Radiotherapy-induced Lung Fibrosis Might Be Prevented by Blocking NOX1

According to research published in the journal Molecular Medicine Reports, blocking the reactive oxygen species-producing NOX1 enzyme prevented fibrotic changes in the lungs of mice exposed to irradiation, suggesting that pulmonary fibrosis caused by chest radiotherapy might be prevented by the use of specific blockers of the enzyme NOX1.

Lung fibrosis is a devastating complication of chest radiotherapy used for cancer treatment. The exact mechanisms behind the development of fibrosis in these patients are not clear, but researchers believe inflammatory factors and harmful reactive oxygen species to be involved in the process. Antioxidant enzymes have been suggested to reduce radiation-induced damage.

The research group from the Korea Institute of Radiological and Medical Sciences analyzed cultured human pulmonary artery endothelial cells exposed to irradiation, and focused on the actions of the NOX enzymes — producers of various reactive oxygen species.

The cells were treated with specific blockers of NOX1, 2 and 4 — which have been shown to increase after irradiation — or the more general NOX blocker VAS28701. Blocking NOX activity with VAS28701 resulted in a lower formation of reactive oxygen species after irradiation and a reduced extent of fibrotic changes in the cells, characterized by a lower expression of endothelial cell markers and increased expression of α-SMA — a marker of fibrotic activity.

Such changes represented what is known as the endothelia-to-mesenchymal transition, in which endothelial cells in the lungs’ blood vessels lose their properties and start behaving like reactive fibroblast cells, producing excessive collagen and potentially leading to fibrosis.

The study ”Effects of NOX1 on fibroblastic changes of endothelial cells in radiation‑induced pulmonary fibrosis” then explored the effects of specific NOX blockers and reported that inhibition of NOX1, 2 and 4 reduced reactive oxygen species to a similar extent, but the blockage of NOX 1 seemed to be a more specific regulator.

Since a general NOX blockade can be toxic, the team continued to study only the selective NOX1 inhibitor, and demonstrated that blockage of only this type of NOX was enough to reduce the appearance of fibrotic changes.

The research team then studied the same processes in mice, showing that by blocking NOX1, radiation-triggered collagen deposits in the lungs could be prevented. The treatment also prevented the fibrotic changes previously observed in the cultured cells.

“The results suggested that radiation-induced pulmonary fibrosis may be efficiently reduced by specific inhibition of NOX1, an effect mediated by reduction of fibrotic changes of ECs [endothelial cells],” concluded the research team in their article.