Heme is an essential component of hemoglobin, the protein in red blood cells that transports oxygen.
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Scientific Frontline: Extended "At a Glance" Summary: Heme-Induced Inflammation
The Core Concept: When red blood cells break down, they release heme, an essential, oxygen-transporting component of hemoglobin. Once outside the red blood cell, free heme acts as a harmful agent that can trigger severe inflammatory reactions and damage tissues and blood vessels.
Key Distinction/Mechanism: Free heme binds to and activates the protein factor XII in the bloodstream, which subsequently activates an inflammatory protein network known as the kallikrein-kinin system. This cascade releases bradykinin, a molecule that dilates blood vessels and increases their permeability, causing fluid to leak into surrounding tissues, resulting in swelling, inflammation, and a drop in blood pressure.
Major Frameworks/Components:
- Hemolysis: The physical breakdown of red blood cells caused by infections, trauma, burns, or mechanical stress (such as from mechanical heart valves).
- Factor XII Activation: The initial protein binding site for free heme that acts as the catalyst for the inflammatory cascade.
- Kallikrein-Kinin System: The specific inflammatory pathway in the blood that is triggered by factor XII.
- Bradykinin Release: The molecular output that directly alters blood vessel permeability.
- C1-Inhibitor Intervention: An existing drug used successfully in experimental models to inhibit the kallikrein-kinin system and block the inflammatory reaction.
Branch of Science: Hematology, Immunology, Pathology, and Cell Biology.
Future Application: The successful experimental use of the C1-inhibitor suggests a pathway for repurposing existing drugs to treat or block severe inflammation in patients suffering from malaria, sickle cell anemia, enterohemorrhagic Escherichia coli (EHEC) infections, and mechanical trauma.
Why It Matters: This research provides a novel, mechanistic explanation for how fragmented red blood cells independently drive severe vascular inflammation, regardless of the underlying cause of the hemolysis. It establishes a critical new target for therapeutic interventions in a wide array of diseases characterized by extensive red blood cell breakdown.
When red blood cells break down, they release heme, a component of hemoglobin, which can contribute to inflammation and damage tissues and blood vessels. Researchers at Lund University have now identified a mechanism by which heme activates an inflammatory reaction in the blood. They were also able to block this pathway in experimental models. The findings could have implications for diseases and conditions involving the extensive breakdown of red blood cells, including hemolytic uremic syndrome and malaria.
Heme is an essential component of hemoglobin, the protein in red blood cells that transports oxygen. When red blood cells break down, a process known as hemolysis, heme can be released into the bloodstream. Once outside the red blood cell, heme is harmful and can contribute to inflammation. Hemolysis occurs in conditions such as sickle cell anemia, malaria, trauma, and burns, but also when blood is exposed to mechanical stress, such as during cardiopulmonary bypass or through contact with mechanical heart valves.
In the new study, the researchers show how heme can trigger a chain reaction in the blood that activates inflammation, making blood vessels more permeable. They found that heme binds to and activates the protein factor XII, which activates the kallikrein-kinin system, an inflammatory protein system in the blood. This leads to the release of bradykinin, a molecule that causes blood vessels to dilate and become more permeable. As a result, fluid leaks into surrounding tissues, contributing to swelling, inflammation, and a drop in blood pressure.
“This explains how fragmented red blood cells can activate severe inflammation. Free heme can trigger an inflammatory response regardless of what caused the red blood cells to fragment in the first place,” says Diana Karpman, professor of pediatrics at Lund University.
The researchers studied blood samples from 34 children with hemolytic uremic syndrome (HUS), as well as samples from healthy controls. HUS is a serious complication that can occur following enterohemorrhagic Escherichia coli (EHEC) infection and is characterized by low platelet levels, acute kidney injury, and the breakdown of red blood cells. In some of the children, the researchers found evidence of kallikrein-kinin system activation. Depending on the marker used, evidence of activation was observed in 10 of 34 or 17 of 32 children, respectively. Activation was associated with the extent of red blood cell fragmentation (degree of hemolysis) and kidney involvement. The findings were confirmed in experimental models in which the researchers prevented activation using C1-inhibitor, a drug used for another indication that inhibits the kallikrein-kinin system.
“The fact that we were able to block the reaction experimentally makes the finding particularly interesting. However, we have not yet shown that such a treatment works in patients. This now needs to be investigated further,” says Alexandra Gerogianni, who conducted the study during her postdoctoral research at Lund University.
The findings provide a novel mechanistic explanation for how the breakdown of red blood cells can contribute to inflammation. Although the researchers chose to study HUS, hemolysis occurs in many other diseases and clinical situations. Globally, many people are affected by diseases characterized by extensive hemolysis occurring during the disease process, most notably malaria.
“We chose to study HUS because it is an area we work with, but the implications could be much broader. Free heme is present in many conditions involving hemolysis. An important question going forward is how much this mechanism contributes to inflammation and disease,” says Karpman.
Funding: The research was supported by the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the IngaBritt and Arne Lundberg Research Foundation, the Freemasons’ Foundation for Children’s Welfare in Stockholm, the Alfred Österlund Foundation, Skåne University Hospital foundations, the Royal Physiographic Society of Lund, the Swedish Kidney Foundation, and the Sigurd and Elsa Golje Memorial Foundation.
Published in journal: Kidney International
Title: Heme-induced kallikrein-kinin system activation in hemolytic uremic syndrome
Authors: Alexandra Gerogianni, Niklas Friberg, Markus Wendler, Sára Kellnerová, Alex Antill, Ann-Charlotte Kristoffersson, Johan Flygare, Ida Arvidsson, and Diana Karpman
Source/Credit: Lund University | Tove Smeds
Edited by: Scientific Frontline
Reference Number: bio090126_01