Inhibiting a protein called lymphotoxin beta receptor (LTβR) could be an effective therapeutic strategy for chronic obstructive pulmonary disease (COPD), new research suggests.
The findings were published in Nature, in the study “Inhibition of LTβR signalling activates WNT-induced regeneration in lung.”
COPD is characterized by the formation of clusters of immune cells, called inducible bronchus-associated lymphoid tissue (iBALT), in the lungs. In both humans and mouse models, iBALTs are associated with the destruction of lung tissue.
Prior research has implicated LTβR — a protein receptor involved in immune cell signaling — in the development of iBALTs. However, the role of this protein in lung tissue injury remains unclear.
“We wanted to investigate on the role of this receptor and its signaling in COPD and whether we might be able to use it in a therapeutic setting,” Ali Önder Yildirim, director at the Institute of Lung Biology and Disease at Helmholtz Zentrum München, the study’s lead co-author, said in a press release.
The researchers found that the expression of LTβR, as well as related signaling proteins, was increased in samples from humans with COPD. Mice that had been chronically exposed to cigarette smoke — an animal model of COPD — showed similar protein-level changes.
Using a specially engineered protein, the researchers blocked LTβR signaling in the mouse model. In the presence of cigarette smoke, blocking LTβR significantly reduced the formation of iBALTs.
Additional experiments in samples of human lung tissue also suggested that blocking LTβR reduced inflammatory processes.
“These data indicate that disruption of the LTβR signaling pathway reverses cigarette-smoke-induced iBALT formation,” the researchers wrote. Of note, exposure to cigarette smoke is the primary cause of COPD development.
In addition to reducing inflammation and the formation of iBALTs, blocking LTβR signaling in smoke-exposed mice led to restoration of lung tissue. The treatment reduced scarring and inflammatory signaling in the lungs, as well as muscle wasting — an established co-morbidity of COPD — in smoke-exposed mice.
“The lung in those mice regenerated despite the continuous exposure to chronic cigarette smoke,” Thomas M. Conlon, the study’s first author, said. “We observed a full restoration of lung tissue. Moreover, as the mice lungs healed, co-morbidities such as muscle wasting also improved.”
Similar findings were found in experiments using older mice, suggesting that this effect is not dependent on age.
Further analyses and experiments using cells in dishes (in vitro) revealed the mechanism underlying these effects: activating LTβR was found to decrease WNT signaling — WNT is a molecular pathway known to play a central role in the development and growth of the lungs. Conversely, blocking LTβR increased WNT signaling which, in turn, promoted lung regeneration.
Analyses of human and mouse tissue, in this study as well as in previous research, suggested that WNT signaling is decreased in COPD.
“Wnt signaling is an essential pathway for lung development,” said Mathias Heikenwälder, a study lead co-author. “In COPD, it gets switched off preventing lung tissue from being able to repair and regenerate.”
Consistently, treating smoke-exposed mice with a compound that activates WNT signaling resulted in similar lung regenerative effects as blocking LTβR signaling, whereas blocking WNT signaling exacerbated lung damage.
Furthermore, blocking WNT signaling prevented the beneficial effects of blocking LTβR signaling.
Collectively, the findings suggested that blocking LTβR, and/or activating WNT, could be therapeutically efficacious in the treatment of 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 signaling could then induce lung tissue regeneration,” Yildirim said.
“One of the biggest issues in COPD is that the lung cannot regenerate itself,” he added. “Therefore, a treatment that cures the disease needs to focus on lung tissue regeneration and blocking of lung epithelial cell death.”
The team noted that the findings may also have implications for other conditions where iBALT-like immune cell clumps form — for example, such clumps are common in many types of cancer and in some autoimmune diseases.
“We believe it is imperative to conduct future (pre-)clinical studies that incorporate LTβR blockers and WNT/β-catenin activators as a potential dual therapeutic approach,” the researchers concluded.
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