Lund team blocks heme inflammation pathway in lab

When a red blood cell breaks apart, it releases heme into the bloodstream. Researchers at Lund University have identified how that loose heme can turn a blood reaction into inflammation—and have blocked the pathway in experimental models.

The mechanism starts when heme binds to and activates factor XII, a protein in blood. That sets off the kallikrein-kinin system, which releases bradykinin. Blood vessels then dilate and become more permeable: fluid can escape into surrounding tissue, contributing to swelling, inflammation and a drop in blood pressure.

The researchers looked for signs of the process in blood samples from 34 children with hemolytic uremic syndrome, or HUS. The serious complication can follow EHEC infection and combines low platelet levels, acute kidney injury and the breakdown of red blood cells. Depending on the marker used, activation of the inflammatory system was detected in 10 of 34 or 17 of 32 children; it was associated with the degree of hemolysis and kidney involvement.

The team then used C1-inhibitor, a drug used for another indication, to prevent activation in experimental models. In the experimental models, C1-inhibitor prevented activation of this route, which may contribute to inflammation when red blood cells are heavily damaged. The possible reach is broader than HUS, since hemolysis also occurs in malaria, sickle cell anemia, trauma, burns and when blood encounters mechanical stress during cardiopulmonary bypass or through mechanical heart valves.

And what does it change, concretely? It gives researchers a mechanism to test when inflammation accompanies extensive red blood cell breakdown, and a candidate intervention to investigate. It does not yet give doctors a proven treatment: the Lund team has not shown that C1-inhibitor works in patients, and the study’s broader contribution to disease remains an open question.