Blood helps lungs miss the TRALI

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Science Translational Medicine  01 Nov 2017:
Vol. 9, Issue 414, eaaq1226
DOI: 10.1126/scitranslmed.aaq1226


RBCs limit lung injury by sequestering circulating mitochondrial DNA.

Our medical landscape is awash with “biologicals,” from engineered immune cells to anticytokine antibodies. However, the most important biological of all is transfused blood: a centuries-old therapeutic that remains essential for countless patients. Like other biologicals blood has potential toxicities, including a form of respiratory failure called transfusion-related acute lung injury (TRALI). In TRALI, transfused blood promotes endothelial cell death within the lungs of already ill patients, such as trauma victims, leading to ineffective gas exchange. The cause of TRALI is complex but is believed to include factors inherent to the infused blood and factors inherent to the transfusion recipient. In a new report, Hotz et al. provide evidence that both donor and host factors underlying TRALI are connected. They found that red blood cells (RBCs) can bind to and sequester mitochondrial DNA (mtDNA), which is released into the circulation by dying cells during critical illness. Like its bacterial forbearers, circulating mtDNA binds to the pattern recognition receptor Toll-like receptor 9 (TLR9) on endothelial cells, an event known to induce necroptosis and lung injury. Interestingly RBCs turn out to express TLR9 as well, which may help mitigate the toxicity of circulating mtDNA. In support of this, they show that co-infusion of the TLR9 agonist CpG-DNA and RBCs from tlr9-knockout mice yields more lung injury than when TLR9-expressing RBCs are used. The authors also show that RBCs obtained from different human donors express TLR9 to different extents and may therefore help explain why TRALI incidence is sporadic. In the future, it may be possible to prescreen units of RBCs for high TLR9 and thereby mitigate the risk of lung injury in certain patients. It is likely other molecules in addition to mtDNA contribute to TRALI development, and therefore the work of Hotz et al. represents one piece of a larger puzzle. Nevertheless, the paper reflects a growing sense that RBCs are not merely passive carriers of oxygen and carbon dioxide but active players in homeostasis and critical illness.

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