Anti-fibrotic treatments could help patients with chronically rejected lungs
Tuesday, March 28, 2017
A new study from the University of Michigan has found a possible reason for chronic rejection of transplanted lungs.
"Survival of lung transplantation is worse than all other solid organ transplants," said Dr. Vibha Lama, associate chief of basic and translational research at Michigan Medicine's Division of Pulmonary and Critical Care Medicine. "The five-year survival rate is only 50 percent, and the 10-year survival rate is as low as 20 percent. For me to tell my patient that this second chance at life comes with this critical limitation is incredibly hard."
Lungs are sometimes rejected due to bronchiolitis obliterans syndrome (BOS). The process causes scarring in the small airways, which eventually close up.
"The patient will begin to have shortness of breath again, like they did before the transplant, and this scarring can lead to graft problems and ultimately death in some patients," Lama said. "Right now we have nothing to prevent or stop this scarring process once it begins."
To find a treatment, Lama and a team of researchers examined the scarring process in the transplanted lung. The study was published recently in the Journal of Clinical Investigation. The goal of the study was to seek out new therapies to stop scarring in the small airways before it starts.
Samples were collected from lung transplant patients. A liquid is inserted into the lung and drawn back out, which allowed researchers to assess the organ's internal environment. The lungs of transplant patients with BOS and those without were examined.
Among the BOS patients, even after the lung cells were removed from the fibrotic graft, the cells continued to make collagen, which explains how they are able to constantly make scar tissue. The team uncovered a chain of events that starts with autotaxin, an enzyme that prompts the cell membrane to generate lysophosphatidic acid, a lipid. The substance served as the catalyst for the body to produce more collagen and indirectly increased the amount of autotaxin.
"We found that these cells could regulate themselves by increased autotaxin production, which was being further enhanced by an autocrine loop," Lama said. "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. 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 cells' autonomous behavior explains why they can't be turned off, thus causing chronic lung transplant rejection, Lama said. Interrupting the pathway could serve to stop the development of scarring and prevent organ rejection.
The research team tested two drug therapies on mice. One targeted the enzyme; the other targeted the receptor for the lysophosphatidic acid.
Treating the mice with these drugs prevented scarring and led to much less fibrosis in the transplanted lungs. Lama said these drugs should be considered in patients with chronically rejected lungs instead of only using immunosuppressive therapy.
"Drugs targeting this pathway, such as autotaxin inhibitors and LPA1 receptor antagonists, have already been developed and are in clinical trials for other fibrotic conditions of the lung, such as idiopathic pulmonary fibrosis," Lama said. "Now we hope that we can consider similar therapies in BOS, a disease where we have no therapeutic options."
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