In medicine, the term idiopathic is given to diseases for which there is no known cause or which appear to happen spontaneously. Michigan Medicine researchers plumbing the mystery of idiopathic pulmonary fibrosis (IPF), a rare but deadly lung disease, are turning to epigenetics for clues.

Epigenetics refers to changes to the genome that don't alter the underlying DNA sequence. Scientists believe certain diseases may arise due to influences from the environment on the genome, such as nutrition and toxic exposures.

In a new study on IPF led by Steven Huang, M.D., an associate professor in the division of pulmonary and critical care medicine, and his team identified the function of an epigenetically-altered gene, KCNMB1, in cells called fibroblasts from patients. Fibroblasts are cells found in connective tissue that play an important role in wound healing but are also implicated in the progressive scarring that causes the lung stiffness and difficulty breathing characteristics of IPF. 

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"We asked ourselves, what does this gene do in fibroblasts?" says Huang. "We knew from other research that KCNMB1 regulates a potassium channel. There are a lot of studies of these channels in other cells, such as neurons and cardiac muscle, but few in fibroblasts. So we first decided to see if it had functional relevance to what fibroblasts do."

Out of generosity, discovery

This work wouldn't be possible without patients with IPF, notes Huang. He also directs the Medical School's lung biorepository, a collection of samples donated by patients undergoing a lung transplant.

"It's a win-win for our patients because not only are they getting new lungs, but their diseased lungs are going to a good cause, research that will hopefully lead to more treatments for this rare disease," he says. In fact, samples are shared with researchers around the country who are looking at IPF.

For this study, reported in the American Journal of Respiratory Cell and Molecular Biology, Huang's team employed various techniques on donated cells to tease out the gene's function in fibroblast biology. They silenced and activated the gene and used pharmaceutical compounds to turn on and turn off the potassium channel and compared the effects in IPF cells and cells from normal lungs.

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"We found that when the channel was upregulated, fibroblasts from patients with IPF more readily differentiated into myofibroblasts, cells involved in the inflammatory response to injury. This is novel because this gene hadn't been looked at in fibroblasts, let alone in the development of fibrosis," he says.

One pharmaceutical agent they used was iberiotoxin —or purified scorpion venom-- a highly effective potassium channel blocker which, depending on the dose, can lead to death. When the channels were blocked in cells in culture samples, the research team noted that they lost some of their ability to contract. During normal wound healing, fibroblasts' transformation into myofibroblasts is marked by an increase of a protein called alpha smooth muscle actin, which assembles into fibers that cause the cells to contract, allowing wounds to contract and heal.

This discovery, that KCNMB1 and potassium channel activation is important for transformation of fibroblasts into myofibroblasts, is an important first step in identifying potential targets for treating IPF. Next, he says, they plan to look at the gene's effects on fibrosis in animal models. Says Huang, "This work begs the question, if we inhibit these channels, can we prevent this differentiation and scarring?"

Paper cited: "The Role of KCNMB1 and BK Channels in Myofibroblast Differentiation and Pulmonary Fibrosis", American Journal of Respiratory Cell and Molecular Biology. DOI: 10.1165/rcmb.2019-0163OC