TRALI: beginnings are always messy Free

In this issue of Blood, Rebetz et al¹ open a neglected branch of research on pathophysiology of transfusion-related acute lung injury (TRALI). In their article, the researchers unravel pathways that are essential for developing lung injury and then elegantly block these pathways with specific inhibitors. Using this approach, they discovered that mitochondrial DNA (mtDNA) stimulates recipient Toll-like receptor 9 (TLR-9) and promotes the development of TRALI in mice.

TRALI is a severe complication of blood transfusion, which can result in the need for intensive care due to respiratory insufficiency, and even death.² It is a peculiar syndrome because it develops in a “2-hit” fashion and mainly presents with pulmonary symptoms after a systemic insult (ie, blood transfusion). The “first hit” is a clinical insult that increases susceptibility for developing TRALI. Often this is an acute illness associated with systemic inflammation (increased levels of interleukin-6 [IL-6] and IL-8, and acute phase protein C-reactive protein [CRP], and decreased IL-10). Mechanical ventilation has also been identified as risk factor for TRALI, which can make it very difficult to distinguish the syndrome from other causes of sudden respiratory deterioration.² The “second hit” is a transfusion, which induces actual lung injury. Only if the severity of both the first hit and second hit combined crosses a certain “threshold,” the patient develops TRALI. It thus follows that patients receiving intensive care are most prone to develop lung injury after transfusion and are most at risk of its severe sequelae. In at least 80% of cases, antibodies are thought to be causative of TRALI. In most of these cases, anti-HLA class I or II or anti–human neutrophil antigen antibodies can be detected in the transfused blood product or recipient.³ For the remaining 20% of cases, antibody-independent TRALI mechanisms have been suggested as the second hit, which include, for example, bioactive lipids, extracellular vesicles, and stored transfusion products.⁴ 

Various TRALI animal models (mostly mouse models) have been developed to investigate TRALI pathophysiology. However, if one looks more closely at the models that have been published up to date, one sees something interesting: they mainly focus on the biological pathways of the second hit.⁵ Most models use lipopolysaccharide as the first hit. Only a limited number of studies have investigated what this priming entails. These have shown that it results in endothelial activation and sequestration of platelets and neutrophils in the lungs. However, most studies focus on the “main event”: TRALI induction, usually with infusion of anti–major histocompatibility complex class I antibody in mice. Very detailed investigations with various types of knockout mice have shown involvement of many facets of the immune system; implicated pathways and cells include neutrophils, monocytes, complement, platelets, endothelial activation, neutrophil extracellular traps, and neutrophil and endothelial Fcγ receptors. The findings from animal models and human studies have been translated into hypothetical therapeutic targets including infusion IL-10, blocking of CRP, anti–reactive oxygen species therapy, IL-8 receptor blockade, IV immunoglobulin, blocking Fcγ receptors, complement targeting, and antiplatelet therapies.² None of these potential targets have been subjected to intensive investigation in either animals or humans. Thus, to date, to our knowledge, no study has looked at priming for TRALI; what receptors are involved and how the first hit occurs. Rebetz et al have started to illuminate this blind spot. With various combinations of agonists and antagonists, they focused on induction of the first hit. They thus showed that mtDNA can act as a first hit and that the first hit can be prevented by infusion of a TLR-9 antagonist. This is relevant especially for patients who are critically ill because extracellular mitochondria have been shown to be elevated in subsets of patients who are critically ill,⁶ and can be found in blood products.⁷ Decreasing levels of circulating mtDNA or blocking TLR-9 can be investigated as potential preventive strategies.

Rebetz et al, thus, not only pave a pathway into exploration of the pathophysiology of the first hit but also present various potential therapeutic targets. Because their study was performed in mice, the findings will need to be confirmed in humans. Decades of research have shown that TRALI is often missed by treating physicians because TRALI mimics acute respiratory distress syndrome and, even if recognized, is underreported to transfusion medicine services.⁸ This has hampered clinical research on TRALI pathophysiology, and the last case-control studies on patients with TRALI are already 15 years old.^9,10 However, the findings of Rebetz et al deserve and need confirmation with follow-up investigations in clinical studies. For now, their study has given us very valuable new leads on how we understand, and can work to prevent, severe transfusion complications.

Conflict-of-interest disclosure: A.L.P. declares no competing financial interests.