New Views on Relaxin and Relaxin-Receptor Agonists for the Treatment of Lung Fibrosis: Evidences From In Vivo Models

Fibrosis and the balance between organ regeneration and scar repair

Fibrosis is a pathophysiological response to chronic inflammation, characterized by abnormal and excessive deposition of collagen and other extracellular matrix (ECM) components, which disrupts the normal tissue architecture of an organ and eventually leads to its dysfunction. In spite of the diverse etiology of various fibrotic disorders, such as cardiac fibrosis, renal fibrosis, liver cirrhosis, and idiopathic pulmonary fibrosis, a common histopathological hallmark of fibrotic diseases is the presence of myofibroblasts (ie, activated collagen-secreting fibroblasts) in the affected tissue.

Abstract

INTRODUCTION

Fibrosis is a pathophysiological response to injury characterized by excess, abnormal extracellular matrix (ECM) deposition disrupting the normal tissue architecture and function of affected organs. Lung fibrosis may occur as a component of systemic or local diseases, but the most pernicious clinical form is idiopathic pulmonary fibrosis (IPF), which represents a major challenge for pneumologists, being refractory to any conventional therapy. This has prompted the development of suitable animal models of lung fibrosis to test novel therapies.

OBJECTIVES

This mini-review summarizes the current knowledge on the antifibrotic properties of relaxin, a natural hormone capable of modulating ECM turnover in multiple target organs, which can be viewed as a promising antifibrotic drug. In fact, human recombinant relaxin has been and is currently being investigated in clinical trials due to its favorable bioactivity profile.

RESULTS AND CONCLUSION

Based on several in vitro and in vivo studies, relaxin has emerged as a key endogenous factor involved in the regulation of ECM synthesis and remodeling by fibroblasts. Knockout mice for relaxin or its receptor are prone to heart, kidney, and lung fibrosis: in the former animal model, the profibrotic trend can be reverted by exogenous administration of the hormone, implicating its therapeutic potential. To overcome the intrinsic limitations of the peptide properties of the hormone, low molecular weight relaxin receptor agonists have been synthesized and are currently being evaluated as alternative treatments. As shown using a mouse model of bleomycin-induced lung fibrosis, these compounds are capable of blunting the pulmonary inflammatory reaction to bleomycin and the subsequent enhanced collagen deposition. Taken together, these existing notions and clues suggest that relaxin and related molecules deserve to be further investigated as possible antifibrotic drugs.

Keywords

relaxin, lung fibrosis, RXFP1 agonist, animal models of fibrosis