Dissecting the pathophysiology of TRALI: focus on the pulmonary endothelium
Transfusion-related acute lung injury (TRALI) is a syndrome of acute respiratory distress occurring within 6 hours of blood transfusion. In TRALI, respiratory distress is caused by non-cardiogenic pulmonary edema which develops as a result of endothelial cell damage caused by the blood transfusion. There are currently no therapies available for TRALI and consequently it remains a leading cause of transfusion-related deaths.
Unfortunately, the pathophysiology of TRALI is complex and remains incompletely understood. A two-hit model is generally accepted to represent the underlying pathology. The first hit consists of pre-existing patient conditions (e.g. inflammation in general). The second hit consists of factors in the transfusion product such as antibodies (e.g. anti-human leukocyte antigens (HLA) antibodies or anti-human neutrophil (HNA) antibodies) or non-antibody components (e.g. lipids)). Neutrophils (PMNs) are recognized as one of the key pathogenic cells. Interestingly, the anti-inflammatory cytokine interleukin (IL)-10 has previously been shown to prophylactically and therapeutically protect against murine antibody-mediated TRALI (Kapur et al, Blood 2017), however, the mechanism of action has not been identified. It may be possible that IL-10 directly elicits its effect towards the endothelium. It has also not thoroughly been investigated if endothelial cell and/or PMN targeting by TRALI antibodies is required for endothelial cell damage.
In order to further analyze this we have set up a human and murine in vitro platform consisting of pulmonary microvascular endothelial cells, TRALI antibodies and leukocytes including PMNs. Within this system we will measure damage to the endothelial cells (loss of endothelial cell resistance) in a setting of inflammation induced by priming with lipopolysaccharide as a first hit, followed by TRALI induction by anti-leukocyte/endothelium-reactive TRALI antibodies in the presence of PMNs. Using this system, we will also analyze the cell surface expression of various molecules on endothelial cells and leukocytes before and after the first and second hit. In addition, we will investigate the effects of IL-10 on endothelial cell damage and expression of cell surface molecules. We will also investigate if TRALI antibody-binding to endothelial cells and/or to neutrophils is required for endothelial cell damage during TRALI induction. Overall, this will reveal insights into the pathophysiology of TRALI on the level of the pulmonary endothelium.