Antioxidant NAC Found to Ease Lung Scarring in Preclinical Study

Marta Figueiredo PhD avatar

by Marta Figueiredo PhD |

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Antioxidant NAC | COPD News Today | Preclinical research | Illustration of mice among test tubes, beakers

Treatment with the antioxidant N-acetylcysteine (NAC) lowered blood levels of pro-inflammatory molecules and reduced lung scarring, or fibrosis, in a rat model of chronic obstructive pulmonary disease (COPD), a study shows.

This beneficial effect was associated with the suppression of two molecules — von Willebrand factor (VWF) and p38 mitogen-activated protein kinase (MAPK) — which promoted the restoration of immune responses and the repression of epithelial-mesenchymal transition (EMT).

EMT is a key process in fibrosis by which epithelial cells, such as those lining the surface of the lungs, gain migratory and invasive properties.

These findings support the therapeutic benefits of NAC and shed light on its underlying mechanisms, providing new potential therapeutic targets and approaches in COPD, the researchers noted.

The study, “The antioxidant N-acetylcysteine promotes immune response and inhibits epithelial-mesenchymal transition to alleviate pulmonary fibrosis in chronic obstructive pulmonary disease by suppressing the VWF/p38 MAPK axis,” was published in the journal Molecular Medicine.

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COPD is characterized by excessive and sustained airway inflammation, oxidative stress, and fibrosis that lead to permanent lung damage. Oxidative stress is a type of cellular damage resulting from an imbalance between the production of harmful oxidant molecules and the cells’ ability to clear them with antioxidants.

A common over-the-counter oral supplement, NAC is a variant of an amino acid naturally found in the body that has potent antioxidant, anti-inflammatory, and mucolytic (mucus-thinning) properties, making it an attractive treatment candidate for COPD. Amino acids are protein building blocks.

Oral NAC is commonly used as a mucolytic agent in COPD, and some studies have shown that long-term treatment with this antioxidant may help lower the risk of disease-worsening episodes known as exacerbations.

However, the mechanisms behind NAC’s potential benefits in COPD remain largely unknown.

To address this knowledge gap, a team of researchers in China evaluated whether and how oral NAC treatment could reduce lung fibrosis in cellular and animal models of COPD. They also analyzed lung samples from 10 COPD patients who were smokers and 10 non-smokers without COPD.

Using a rat model of COPD, the team first found that NAC treatment significantly improved lung function and reduced lung fibrosis. Blood levels of the pro-inflammatory molecules IL-6 and TNF-alpha were also significantly reduced, approaching those seen in healthy animals.

Normalization of the levels of pro-inflammatory molecules and fibrosis markers were also observed after NAC treatment in a cigarette smoke-induced cellular model of COPD.

By analyzing existing databases in search for genes that could be involved both in NAC effects and COPD, the researchers identified VWF, the gene that provides instructions to produce a blood protein called VWF. This protein is involved in wound healing and is a biomarker of blood vessel damage and inflammation in COPD.

Further analysis showed that VWF levels were significantly increased in lung tissues of COPD patients and in rat and cellular models, compared with their healthy counterparts. Also, treatment with NAC reverted this increase in rats and lab-grown cells to levels comparable to normal.

The team also found that NAC-induced VWF suppression reduced the levels of active p38 MAPK — an enzyme activated by inflammatory and stress signals, such as oxidative stress — that is overly active in COPD patients and contributes to sustained inflammation.

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Moreover, NAC was found to suppress EMT in lab-grown smoke-exposed cells and to restore the levels of immune cells and molecules in the rat model. Both effects were dependent on the reduction of VWF levels and p38 MAPK activation.

These findings suggest that NAC may lessen COPD-induced lung fibrosis “by promoting immune response and [suppressing] EMT process via the VWF/p38 MAPK axis, therefore providing us with a potential therapeutic target for treating COPD,” the researchers wrote.

“Our findings pave way for the development of effective therapeutic strategies for [reducing] pulmonary fibrosis in COPD,” the team wrote, adding that further studies are needed to better understand the roles of NAC, VWF, and p38 MAPK, as well as their interaction, in the progression of COPD-associated lung fibrosis.