Therapeutic Targeting of Systemic Inflammation in Decompensated Liver Cirrhosis

Context
Liver cirrhosis, the result of long-term damage to the liver from various causes, is one of the major reasons for hospitalisation and death in the UK and globally. Worryingly, the number of deaths caused by cirrhosis is rising around the world. However, there has been very little progress in developing treatments for patients with cirrhosis, with liver transplant only suitable for selected patients and limited by a lack of available organs. This highlights the urgent need to find new therapies.
In recent years, it has become clear that cirrhosis doesn’t only damage the liver but also has effects in different organs, resulting in systemic inflammation (SI), a state where the immune system is activated throughout the body and produces high levels of damaging proteins called cytokines. Cirrhosis patients with high SI are more likely to be admitted to hospital and to die, whilst improvements in SI have been linked to patients getting better. This suggests that finding drugs to reduce SI in cirrhosis may offer a new treatment option. However, the mechanisms which cause SI in cirrhosis and how they might be blocked have so far been unclear.
Our previous research aimed to study these mechanisms. We found that monocytes, a type of blood immune cell, made higher levels of inflammatory cytokines in cirrhosis, suggesting that blocking monocyte activation could reduce SI. By studying monocytes in depth we identified a specific protein, called Toll-like receptor 8 (TLR8), which goes up in cirrhosis patients’ blood and liver. Inhibiting monocyte TLR8 in the lab reduced signs of SI, suggesting it could be a promising target to block using drugs. Importantly, some existing drugs currently used to treat other conditions may already be able to block this receptor, even if they were developed for other diseases. This process, known as drug repurposing, allows more rapid development of new treatments as these drugs are already known to be safe.  Alternatively, the...