<p>Liver fibrosis is the result of
different types of chronic liver diseases, such as cholestatic liver disease and nonalcoholic steatohepatitis, among others.
Fibrosis, if left unchecked, may progress to the point of cirrhosis –
permanently affecting liver function detrimentally and potentially leading to
development of hepatocellular carcinoma.
Inflammatory response following tissue injury is vital for the
initiation of fibrosis; chronic inflammation results in abnormal tissue healing
and promotes a pro-fibrogenic response.</p>
<p>Activins are cytokines that
have been identified as members of the TGFβ superfamily of growth and differentiation factors. Activin A and B, in particular, have been
identified as having roles in the pathophysiology of liver disease, but have
not been investigated thoroughly. We
treated mice with concanavalin A, a potent T-cell mitogen with liver
specificity when administered intravenously, and characterized the resulting
response to liver injury and how activin A and B are modulated during this
acute inflammatory phase. We showed that
activin B is highly increased in circulation following inflammation, as well as
locally in the liver as well as the spleen.
We then neutralized activin A and B via neutralizing antibodies in our
concanavalin A-induced liver injury model to determine if inhibition of these
ligands may confer protective effects during the acute inflammatory response in
liver. Neutralization of either activin
A or activin B protected hepatocytes, improved liver function, and
significantly reduced circulating cytokines following concanavalin A
administration. Finally, we determined
whether inhibition of activin A or B might prevent or reverse the development
of liver fibrosis after disease has been established. We induced liver fibrosis in mice via the
hepatotoxin carbon tetrachloride, and then treated with neutralizing antibodies
while still maintaining carbon tetrachloride administration. Neutralization of activin A and B markedly
reduced liver fibrosis, protected hepatocytes, and improved liver
function. Our findings implicate both
activin A and B as major players in the acute inflammatory response to liver
injury, as well as during chronic injury and fibrogenesis, and demonstrate the
therapeutic potential of targeting these ligands for the treatment of fibrosis
in chronic liver diseases.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/8049611 |
| Date | 15 May 2019 |
| Creators | Matthew Joseph Hamang (6640730) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/The_Roles_of_Activin_A_and_B_in_Liver_Inflammation_and_Fibrosis/8049611 |
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