Preventing Certain Type of Cell Death May Help Treat COPD
Preventing a specific type of cell death, called necroptosis, may provide a new way of treating chronic obstructive pulmonary disease (COPD), according to data from a recent study.
Patients with COPD have elevated levels of necroptosis, the study revealed. Stopping that type of cell death leads to significant reductions both in chronic airway inflammation and in lung damage, the researchers said.
Titled “Necroptosis Signalling Promotes Inflammation, Airway Remodelling and Emphysema in COPD,” the study was published in the American Journal of Respiratory and Critical Care Medicine.
The process by which a cell dies affects what happens around it, according to researchers. There are several paths leading to cell death, including apoptosis, which is tightly controlled and triggered as part of the body’s own quality control processes. Necrosis, another type of cell death, happens in an uncontrolled way and is driven by external factors.
Necroptosis is a regulated form of necrosis but one that is known to drive tissue inflammation and destruction.
“Necroptosis, apoptosis and necrosis are all forms of cell death but they operate in distinctly different ways,” Philip Hansbro, PhD, the study’s senior author, said in a press release.
“Significantly, in necroptosis, a cell bursts, dispersing its contents into nearby tissues, resulting in an immune and inflammation response,” said Hansbro, director of the Centenary University of Technology Sydney (UTS) Centre for Inflammation.
While necroptosis is a known driver of inflammation and tissue destruction, its role in COPD, an inflammatory lung disorder, is still poorly understood.
To learn more, Hansbro and his colleagues compared the levels of RIPK3, MLKL, and phospho-MLKL (an activated form of MLKL) — all key mediators of necroptosis — in the lungs of people with and without COPD.
The results showed that lung tissues from individuals with COPD contained higher levels of MLKL and phospho-MLKL than did those of both people who never smoked and smokers who did not have COPD.
The team also assessed the levels of necroptosis-related messenger RNA (mRNA) and proteins, as well as overall cell death, in the lungs of a cigarette smoke-induced COPD mouse model. Of note, mRNA is the molecule that cells use as a template for producing proteins.
In addition, the lungs of mice that were genetically engineered to be unable to produce RIPK3 and MLKL were examined to see how they responded to cigarette smoke exposure.
These experiments showed that mice with smoke-induced COPD had higher levels of necroptosis-related mRNA and proteins in their lungs, much like COPD patients. However, in mice that were unable to produce necroptosis-related mediators, inflammation in response to smoke exposure was reduced.
Finally, the scientists examined the effects of inhibiting apoptosis and necroptosis in cells taken from mice with smoke-induced COPD. While blocking both processes successfully reduced smoke-induced inflammation, stopping necroptosis was the only way to prevent airway remodeling — structural changes associated with COPD and other chronic illnesses — and emphysema, a severe form of COPD.
“Necroptosis is generally pro-inflammatory. Apoptosis, however, tends to be non-inflammatory as it’s a more ordered form of cell death — a cell self-degrades as opposed to bursting and there’s no leakage of cell contents,” said Zhe Lu, PhD, the study’s lead author. “This may explain why, in our study, it’s the inhibition of necroptosis and not apoptosis that reduces lung damage and COPD-associated inflammation.”
The group’s findings raise the possibility that targeted therapies capable of specifically inhibiting necroptosis may one day be adopted to treat COPD.
“Our research suggests that inhibiting necroptosis and preventing this inflammation response may be a new therapeutic approach to treating COPD,” said Hansbro.