Scarring of the liver was once thought to be an irreversible situation,
but a new and exciting field of experimental drugs
may put an end to this dogma.
The liver is a large smooth organ
that carries out many essential functions.
It stores and releases nutrients,
aids digestion and breaks down unwanted substances.
Unfortunately, numerous chronic diseases damage the liver
and when they continue for a long time they cause scarring
— a condition called fibrosis.
The most common causes arehepatitis viruses, long-term heavy drinking
and fatty liver disease associatedwith obesity and diabetes.
This scarring is caused by a buildup of fibrous collagen proteins
which begin to replace healthy tissue.
If the fibrosis keeps worsening,
the liver can progress to a state known as cirrhosis
At this stage,
excessive scarring hampers the liver’s blood flow
and stops it being able to do its job.
Unchecked cirrhosis can lead directly to liver failure,
and puts patients at high risk for liver cancer.
Cirrhosis currently kills a million people worldwide each year.
The good news is that the liver has its own mechanisms that degrade scar tissue,
and this discovery has spurred a new wave of research
into developing drugs
which can halt the progression of fibrosis,
or speed up healing once the underlying disease has been treated.
The best way to reduce fibrosis is to avoid it altogether
by removing the risk factors associated with the disease,
but now scientists are examining the biology of the scar-causing cells
as potential targets for therapeutic interventions
Scars are generated by cells called myofibroblasts.
When these cells become activated,
they proliferate, migrate to injury sites
and secrete collagen into the extracellular matrix.
As these collagen fibres accumulate,
they become cross-linked into a mesh
which stiffens the tissue and blocks its function.
So researchers are aiming their sites, first and foremost, at myofibroblasts.
One strategy is to target the messenger molecules which coordinate their activation.
These are released by damaged liver cells and immune cells
and could targeted by new drugs.
One example is a drug called Cenicriviroc
that blocks receptors for profibrosis
messengers called cytokines.
Another set of drugs could inactivate myofibroblasts by targeting receptors on their surface called integrins
that allow them to interact with other cells
and the extracellular matrix.
Multiple drugs that work this way are currently being explored
and will enter human trials soon.
Blocking the myofibroblasts’ ability to make collagen is another option.
These drugs work by inserting small bits of RNA into the nucleus of myofibroblasts,
destabilising the machinery that creates collagen fibres.
Another approach is to block the enzymes that cross-link collagen fibres
to stiffen the scar matrix.
This makes the collagen easier for the body to degrade.
Finally, an exciting new avenue is the use of cell therapies.
Introducing extra immune cells called macrophages into rodents’ livers
strongly boosts the organ’s intrinsic anti-scarring mechanisms
and now human trials using patient’s own macrophages have begun.
All these therapies will require clinical trials,
and due to the slow progressive nature of liver fibrosis,
this may take years.
But new biomarkers in development
may speed up trials considerably
by showing whether the drugs are working,
even before the overall fibrosis starts to decline.
Hopefully these new approaches will help us to victory in the scar wars.