New research suggests that lung fibrosis develops when scar tissue cells escape immune surveillance, suggesting potential therapy.
Idiopathic lung fibrosis is a debilitating disease with a dismal prognosis. It’s caused by progressive scarring in the lungs, making it difficult to breathe, and patients become dependent on oxygen. Treating the disease is a challenge because it’s unclear why the scarring begins and spreads.
Now a team of researchers led by assistant professor of pathology Gerlinde Wernig, MD, at the Stanford Institute for Stem Cell Biology and Regenerative Medicine, has shown that scar tissue cells called fibroblasts are able to proliferate by avoiding immune surveillance, much like cancer cells. A therapy may lie in reactivating that immune function.
The work was published online in Nature Communications in June.
Immune surveillance is the process the body uses to keep tissues healthy and to eliminate cells that might cause disease. For instance, roving immune cells detect and remove pre-cancerous cells. More advanced cancer cells can resist this process by presenting protective molecular signals.
One of these protective signaling proteins, CD47, is used by cancer cells as a “don’t eat me” signal that stops immune cells called macrophages from devouring cells. Another, called PD-L1, is sometimes used by aberrant cells to keep macrophages and other immune cells called T-cells from attacking them.
“In idiopathic lung disease, these fibroblasts behave almost like cancer cells,” Wernig said. “They grow over normal lung structures, obliterating airways, and blocking the passage of air in and out of the blood.” Like cancer cells, Wernig has discovered, fibroblasts also evade the immune system using these immune-dampening proteins.
In previous work, Wernig and her colleagues showed that a gene called JUN is a master regulator of fibrotic processes in mice. Expression of the gene caused fibrosis of the lung, liver, skin, bone marrow, and the kidney in mice. In the current work, Wernig and her colleagues showed that in tissue samples from end-stage lung fibrosis patients, JUN directly activates the genes for CD47 and PD-L1, leading to increased production of these proteins in fibrotic scar-forming lung cells.
The researchers also showed the critical role of another inflammatory molecule called IL-6 in fibrotic disease. “When we looked at clinical tissue samples from lung fibrosis patients, we saw a huge increase in IL-6,” Wernig said. “IL-6 is known to be associated with chronic inflammatory disease, but it wasn’t clear how the molecule was contributing to the scarring process.” The researchers subsequently found that JUN activation also leads to increased IL-6 levels, which in turn amplify the production of CD47, thus further increasing the fibroblasts’ resistance to immune-cell regulation.
When the researchers blocked signaling by IL-6 and CD47 simultaneously, the treatment dramatically improved lung tissue in mice by increasing the removal of fibrotic cells. “In mice, with the combined blockade of inflammation and the ‘don’t eat me’ signal, we were able to eliminate established, end-stage fibrosis,” Wernig said.
“This study presents hope for a new treatment option that could improve the condition of patients with lung fibrosis,” Wernig said. Currently, the only remedy for lung fibrosis is a lung transplant, she notes.
Other Stanford scientists involved in the research were Garry Nolan, Ph.D., the Rachford and Carlota Harris Professor of pathology; postdoctoral fellows Lu Cui, Ph.D., and Tristan Lerbs, MD; former postdoctoral fellows Shih-Yu Chen, Ph.D., and Paola Betancur, Ph.D.; former graduate student Sydney Gordon, Ph.D.; and software developer Jin-Wook Lee, MS.
The research was supported by the National Heart, Lung and Blood Institute (NHLBI grant 1222520-100-PAPGN); a basic science research grant by Boehringer-Ingelheim; and funding from the Scleroderma Research Foundation.
The Stanford Institute for Stem Cell Biology and Regenerative Medicine also supported the work.