Discovery of CMA-1 Enzyme May Lead to New Treatment for COPD

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by Steve Bryson, PhD |

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Scientists say the discovery of a triggering enzyme in the lung tissue of people with severe chronic obstructive pulmonary disease (COPD) could lead to a new treatment for the inflammatory disorder.

Elevated levels of the newly uncovered enzyme, called chymase-1 or CMA-1, were found in tissue isolated from the lungs of COPD patients.

CMA-1 was found to trigger the release of TNF-alpha, a pro-inflammatory signaling protein or cytokine. According to researchers, blocking the activity of CMA-1 in an experimental COPD mouse model ameliorated the signs and symptoms — including inflammation and impaired lung function — of the chronic disease.

“There is currently no cure for COPD and effective therapies to treat and manage the disease are urgently needed,” Phil Hansbro, PhD, director of the Centenary University of Technology Sydney (UTS) Centre for Inflammation, in Australia, said in a university press release.

“Our study suggests that developing new drugs to inhibit CMA1 and reduce cytokine inflammation may be a novel treatment for this devastating disease that affects so many lives,” added Hansbro, the study’s senior author.

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The study, “Adverse roles of mast cell chymase-1 in chronic obstructive pulmonary disease,” was published in the European Respiratory Journal.

COPD is a chronic inflammatory disease of the lungs that leads to airway blockage, cough with mucus, wheezing, and shortness of breath. Although the causes of COPD are not fully understood, long-term exposure to irritants, particularly cigarette smoke, air pollution, and other particulate matter, have been cited as contributing factors.

“Over time the lungs breathe in toxic material and become inflamed,” said Gang Liu, PhD, a researcher at the Centenary UTS Centre and the study’s lead author. “Lung function is subsequently impaired leading to breathing difficulties which can then turn fatal.”

Chymase-1 is an enzyme produced by immune mast cells that participates in inflammatory responses and plays a harmful role in various disorders.

Because its role in COPD is unknown, Hansbro, Liu, and their colleagues measured CMA-1 levels in lung tissue samples isolated from COPD patients and healthy people who served as controls. The team then investigated the enzyme in related mouse models.

The lung samples had been collected from COPD patients with severe and early/mild disease, as well as from people without COPD who smoked, and the healthy controls.

The scientists measured the number of mast cells containing CMA-1, along with the levels of CMA-1 messenger RNA (mRNA) — the molecule that cells use as a template to produce CMA-1.

Compared with all other samples, those from severe COPD patients had elevated numbers of mast cells containing CMA-1. They also were found to have higher levels of CMA-1 mRNA — a sign of increased gene expression (activity). Mice with induced COPD also had elevated mast cell numbers and increased levels of mMCP5, which is the mouse equivalent to CMA-1.

To investigate further, mice with or without the gene encoding for mMCP5 were exposed to cigarette smoke extract. Mice with mMCP5 had increased numbers of immune macrophages, a type of white blood cell, and developed inflammation and emphysema. Emphysema is a condition characterized by damage to the lungs’ tiny air sacs, or alveoli.

These animals also had structural changes to the airways with impaired lung function.

In contrast, mice lacking the gene for mMCP5 were protected from these induced symptoms.

Next, mast cells were isolated from normal and genetically engineered mice, co-cultured with macrophages, and challenged with cigarette smoke extract. Macrophages from normal mice, but not those lacking mMCP5, released the pro-inflammatory cytokine TNF-alpha.

Consistent with these findings, exposure to cigarette smoke extract caused human mast cells to release CMA-1. A lab-made version of human CMA-1 (hCMA-1) also induced the release of TNF-alpha from human macrophages.

“CMA1 induces macrophages (a type of white blood cell) to release pro-inflammatory cytokines in the lung,” said Liu. “It’s this increased inflammation that can drive the development of COPD and poor outcomes for patients.”

Lastly, researchers showed that treating mice with a compound that blocked (inhibited) the activity of CMA-1 suppressed these hallmark features of COPD in the experimental mouse model.

“We were able to show in experimental COPD, that inhibiting mMCP5 provided protection against inflammation and macrophage accumulation, harmful structural changes of the lung, emphysema and impaired lung function,” added Liu.

“CMA1/mMCP5 promotes the pathogenesis [development] of COPD, in part, by inducing TNF-[alpha] expression and release from lung macrophages,” the team wrote, concluding, “Inhibiting hCMA1 may be a novel treatment for COPD.”