Blocking Cholesterol Derivative May Offer Way to Treat COPD, Study Suggests

Blocking a cellular pathway related to cholesterol metabolism shows early promise in treating chronic obstructive pulmonary disease (COPD), a German study in mice reports.

The research, “Cholesterol metabolism promotes B-cell positioning during immune pathogenesis of chronic obstructive pulmonary disease,” was published in the journal EMBO Molecular Medicine.

Cigarette smoking and environmental pollution are the major risk factors for COPD development, causing an inflammatory reaction in the airways and lung that progressively impairs breathing.

Although the underlying processes of COPD remain largely unknown, increasing evidence supports a key role for inducible bronchus-associated lymphoid tissue (iBALT), a type of lung lymphoid tissue that develops after pulmonary infection or inflammation. iBALTs are tertiary lymphoid organs, which form near sites of inflammation.

The processes driving iBALT generation, especially during chronic exposure to cigarette smoke, are also unknown. To address this gap, scientists analyzed known processes in other lymphoid tissues, in particular the metabolism of oxysterols, which are derivatives of cholesterol with an important role in various biological processes. One such process is the positioning of immune cells in lymphoid tissue.

“We wanted to find out whether that is also the case around the lungs and specifically in cigarette-smoke-induced COPD,” Ali Önder Yildirim, PhD, a researcher at the Helmholtz Zentrum München, and one of the study’s senior authors, said in a news release.

“We focused on tertiary lymphoid organs in the bronchi. It is believed that the development of iBALT plays a key role in the deterioration of COPD but until now it was unclear exactly how iBALT forms,” Yildirim added.

Results revealed that airway cells taken from the lungs of COPD patients and cigarette smoke-exposed mice had higher-than-usual levels of metabolic enzymes involved in oxysterol metabolism, and in regulating cigarette smoke-induced migration of B-cells (a type of immune cell) and iBALT formation.

Additional mice experiments showed that the absence of these enzymes reduced iBALT generation, and lessened evidence of cigarette smoke-caused emphysema, immune cell migration and lung damage.

Blocking oxysterol’s molecular pathway with clotrimazole, an approved treatment, prevented immune cell migration and iBALT formation, and reduced emphysema.

Overall, the findings “identify a novel therapeutic target for the treatment of COPD and potentially other diseases driven by the generation of tertiary lymphoid organs,” the researchers wrote.

“Our future goal is to transfer the results from the model to humans with a view to intervening in the development of COPD,” Yildirim said. “There is still a lot of work to do, however we are very much looking forward to it.”