In chronic obstructive pulmonary disease (COPD), the patients’ lungs lose their ability to repair damage on their own. Scientists at the Helmholtz Zentrum München, partner in the German Center for Lung Research, now have a new idea about why this may occur. In the Journal of Experimental Medicine, they blame the molecule Wnt5a for this problem.
The first indication of COPD is usually a chronic cough. As the disease progresses, the airways narrow and often pulmonary emphysema develops. This indicates irreversible expansion and damage to the alveoli, or air sacs. "The body is no longer able to repair the destroyed structures," explains Dr. Melanie Königshoff, head of the Research Unit Lung Repair and Regeneration (LRR) at the Comprehensive Pneumology Center of Helmholtz Zentrum München. Dr. Königshoff and her team are working to understand how this happens.
"In our current work, we have been able to show that COPD results in a change in the messengers that lung cells use to communicate with one another," she continues. Specifically, the scientists discovered increased production of the Wnt5a molecule, which disrupts the classic (or canonical) Wnt/beta-catenin signaling pathway that is responsible for such repairs.
"Our working hypothesis was that the relationship between different Wnt messengers is no longer balanced in COPD," reports Dr. Hoeke Baarsma, LRR scientist and the study’s first author. The team correspondingly searched for possible interference signals. "In both the preclinical model and the tissue samples from patients, we found that in COPD tissue, particularly, the noncanonical Wnt5a molecule is increased and occurs in a modified form." According to the authors, stimuli that typically cause a reaction in COPD, such as cigarette smoke, additionally lead to increased production of Wnt5a and consequently to impaired lung regeneration.
In the next step, the researchers were able to show where the misdirected signal originates: "It is produced by certain cells in the connective tissue, the so-called fibroblasts," Dr. Baarsma says. When pulmonary epithelial cells were treated with the Wnt5a derived from the fibroblasts, the cells lost their healing ability. The scientists were also able to use antibodies directed against Wnt5a in two different experimental models to slow down the lung destruction and better maintain the lung function.
"Our results show that the classic Wnt/beta-catenin signal cascade is disrupted by the Wnt5a ligand. This is a completely new mechanism in association with COPD and could lead to new therapeutic approaches, which are urgently needed for treatment," Dr. Königshoff says.
Source: Helmholtz Zentrum München; December 16, 2016.