Treatment may be able prevent the progressive accumulation of scar tissue (fibrosis) in newly transplanted lungs that eventually cause those organs to fail, researchers at the University of Michigan report.
The study, “Autocrine lysophosphatidic acid signaling activates beta-catenin and promotes lung allograft fibrosis,” was published in the Journal of Clinical Investigation.
Patients with lung diseases such as pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and cystic fibrosis, in most cases, have no other option but to undergo a lung transplant. Unfortunately, for the majority, a progressive buildup of scar tissue in the airways — triggered by an aggressive and almost “cancer cell-like” process — leads to an irreversible condition known as bronchiolitis obliterans syndrome (BOS) that results in organ rejection and failure.
According to the researchers, patients who develop BOS will eventually experience the same shortness of breath and inability to breathe without assistance devices as they did pre-transplant. Currently, no treatments are able to stop BOS or prevent it after transplantation, so that the five-year survival rate for patients is only 50 percent, and the 10-year survival rate is as low as 20 percent — making lung transplants the least effective solid organ transplant procedure in terms of survival time.
Researchers led by Vibha Lama, MD, a professor of internal medicine and associate chief of basic and translational research in the Division of Pulmonary and Critical Care Medicine, examined the scarring process in transplanted lungs of a novel mouse model of BOS to identify potential therapeutic targets.
They began by collecting tissue samples from lung transplant patients using a routine procedure, known as bronchoalveolar lavage. This allowed them to study the internal environment of the transplanted organ.
Next, the researchers looked at the tissues’ cellular matrix to distinguish between harvested cells with BOS pathology and those without it.
Analysis of cells with BOS pathology (i.e., evidence of changes caused by disease) showed collagen producing activity even after removal from the transplanted organ. The inability of these cells to turn off collagen production is what leads to the scarring.
The team then examined collagen production processes and discovered a cellular signaling pathway that starts with autotaxin, an enzyme that acts on the cell membrane to generate lysophosphatidic acid. This acid, a potent lipid mediator, was triggering the cells to produce more collagen, and indirectly to increase autotaxin levels.
“The dysregulated behavior of these cells essentially makes them become autonomous in behavior and helps us further understand why we can’t stop the scarring process just by changing the environment around the cell, which does not make a difference. They have already begun not listening to anything around them,” Lama said in a university news “lab” report written by Kylie O’Brien.
“What’s so fascinating about this is that it means the cell no longer needs an inflammatory environment, or stimulation in its environment, to produce the collagen,” she added. “That’s extremely novel because we have never thought of these cells as essentially cancer cell-like in nature, but they are regulating their own behavior like a cancer cell does.”
The discovery led the team to focus on therapies that could interrupt this cellular pathway to stop further scarring, potentially saving the transplanted lung and patients from organ failure.
Potential treatments tested were PF-8380, targeting the autotaxin enzyme, and AM095, targeting the lysophosphatidic acid receptor.
Working with a lung transplant mouse model of chronic rejection, researchers found that treated animals were protected from the scarring process and showed statistically significant decreased fibrosis in transplanted lungs.
“These findings suggest that understanding the pathways that activate a mesenchymal cell and targeting them is crucial if we want to contain the progression of BOS,” Lama said. “We hope this work … will be able to be translated back from the bench to the bedside to make an impact on the lives of our patients.”
In other words, the team hopes these findings will lay the foundation for future clinical trials. And, the researchers suggested, anti-fibrotic treatments should be considered for patients with chronically rejected lungs, instead of just immune suppressive drugs.