April 3, 2024  Print

New research conducted at WIMR, and published in Science Translational Medicine, shows, for the first time, that inhibiting a gene called Mer tyrosine kinase (MERTK) can reduce fibrosis in multiple organs, including the liver, kidneys and lungs. This finding could lead to the development of much-needed anti-fibrotic treatments.

A world first, this study confirms the role of MERTK in multiple organ fibrosis and examines the mechanisms, including identifying MERTK’s role in the sharing pathways that are involved in the development of fibrosis.

Fibrosis is the development of thick, fibrous (or scar) tissue, in response to damage or injury.  It can affect every tissue in the body and is associated with most chronic diseases. In cases where excess scarring occurs, organs can lose functionality and even die.

Nearly half of all deaths in affluent countries can be attributed to fibrotic diseases[1].

Dr Ziyan Pan is first author on this study, and a researcher at WIMR’s Storr Liver Centre.  He says, “There are currently no anti-fibrotic drugs available, but they are urgently needed.  So, discoveries like this, identifying a potential gene target to reduce fibrosis, is very exciting.”

Dr Pan explains, “The primary driver behind the process of fibrosis is a protein called transforming growth factor-β (TGFβ).  While it may seem logical to target TGFβ to reduce fibrosis, TGFβ is also involved in many other biological processes, so this makes it difficult to target without impacting its other functions.

“We know that the MERTK gene influences TGFβ function in both human and animal models by promoting signaling that induces fibrosis.

“Our research team was able to demonstrate that deleting the MERTK gene in animal models prevented fibrosis from developing in liver, kidney and lungs. We went on to show that a treatment that inhibits MERKT was able to reduce the severity of existing fibrosis.

“While our study focused on reducing liver fibrosis, the basic process of fibrosis is similar in all organs, and we were excited to see, for the first time, the potential to reduce kidney and lung fibrosis as well.”

A treatment for multiple organ fibrosis is urgently needed
Professor Mohammed Eslam, Deputy Director of WIMR’s Storr Liver Centre and corresponding author on the study, says, “Finding an anti-fibrotic therapy that is suitable for multiple organs has proven to be extremely challenging, which is why our research findings are so important.”

It is estimated that liver cirrhosis (the development of fibrosis and nodules that reduce liver function) affects at least one in 200 Australians[2], and is associated with 2.4% of global deaths[3].

1.7 million adult Australians have biomedical signs of chronic kidney disease (CKD)[4], of which fibrosis is an early indication. Globally, approximately 1.2 million people die from CKD each year[5].

Idiopathic Pulmonary Fibrosis (IPF) is the most common form of pulminary fibrosis (lung scarring), with more than 2,170 people Australians diagnosed each year[6], and around 3 million people worldwide[7].

Yet, despite fibrosis increasingly identified as a global health burden, currently, there are no anti-fibrotic treatments available.

Professor Mohammed Eslam says, “This is why these findings are so important.  The ability to develop treatments to prevent and reduce fibrosis in, not only the liver, but also for the first time, kidneys and lungs, is exciting.  However, I feel this is the tip of the iceberg.  There are many other organs that are susceptible to fibrosis that could benefit from these findings. The potential global impact of these findings is profound.”

[1] Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol 2004;4:583-594.
[2] https://liver.org.au/your-liver/liver-diseases/cirrhosis
[3] The Global Health Observatory. Global health estimates: Leading causes of death. WHO https://www.who.int/data/gho/data/themes/mortality-and-global-health-estimates/ghe-leading-causes-of-death. (2023).
[4] https://www.aihw.gov.au/reports/chronic-kidney-disease/chronic-kidney-disease/contents/how-many-people-are-living-with-ckd
[5] Collaboration GBDCKD. Global, regional, and national burden of Chronic Kidney Disease, 1990–2017: a systematic analysis for the global burden of Disease Study 2017. Lancet. 2020;395(10225):709–33.
[6] https://lungfoundation.com.au/patients-carers/living-with-a-lung-disease/pf/overview/#:~:text=For%20IPF%2C%20there%20is%20a,currently%20living%20with%20the%20condition
[7] https://www.boehringer-ingelheim.com/human-health/lung-diseases/pulmonary-fibrosis/facts-about-ipf