Dual Action Effects of Serelaxin on Histopathology and Pathophysiology of Chronic Allergic Airways Disease

Abstract

One of most therapy‐resistant aspects of severe asthma is remodeling of the airway wall encompassing the epithelium, airway smooth muscle as well as fibrosis. This histopathology has implications for airway function and influences airway hyperresponsiveness and fixed airway obstruction which are not fully treated by existing medications. For instance, even long acting beta agonists only have transient bronchodilator effects. An ideal therapy for asthma would have dual action effects against airway remodeling and bronchoconstriction and could be used alongside existing anti‐inflammatory therapies. The recombinant form of the peptide hormone relaxin, Serelaxin, has attracted intense recent interest for its anti‐fibrotic and vasodilatory properties, culminating in Serelaxin being awarded Breakthrough Designation (2013) by the FDA for the treatment of acute heart failure. Serelaxin has previously been shown to act as a functional antagonist of endothelin (ET‐1) by up‐regulating endothelin receptor B (ETB) activity, as well as downregulating TGF‐beta1 and upregulating gelatinases.Serelaxin reverses airway fibrosis and also provides long term opposition to contraction, by dilating airways in lung disease. We aim to test if RLN is a bronchodilator, reverses airway remodeling and fibrosis and can be delivered to the lung.Experiments were performed using a mouse model of chronic allergic airways disease incorporating airway epithelial damage and repair. Experimental groups (n=10) included allergic airways disease, diseased mice treated with Serelaxin over a period of one or two weeks post established disease via systemic (osmotic pump) or local delivery to the lung (intranasal instillation), and naïve controls. Lung function (post long term and acute Serelaxin treatment) was assessed and histopathological (H&E, Masson trichrome and ABPAS) and quantitative immunohistochemical analysis (Aperio) was performed on formalin‐fixed paraffin‐embedded murine lung tissue as well as human lung tissue.Serelaxin delivered directly to the lung had similar efficacy to when delivered systemically. Relevant preclinical endpoints of airway resistance, dynamic compliance, peribronchial fibrosis (p<0.05) were all ameliorated by treatment with Serelaxin. The drug‐treated mice also had reduced markers of fibrosis and increased matrix metalloprotease expression (p<0.05) consistent with an anti‐remodeling/reversal of fibrosis effect. Serelaxin treatment also had acute bronchodilator effects in airways. The main receptor for Serelaxin (RXFP1) was expressed in bronchial epithelial cells and airway smooth muscle in humans and mice.When administered to the lungs of mice with a chronic allergic airways disease Serelaxin has anti‐fibrotic effects and has the ability to normalize airway structure with reduction of airway collagen thickness and total lung collagen. This is reflected in the reduced airway hyperresponsiveness to methacholine in in vivo lung function experiments but may also be a manifestation of the bronchodilatory effects of Serelaxin. These effects are demonstrable ex vivo. The constitutive expression of RXFP1 in airway epithelium and smooth muscle suggests a role for these cell types in these effects and the homology of expression profile of these molecules and the endothelin system in human and mouse opens up the possibility that Serelaxin treatment may have applicability as a dual therapy in inflammatory airway disease.