Cigarette smoke curbs lung's self-healing
German Research Center for Environmental Health
Cough, bronchitis and breathing difficulties – these are the
typical manifestations of COPD. Exact figures are not available, but estimates
assume that ten to twelve percent of the adults over 40 years of age in Germany
suffer from the disease.
Experts estimate the national economic costs of the
disease at almost six billion euros annually.* Scientists around the world are
attempting to discover how the disease develops and what biological adjustments
can be made to stop it.
One
approach involves the lung's natural self-healing, which no longer takes place
in COPD. “In healthy patients, the so-called WNT/beta-catenin signaling pathway
is responsible for the lung's homeostasis.
Until now, it was not clear why it was silenced in patients with COPD,” explains Dr. Dr. Melanie Königshoff, head of the Lung Repair and Regeneration (LRR) Research Unit of the Comprehensive Pneumology Center (CPC) at Helmholtz Zentrum München.
She and her team spent
the last few years tackling this question in the framework of an ERC Starting
Grant and discovered that one of the Frizzled molecules– Frizzled 4 –plays an
important role.
“Frizzled
4 is a receptor molecule that sits on the surface of lung cells, where it
regulates their self-renewal via WNT/beta-catenin,” explains first author
Wioletta Skronska-Wasek, doctoral candidate at the LRR.
"However if the
cells are exposed to cigarette smoke, Frizzled 4 disappears from the surface
and cell growth comes to a halt.”
Successful
reversal in cell culture
The
starting point for the current study was the team's observation that in the
lung tissue of COPD patients, and especially that of smokers, there were
significantly fewer Frizzled 4 receptors than in non-smokers.
“In the next
step, we were able to prove in cell culture and model systems that inhibition
of Frizzled 4 signaling on the cells led to decreased WNT/beta-catenin
activity and consequently to reduced wound healing and repair capacity,”
described Dr. Ali Önder Yildirim, an expert on the effects of cigarette smoke
in the lung.
He is a group leader at the Institute of Lung Biology of the CPC
at the Helmholtz Zentrum München and also participated in the study. The
authors additionally recognized that without the receptor, there was a loss of
certain proteins that are important for the structure of lung tissue (including
elastin, fibulin and IGF1) and the lung’s elasticity, allowing patients to
breathe.
To confirm their results, the scientists artificially increased Frizzled 4 levels in a cell culture test to stimulate its production.
To confirm their results, the scientists artificially increased Frizzled 4 levels in a cell culture test to stimulate its production.
The increase in
Frizzled 4 reactivated the blocked repair process and led to the production of
many of the previously reduced proteins.
“The activation of the Frizzled 4
receptor can restore the WNT/beta-catenin signaling pathway and consequently
lead to repair in the lung,” explains Melanie Königshoff. This is an exciting
starting point for further research which might develop new therapies for COPD
patients.**
Further Information
*
Source: www.lungeninformationsdienst.de
**
Melanie Königshoff's research unit is a part of the German Center for Lung
Research (DZL). Since the end of last year, she is also been
setting up a new laboratory at the University of Colorado, Denver, where she
will further expand her research program on lung regeneration.