CD38 levels rise with age and ischemic stress in donor lungs; inhibiting CD38 reduced injury after blood flow was restored in mice
CD38 levels rise with age and ischemic stress in donor lungs; inhibiting CD38 reduced injury after blood flow was restored in mice
On October 21, researchers at Ohio State University posted a preprint examining how donor lung age relates to injury during transplantation. In human tissue, CD38 levels were higher in lungs from older donors and after donation following circulatory death. In mice, deleting the CD38 gene or administering the inhibitor 78c reduced lung injury after ischemia and reperfusion.
When a lung is retrieved, it loses its normal blood supply. Blood and oxygen return after implantation; this abrupt transition increases vascular permeability, causes edema, and intensifies inflammation. This ischemia-reperfusion injury is one of the risks of transplantation.
In the preprint, the authors compared tissue from donor lungs. CD38 levels were higher in lungs from older donors and after donation following circulatory death, when the organ spends longer without blood flow. Markers of cellular senescence and inflammation were also elevated. CD38 is an enzyme that consumes NAD⁺, a molecule cells need for metabolism and stress responses. The ratio of NAD⁺ to NADH was lower in tissue from older donors. These observations pointed to CD38 as a potential target for protecting the organ.
To test this hypothesis, the authors induced ischemia-reperfusion injury in mice. They blocked blood flow to the left lung for an hour, then restored it for 24 hours. Mice lacking CD38 and those given 78c before blood flow was restored had better lung inflation, less edema, and fewer inflammatory cells in their lungs than control animals. Both approaches to reducing CD38 activity produced similar results in this mouse model.
In human umbilical vein endothelial cells, oxygen deprivation followed by reoxygenation increased CD38 levels and markers of cellular senescence. Suppressing CD38 with small interfering RNA or 78c improved cell survival and reduced the release of LDH, an enzyme released by damaged cells.
In the United States in 2023, 9% of lungs recovered for transplantation were never transplanted; this proportion was highest among donors aged 55 and older, according to the SRTR annual report. In an NHS project using the XVIVO system, donor lungs are warmed, ventilated, and perfused outside the body to assess them and address some reversible problems. The authors propose briefly inhibiting CD38 while the organ is in storage or undergoing this type of perfusion. This would allow researchers to test directly in donor lungs whether the intervention reduces injury when blood flow is restored.