Fibrosis refers to the hardening or scarring of tissues that usually results from aberrant wound healing in response to organ injury, and its manifestations in various organs have collectively been estimated to contribute to around 45-50% of deaths in the Western world. Despite this, there is currently no effective cure for the tissue structural and functional damage induced by fibrosisrelated disorders. Relaxin meets several criteria of an effective anti-fibrotic based on its specific ability to inhibit pro-fibrotic cytokine and/or growth factor-mediated, but not normal/unstimulated, fibroblast proliferation, differentiation and matrix production. Furthermore, relaxin augments matrix degradation through its ability to up-regulate the release and activation of various matrix-degrading matrix metalloproteinases and/or being able to down-regulate tissue inhibitor of metalloproteinase activity. Relaxin can also indirectly suppress fibrosis through its other well-known (anti-inflammatory, antioxidant, antihypertrophic, anti-apoptotic, angiogenic, wound healing and vasodilator) properties. This review will outline the organ-specific and general anti-fibrotic significance of exogenously administered relaxin and its mechanisms of action that have been documented in various non-reproductive organs such as the cardiovascular system, kidney, lung, liver, skin and tendons. In addition, it will outline the influence of sex on relaxin's anti-fibrotic actions, highlighting its potential as an emerging anti-fibrotic therapeutic.
LINKED ARTICLESThis article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc Abbreviations α-SMA, α-smooth muscle actin; AT 2 receptor, angiotensin type 2 receptor; CCl 4 , carbon tetrachloride; ECM, extracellular matrix; HSC, hepatic stellate cell; INSL, insulin-like; KO, knockout; MSC, mesenchymal stem cell; PMA, phorbol 12-myristate 13-acetate; RLN, relaxin gene; rhRLX, synthetically or recombinantly produced drug form of relaxin; RXFP1, relaxin family peptide receptor 1; TIMP, tissue inhibitor of metalloproteinase
IntroductionThe tissue response to stress depends on a number of intrinsic and extrinsic factors including the length and extent of injury. When injury or disease is mild or transient, then the tissue response leads to remodelling or regeneration of the organ parenchyma. However, if the injury is either severe or prolonged, the process is characterized by ongoing inflammation and extracellular matrix (ECM) production. Fibrosis is therefore a failure of the wound healing process, where ECM synthesis is ongoing (Wynn, 2008;Hewitson, 2009). This maladaptive response is particularly dependent on paracrine and autocrine production of TGF-β1 and the consequent recruitment of activated fibroblasts (myofibroblasts). Over-abundant ECM production and failure to resolve lead to significant organ damage and dysfunction, wh...
