",
abstract = "Although corticosteroids demonstrate potent effects in the control of airway inflammation in asthma, many patients continue to experience symptoms and airway hyperresponsiveness despite optimal treatment with these agents, likely due to progressive airway remodeling. Identifying novel therapies that can target airway remodeling and/or airway reactivity may improve symptom control in these patients. We have previously demonstrated that the anti-fibrotic hormone relaxin can reverse airway remodeling (epithelial thickening and subepithelial fibrosis) and airway hyperresponsiveness in a murine model of allergic airways disease. In this current study, we compared the effects of relaxin to a corticosteroid (methyl prednisolone) on airway remodeling and airway hyperresponsiveness when administered independently or in combination in the mouse allergic airways disease model. Six-to-eight week old female mice were sensitized and challenged to ovalbumin over a 9 week period and treated with methylprednisolone, relaxin, a combination of both treatments, or vehicle controls. Methylprednisolone was administered i.p. on the same day as nebulization for 6 weeks; while recombinant human relaxin-2 was administered via s.c. implanted osmotic mini-pumps from weeks 9-11. Relaxin or methylprednisolone alone were both able to significantly decrease subepithelial thickness and total lung collagen deposition; while relaxin but not methylprednisolone significantly decreased epithelial thickness and airway hyperresponsiveness. Additionally, combination therapy with corticosteroid and relaxin more effectively reduced subepithelial collagen thickness than either therapy alone. These findings demonstrate that relaxin can modulate a broader range of airway remodelling changes and airway hyperresponsiveness than methylprednisolone and the combination of both treatments offers enhanced control of subepithelial fibrosis.",
author = "Royce, {Simon G} and Amelia Sedjahtera and Samuel, {Chrishan S} and Tang, {Mimi LK}",
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AU - Tang, Mimi LK

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N2 - Although corticosteroids demonstrate potent effects in the control of airway inflammation in asthma, many patients continue to experience symptoms and airway hyperresponsiveness despite optimal treatment with these agents, likely due to progressive airway remodeling. Identifying novel therapies that can target airway remodeling and/or airway reactivity may improve symptom control in these patients. We have previously demonstrated that the anti-fibrotic hormone relaxin can reverse airway remodeling (epithelial thickening and subepithelial fibrosis) and airway hyperresponsiveness in a murine model of allergic airways disease. In this current study, we compared the effects of relaxin to a corticosteroid (methyl prednisolone) on airway remodeling and airway hyperresponsiveness when administered independently or in combination in the mouse allergic airways disease model. Six-to-eight week old female mice were sensitized and challenged to ovalbumin over a 9 week period and treated with methylprednisolone, relaxin, a combination of both treatments, or vehicle controls. Methylprednisolone was administered i.p. on the same day as nebulization for 6 weeks; while recombinant human relaxin-2 was administered via s.c. implanted osmotic mini-pumps from weeks 9-11. Relaxin or methylprednisolone alone were both able to significantly decrease subepithelial thickness and total lung collagen deposition; while relaxin but not methylprednisolone significantly decreased epithelial thickness and airway hyperresponsiveness. Additionally, combination therapy with corticosteroid and relaxin more effectively reduced subepithelial collagen thickness than either therapy alone. These findings demonstrate that relaxin can modulate a broader range of airway remodelling changes and airway hyperresponsiveness than methylprednisolone and the combination of both treatments offers enhanced control of subepithelial fibrosis.

AB - Although corticosteroids demonstrate potent effects in the control of airway inflammation in asthma, many patients continue to experience symptoms and airway hyperresponsiveness despite optimal treatment with these agents, likely due to progressive airway remodeling. Identifying novel therapies that can target airway remodeling and/or airway reactivity may improve symptom control in these patients. We have previously demonstrated that the anti-fibrotic hormone relaxin can reverse airway remodeling (epithelial thickening and subepithelial fibrosis) and airway hyperresponsiveness in a murine model of allergic airways disease. In this current study, we compared the effects of relaxin to a corticosteroid (methyl prednisolone) on airway remodeling and airway hyperresponsiveness when administered independently or in combination in the mouse allergic airways disease model. Six-to-eight week old female mice were sensitized and challenged to ovalbumin over a 9 week period and treated with methylprednisolone, relaxin, a combination of both treatments, or vehicle controls. Methylprednisolone was administered i.p. on the same day as nebulization for 6 weeks; while recombinant human relaxin-2 was administered via s.c. implanted osmotic mini-pumps from weeks 9-11. Relaxin or methylprednisolone alone were both able to significantly decrease subepithelial thickness and total lung collagen deposition; while relaxin but not methylprednisolone significantly decreased epithelial thickness and airway hyperresponsiveness. Additionally, combination therapy with corticosteroid and relaxin more effectively reduced subepithelial collagen thickness than either therapy alone. These findings demonstrate that relaxin can modulate a broader range of airway remodelling changes and airway hyperresponsiveness than methylprednisolone and the combination of both treatments offers enhanced control of subepithelial fibrosis.

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