New highlights for relaxin
Authors: Klaas Poelstra
Journal: Hepatology (2013)

Liver fibrosis is characterized by an excessive deposition of extracellular matrix after chronic damage to the liver. The main producers of this matrix are myofibroblasts,1 derived from activated hepatic stellate cells (HSC) or portal fibroblasts.1, 2 Sinusoidal endothelial cells, Kupffer cells, damaged hepatocytes, and infiltrating inflammatory cells all act in concert to generate stimuli that elicit activation and proliferation of myofibroblasts.1-3 Numerous experimental antifibrotic drugs have been explored, many with high therapeutic efficacy in animal models, but to date none of these compounds has reached daily clinical practice.1, 3, 4 So, apart from effective removal of the inciting stimulus, no effective antifibrotic therapy is available yet. Key problems that hamper setting up clinical trials in particular in cirrhosis patients are clear.3, 4 An important hurdle is the slow disease progression, which necessitates long clinical trials for antifibrotic drugs. Indeed, the average length of clinical trials with liver fibrosis as the primary endpoint that are currently ongoing3 is 80.8 weeks, which obviously takes a huge amount of time, money, and patience of all participants to obtain proof-of-principle in patients. The absence of reliable quantitative readout parameters to monitor disease progression and drug effectivity represents an additional key problem. Liver biopsies were the gold standard for a long time, but in recent years much progress has been made to monitor the fibrotic process quantitatively. To date, out of 250 ongoing clinical trials in patients with liver fibrosis, 37 (15%) are dedicated to find noninvasive markers for disease activity (see www.clinicaltrails.gov). However, it is clear that liver fibrosis is much more difficult to assess than fibrosis in skin, heart, lung, and kidney, whose appearance or output is much more easily quantifiable. The subclinical nature of the disease also leads to a situation where adverse effects of antifibrotic drugs in the early stages of fibrogenesis are not tolerated and experimental drugs can only be tested in patients with advanced cirrhosis. Next to these challenges, very complex opposing homeostatic processes characterize liver fibrosis. For instance, death and apoptosis of hepatocytes is accompanied by proliferation of fibroblasts, fibroblast-like cells, and neoplastic cells, thus making the systemic administration of compounds that affect cell proliferation or apoptosis risky.1, 3 Also, other systemic approaches can be troublesome; while chronic inflammation stimulates fibrogenesis, lack of macrophages prevents regression of fibrosis,5 and while stimulation of extracellular matrix degrading activity is essential to reverse fibrosis, this may in turn stimulate metastasis of hepatocellular carcinoma, also associated with cirrhosis.6 Manipulation of thrombosis, which stimulates fibrogenesis,7 faces the challenge that within the liver prothrombotic activities prevail, whereas systemic clinical problems comprise enhanced risk of bleeding. In addition, portal hypertension—the major cause of morbidity and mortality in cirrhosis patients8—is associated with a reduced extrahepatic arterial pressure, which renders the systemic use of vasodilating drugs difficult. Therefore, therapeutics should be liver-specific, which is not the case for most experimental antifibrotic drugs. In the present issue of Hepatology, Fallowfield et al.9 present data on the antifibrotic effects of relaxin. There are a number of interesting elements in this study. A significant reduction in portal pressure, intrahepatic nitrous oxide (NO levels), HSC activation, as reflected by cytoskeletal filament markers, accompanied by an improved liver function, indicated by increased serum albumin levels, was found after administration of relaxin in different experimental models (the carbon tetrachloride [CCL4] model in mice and the bile duct-ligated [BDL] model in rats). Therapeutic intervention started after 8 of 16 weeks of CCL4 administration or 18 days after BDL, that is, in established or advanced fibrosis and intervention lasted for only 72 hours. This is a highly effective treatment. Antifibrotic effects of relaxin have been demonstrated earlier in animal models of liver fibrosis,10, 11 but the present study extends these observations by showing the potency of this approach in advanced fibrosis and by presenting data on its mechanism of action. The first studies showed only the protective effects of relaxin,11, 12 while the present study and a recent study of Bennett et al.,13 published nearly parallel with this study, now also show therapeutical effects during established fibrosis. Relaxin directly affects the contractility of HSC, as shown in vitro by these authors, and the contraction of HSC is one of the major contributing factors to portal hypertension.14 This is therefore a rapid readout parameter directly related to HSC activity, which is relevant for clinical trials. Obviously, reduced scar tissue deposition cannot be expected in this short treatment interval, but proof-of-principle for effectivity can thus be directly obtained in cirrhosis patients without long-lasting trials. Portal hypertension is reported to be a good predictive marker for hepatic decompensation and mortality,8 so this is a relevant parameter too. Importantly, the effect of relaxin was organ-specific. No effects of relaxin were found on hemodynamic parameters outside the liver. As outlined above, and by the authors themselves, this is a key element in antifibrotic therapies directed at modulation of portal hypertension. The antifibrotic activities of relaxin have been demonstrated earlier in several other models of fibrosis in skin, kidney, lung, and heart.15-17 Relaxin appears to be a paracrine inhibitor of fibrogenesis whose receptor expression is restricted, that is, only in reproductive organs during pregnancy and fibrotic organs in patients.10 Serum levels of maternal relaxin already increase in the first trimester of pregnancy,10, 18 and since it can cross the placenta in low amounts,18 off-target effects of this protein would be deleterious during embryogenesis, where well-controlled matrix turnover is a hallmark. Relaxin may therefore represent an endogenous inhibitor of fibrosis that may form the basis of a new therapeutic strategy in liver fibrosis. This compound may be added to the long list of experimental antifibrotic compounds that already exists, but its direct effect on rapid readout parameters during advanced fibrosis and it organ specificity are important assets in clinical trials in cirrhosis patients. First in-man studies with relaxin already have been performed for other diseases (see www.clinicaltrials.gov), so many of the liver-specific hurdles for experimental antifibrotic drugs are addressed now. However, although we have entered the era of biological therapeutics, the step of such compounds to the clinic remains full of challenges.19