Researchers develop a new therapeutic approach against chronic obstructive pulmonary disease (COPD) by preventing lung epithelial cell death and encouraging lung epithelial cell regeneration.
More than 250 million people suffer from COPD, a progressive inflammatory lung disease. On the list of the most frequent causes of death worldwide, COPD ranks third behind heart attacks and stroke. The primary cause of COPD is exposure to cigarette smoke. Approximately 90 percent of COPD patients are or have been chronic smokers. Other risk factors include exposure to air pollution. Despite intensive research efforts, there is no cure for COPD. Resulting fibrosis and lung epithelial cell death are key features of COPD, preventing patients from breathing effectively. Current therapies focus on relieving symptoms and reducing the progression of the disease and its comorbidities. In severe cases, patients require lung transplantation.
“One of the biggest issues in COPD is that the lung cannot regenerate itself,” said Dr Ali Önder Yildirim, Director at the Institute of Lung Biology and Disease at Helmholtz Zentrum München and lead of the study. “Therefore, a treatment that cures the disease needs to focus on lung tissue regeneration and blocking of lung epithelial cell death.”
In 2009, the research group of University Professor Mathias Heikenwälder at DKFZ prevented liver tissue from chronic inflammation and fibrosis. They had achieved this by blocking the lymphotoxin beta receptor signalling pathway within the liver, which is responsible for the activation and organization of immune cells as well as for chronic liver inflammation leading to fibrosis. “This is why we have long suspected that the blocking of lymphotoxin beta receptor could also play a role in regenerative processes in other organs,” explained Professor Heikenwälder.
The development of diseases in the liver and the lung show many similarities. In COPD, immune cells form newly organized structures in the lung, known as tertiary follicles, which play an important role in the disease progression. The formation of these follicles requires the activation of the lymphotoxin beta receptor in the lung - the same receptor which was targeted in Professor Heikenwälder's study in the liver.
“We wanted to investigate on the role of this receptor and its signalling in COPD and whether we might be able to use it in a therapeutic setting,” said Dr Yildirim. The researchers blocked the signalling of the lymphotoxin beta receptor in lungs of mice which had developed smoke-induced COPD typical immune cell follicles, fibrosis and lung epithelial cell death.
Blocking of lymphotoxin beta receptor signalling in mice lung tissue disrupted the formation of the immune cell follicles, preventing lung epithelial cell death and, surprisingly, at the same time triggering lung tissue regeneration. “The lung in those mice regenerated despite the continuous exposure to chronic cigarette smoke. We observed a full restoration of lung tissue,” said Dr Thomas M. Conlon, part of Yildirim's group at Helmholtz Zentrum München.
The researchers found that the regeneration of compromised lung epithelial cells is induced by so-called Wnt signalling which is automatically activated through the blocking of lymphotoxin beta receptor signalling in those cells. “Wnt signalling is an essential pathway for lung development. In COPD, it gets switched off preventing lung tissue from being able to repair and regenerate.” Said Professor Heikenwälder. In previous experiments, re-activation of Wnt signalling in mice has been proven to induce lung repair.
“This could become a novel therapeutic approach for COPD. Our idea is to develop lymphotoxin beta receptor blockers for COPD which reduce lung epithelial cell death and lung inflammation. The automatic activation of Wnt signalling could then induce lung tissue regeneration,” Said Dr Yildirim.
In first preclinical experiments, the group showed that the lymphotoxin beta receptor signalling in human lung tissue is identical to the signalling in mice. This offers great potential for implementing lung regenerative medicine approaches in the clinic. To achieve this ultimate goal, the researchers aim to test this novel therapeutic approach in human clinical trials over the coming years.