Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality, but its pathogenesis is complex and not well understood. TRALI is thought to develop under a “2-hit” model. In 80% of cases, the second hit is caused by antibodies (specifically anti-HLA class I or II or anti-human neutrophil antigen antibodies); bioactive lipids, extracellular vesicles and other storage-related transfusion products have been linked to the remainder of the TRALI cases. The first-hit, which is related to the patient’s underlying clinical condition, is less well defined. Since patients receiving intensive care are more prone to TRALI and often have elevated levels of extracellular mitochondrial DNA (mtDNA), researchers used a murine model to examine whether mitochondria, mtDNA or other damage-associated molecular patterns (DAMPs) can act as a first-hit in an antibody-dependent murine model of TRALI. Injection of purified mitochondria or mtDNA followed by a monoclonal antibody (as a second-hit) caused significantly greater lung injury with increased pulmonary edema, elevated plasma macrophage inflammatory protein-2 (MIP-2; the mouse ortholog of human IL-8), enhanced neutrophil lung infiltration, hypothermia, and respiratory distress compared to an isotype control. Researchers found that an antagonist to toll-like receptor-9 (TLR-9) attenuated many of the TRALI-like symptoms in mice suggesting that mtDNA and TLR-9 may be involved in the first-hit in some TRALI cases. Targeting mtDNA or the TLR-9 receptor may prove to be a novel therapeutic strategy to prevent the first-hit and TRALI, but further research is needed.
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