ARDS New Treatment Target Discovered

According to recent findings published in Science Translational Medicine on August 16, a new Northwestern Medicine study has uncovered a novel therapeutic target and therapeutic drugs for older individuals with acute respiratory distress syndrome (ARDS).

According to the American Lung Association, around 190,000 Americans are diagnosed with ARDS each year. The condition develops when fluid leaks into the lungs, preventing oxygen from entering the bloodstream. ARDS is primarily caused by lung injury, however aging is also a key risk factor that raises the risk of death.

Despite advances in our understanding of ARDS, there are presently no targeted medicines available for patients, and the mortality rate remains high—around 40%.

“Compared to young adults, the incidence of ARDS resulting from sepsis, pneumonia and COVID-19 in the elderly is as much as 20-fold greater, and mortality is up to 10-fold greater,” said senior study author YouYang Zhao, professor of pediatric clinical care at Northwestern University Feinberg School of Medicine.

Zhao’s team discovered that persistent lung injury and high mortality after sepsis due to ARDS were caused by impaired regeneration of endothelial cells in the lungs (cells that line blood vessels in the lungs to regulate the exchange of oxygen between the bloodstream and surrounding tissue) and lung repair using genetic lineage tracing in both aged and young mouse models of ARDS.

The expression of the gene FOXM1, a previously identified mediator of endothelial cell regeneration, was specifically reduced in the lungs of elderly mice but not in younger mice.

“Employing an endothelium-targeted nanoparticle to deliver FOXM1 to the vascular endothelial cells in aged mice could reactivate the regenerative and reparative program and promote survival after sepsis,” said Zhao, who also is a professor of pulmonary and critical care medicine and of pharmacology at Feinberg.

To corroborate their findings, the researchers gave the elderly mice the FDA-approved chemotherapeutic medication decitabine, which reactivated endothelial cell regeneration, reversed poor clearance of lung injury, and enhanced overall survival.

The researchers also collected samples of COVID-19-infected lungs from elderly and middle-aged patients. They discovered that FOXM1 expression was not raised in lung endothelial cells from individuals aged 80 and beyond, but was significantly induced in samples from patients aged 50 to 60 years.

According to Zhao, the data indicate to FOXM1 as a possible treatment target for elderly patients with ARDS.

The delineation of the molecular mechanisms of aging-impaired endothelial regeneration is most important, which could lead to novel therapeutic strategy and agents for potential treatment of ARDS in elderly patients,” Zhao said.

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