Intranasally administered serelaxin abrogates airway remodelling and attenuates airway hyperresponsiveness in allergic airways disease

Royce, Simon G.; Lim, Clarice X.; Patel, Krupesh; Wang, Bo; Samuel, Chrishan S.; Tang, Mimi L.K.

doi:10.1111/cea.12391

Cited by 31 publications

(32 citation statements)

References 37 publications

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“…Moreover, RLX was able to counteract the adverse bronchial remodeling induced by CS exposure by reducing goblet cell hyperplasia, smooth muscle wall thickening, and fibrosis, and it was able to blunt emphysema of the distal air spaces. These effects of RLX fit well with previous reports that this hormone reduces inflammation and fibrosis in many in vitro and in vivo models of disease (Masini et al, 1994(Masini et al, , 2004Nistri et al, 2003Nistri et al, , 2008Lekgabe et al, 2005;Bonacchi et al, 2009;Sasser, 2013;Royce et al, 2014;Samuel et al, 2014). In Fig.…”

Section: Discussionsupporting

confidence: 91%

“…Moreover, the finding of undetectable levels of RLX in the plasma of the aerosol-treated animals accounts for a local action of this hormone on lung tissues. This possibility is supported by the observation that the specific RLX receptor RXFP1 is expressed by lung tissues (Samuel et al, 2003;Scott et al, 2004;Royce et al, 2014). The aerosol route of delivery is particularly attractive because it offers easier use and better patient compliance than systemic delivery.…”

Section: Discussionmentioning

confidence: 99%

“…RLX, best known for its effects on reproduction (Sherwood, 2004), also exhibits anti-inflammatory and antifibrotic properties (Masini et al, 2004;Samuel et al, 2007;Bonacchi et al, 2009). In a setting of allergic airway disease, RLX has been shown to inhibit infiltration of proinflammatory cells into the lung and adverse airway remodeling (Bani et al, 1997;Royce et al, 2009Royce et al, , 2014, promote dilation of alveolar blood capillaries, and reduce the thickness of the air-blood barrier (Bani et al, 1997). In an in vivo model of fibrosis, RLX treatment markedly decreased bleomycin-induced lung fibrosis and improved alveolar thickening (Unemori et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Protection from Cigarette Smoke-Induced Lung Dysfunction and Damage by H2 Relaxin (Serelaxin)

Pini

Boccalini

Lucarini

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Cigarette smoke (CS) is the major etiologic factor of chronic obstructive pulmonary disease (COPD), which is characterized by airway remodeling, lung inflammation and fibrosis, emphysema, and respiratory failure. The current therapies can improve COPD management but cannot arrest its progression and reduce mortality. Hence, there is a major interest in identifying molecules susceptible of development into new drugs to prevent or reduce CS-induced lung injury. Serelaxin (RLX), or recombinant human relaxin-2, is a promising candidate because of its anti-inflammatory and antifibrotic properties highlighted in lung disease models. Here, we used a guinea pig model of CSinduced lung inflammation, and remodeling reproducing some of the hallmarks of COPD. Animals exposed chronically to CS (8 weeks) were treated with vehicle or RLX, delivered by osmotic pumps (1 or 10 mg/day) or aerosol (10 mg/ml/day) during CS treatment. Controls were nonsmoking animals. RLX maintained airway compliance to a control-like pattern, likely because of its capability to counteract lung inflammation and bronchial remodeling. In fact, treatment of CS-exposed animals with RLX reduced the inflammatory recruitment of leukocytes, accompanied by a significant reduction of the release of proinflammatory cytokines (tumor necrosis factor a and interleukin-1b). Moreover, RLX was able to counteract the adverse bronchial remodeling and emphysema induced by CS exposure by reducing goblet cell hyperplasia, smooth muscle thickening, and fibrosis. Of note, RLX delivered by aerosol has shown a comparable efficacy to systemic administration in reducing CS-induced lung dysfunction and damage. In conclusion, RLX emerges as a new molecule to counteract CS-induced inflammatory lung diseases.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protection from Cigarette Smoke-Induced Lung Dysfunction and Damage by H2 Relaxin (Serelaxin)

Pini

Boccalini

Lucarini

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…Airway remodeling refers to structural changes in airways of asthma patients, which include elevated numbers of inflammatory cells, deposition of collagen and fibronectin in the subepithelial basement membrane, hyperplasia and hypertrophy of airway smooth muscle, and hypertrophy of submucosal glands [5, 6]. Our in vivo animal model showed that sensitization and challenge of mice with OVA induced asthma as demonstrated by the increased airway response in enhanced pause, high serum OVA-specific IgE levels, and increase percentage of eosinophils and inflammatory cells in BALF.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the presence of inflammatory cells in the airway, the airways demonstrate varying levels of structural changes termed airway remodeling [3, 4]. Structural changes of airway remodeling include elevated numbers of inflammatory cells, deposition of collagen and fibronectin in the subepithelial basement membrane, hyperplasia and hypertrophy of airway smooth muscle, and hypertrophy of submucosal glands [5, 6]. …”

Section: Introductionmentioning

confidence: 99%

CTGF upregulation correlates with MMP-9 level in airway remodeling in a murine model of asthma

Lin¹,

Chou²,

Chiang³

et al. 2017

aoms

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IntroductionConnective tissue growth factor (CTGF) mediates hypertrophy, proliferation, and extracellular matrix synthesis. Matrix metalloproteinase (MMP) plays a role in airway extracellular matrix remodeling. The correlation between CTGF and MMP in airway remodeling of asthma was unknown. This study investigated lung CTGF expression and its correlation with MMP and airway structural changes in a murine model of asthma.Material and methodsFemale BALB/c mice were sensitized and challenged by intraperitoneal injections and intranasal phosphate-buffered saline (PBS) or ovalbumin (OVA). Airway responsiveness and serum OVA-specific IgE were measured. Airway structural changes were quantified by morphometric analysis. Differential cell counts and MMP-2, MMP-9, and tissue inhibitor of metalloproteinase (TIMP)-1 were evaluated in bronchoalveolar lavage fluid (BALF). Lung CTGF was determined by Western blot.ResultsSerum OVA-specific IgE level and airway responsiveness in enhanced pause (Penh) is significantly higher in sensitized mice challenged with OVA compared to PBS-challenged mice. MMP-2, MMP-9, and TIMP-1 in BALF were significantly higher in OVA mice. Airway structural changes of animals’ lungs with OVA challenge showed increased thickness of the smooth muscle layer and numbers of Goblet cells and inflammatory cells and eosinophils near airways and perivascular areas. Lung CTGF expression significantly increased in OVA-challenged mice. CTGF expressions positively correlated with MMP-9 (r = 0.677, p < 0.05), TIMP-1 (r = 0.574, p < 0.05) and thickness of the smooth muscle layer (r = 0.499, p < 0.05).ConclusionsThis study indicates that CTGF upregulation correlates with MMP-9, probably involved in the pathogenesis of airway remodeling of asthma.

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Relaxing the artery: A new strategy to limit atherogenesis

Bot

Kuiper

2016

Atherosclerosis

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Intranasally administered serelaxin abrogates airway remodelling and attenuates airway hyperresponsiveness in allergic airways disease

Abstract: Intranasal delivery of serelaxin can effectively reduce airway remodelling and AHR, when administered once daily. Respirable preparations of serelaxin may have therapeutic potential for the prevention and/or reversal of established airway remodelling and AHR in asthma.

Cited by 31 publications

References 37 publications

Protection from Cigarette Smoke-Induced Lung Dysfunction and Damage by H2 Relaxin (Serelaxin)

Protection from Cigarette Smoke-Induced Lung Dysfunction and Damage by H2 Relaxin (Serelaxin)

CTGF upregulation correlates with MMP-9 level in airway remodeling in a murine model of asthma

Relaxing the artery: A new strategy to limit atherogenesis

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