A compound called tubastatin inhibits an enzyme-linked cell signaling pathway associated with lung tissue scarring, reducing pulmonary fibrosis, a study reports.
The research on the HDAC6 enzyme in laboratory cell cultures and mice was able to identify only part of the mechanism involved in alleviating the scarring, however. The full scientific name of HDAC6 is histone deacetylase 6.
Idiopathic pulmonary fibrosis leads to progressive lung scarring, or fibrosis. During the course of the disease, cells known as myofibroblasts form and produce extracellular matrix proteins, such as type-1 collagen. Scientists have linked type-1 collagen in particular to the progression of IPF.
Myofibroblasts are formed from fibroblasts through fibroblast-to-myofibroblast differentiation, or FMD. A process known as epithelial-mesenchymal transition, or EMT, is also thought to be involved in myofibroblast accumulation in the lungs.
Proteins known as cytokines regulate myofibroblast formation, and hence fibrosis. Cytokines such as transforming growth factor (TGF)-β1 do this by activating the Smad3 and Akt cell signaling pathways.
This means that Inhibiting TGF-β1 would also inhibit the signaling pathways. Taking the logic further leads to the notion that reining in the production of TGF could be a way to prevent fibrosis.
Another piece of this potential fibrosis-treatment equation is that HDAC6 can temper TGF-β1-triggered epithelial-mesenchymal transition. This finding in previous research is another indication that HDAC6 inhibitors like tubastatin could be used to treat IPF.
Researchers decided to investigate this possibility in laboratory and mouse models of the disease.
Their study, “Tubastatin ameliorates pulmonary fibrosis by targeting the TGFβ-PI3K-Akt pathway,” appeared in the journal Plos One.
The team’s first step was to check levels of HDAC6 in cells from IPF patients and healthy controls. They found more HDAC6 in the IPF cells, although not a statistically significant amount.
Then they looked at whether inhibiting HDAC6 would reduce fibroblast-to-myofibroblast differentiation. They discovered that tubastatin significantly reduced TGF-β1-triggered levels of type-1 collagen, excessive amounts of which are associated with IPF.
Tubastatin reduced collagen production by inhibiting the Akt signaling pathway, they discovered. Other HDAC6 inhibitors that they tried failed to yield the same results, they said.
The researchers’ next step was to see if their cell-culture findings would apply to mouse models of IPF as well.
A key finding was that tubastatin reduced type-1 collagen levels in the mice, protecting them against pulmonary fibrosis.
The team then checked to see if tubastatin could inhibit the Akt signaling pathway without inhibiting HDAC6. In this experiment they used cells that lacked HDAC6. They discovered that tubastatin inhibited the signaling pathway even when HCAC6 wasn’t present.
Based on the results, the team concluded that “our data suggests that tubastatin ameliorates pulmonary fibrosis by targeting the TGFβ-PI3K-Akt pathway, likely via an HDAC6-independent mechanism.”