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04.11.2020

ILBD/CPC Researchers cured COPD in experimental research

Researchers at the Institute of Lung Biology and Disease (Helmholtz Zentrum München) have succeeded in curing COPD in mice. Their goal is to test the novel therapeutic approach in human clinical trials over the next few years. The paper was published in Nature, 2020.

Lung section from mice exposed to chronic cigarette smoke for six months highlighting the developing follicles, seen as dense tightly packed inflammatory cells, and increased airspace enlargement from damaged alveolar structures - both characteristic pathological features of COPD. ©Helmholtz Zentrum München

Chronic obstructive pulmonary disease (COPD) is one of the most common and deadliest diseases worldwide. Until today, COPD is not curable.

“One of the biggest issues in COPD is that the lung cannot regenerate”, says Dr. Ali Önder Yildirim, Director at the ILBD. Therefore, a treatment that cures the disease needs to focus on lung tissue regeneration.

In COPD, immune cells (B-cells and T-cells) form newly organized structures in the lung, follicles, which are known to play an important role in the disease progression. The formation of these structures requires the activation of a specific cellular receptor: the lymphotoxin beta receptor which is also a regulator of cell death. The death of epithelial lung cells is another feature of COPD observed in patients, preventing them from breathing effectively.

“We wanted to find out whether the role of this receptor and its signaling is crucial for the disease and if yes, whether we might be able to manipulate it in a beneficial way”, says Yildirim. Together with the DKFZ, Yildirim and his team used a decoy receptor to test its effect on lymphtoxin beta receptor signaling in the lung. For this, they worked with mice which had been exposed to chronic cigarette smoke and had developed COPD typical immune cell follicles in the lung.

Full restoration of lung tissue in mice

The result: Blocking of the lymphotoxin beta receptor and its signaling in the lung disrupted the formation of the immune cell follicles and prevented lung epithelial cell death. “The lung in those mice regenerated. We saw a full restoration of lung tissue”, says Dr. Thomas M. Conlon, part of Yildirim’s group at Helmholtz Zentrum München. “Moreover, as the mice lungs healed, co-morbidities like muscle wasting also improved.”

The group found that the blocking of lymphotoxin beta receptor signaling leads to the activation of so-called Wnt signaling. Wnt signaling is an essential pathway for lung development. In COPD patients this pathway gets switched off preventing the lung from being able to repair and regenerate. In previous experiments, re-activation of Wnt signaling in chronic cigarette smoke exposed mice has been proven to induce lung repair.

In first translational experiments, the group showed that the lymphotoxin beta receptor signaling switched off the Wnt pathway in sliced human lung tissue and impaired the ability of human lung epithelial stem cells to form mini lung organoids.

This work published in Nature journal offers great potential for implementing lung regenerative medicine approaches in the clinic. To achieve this ultimate goal, the group aims to test the novel dual therapeutic approach in human clinical trials over the coming years.

Original publication:
Conlon et al., 2020: Inhibition of LTβR-signaling activates Wnt-induced regeneration in lung. Nature, 2020