Reproduction of transfusion-related acute lung injury in an ex vivo lung model [see comments]

Abstract

Leukoagglutinins are implicated in transfusion-related acute lung injury (TRALI). In the present study, severe lung vascular leakage was reproduced by application of a leukoagglutinating antibody of anti-5b specificity in an ex vivo lung model. The antibody originated from a multiparous donor-plasma, observed to cause noncardiogenic edema during transfusion therapy. Heated full plasma (anti-5b-titer 1/128) or purified immunoglobulin G fraction was used for the studies. Ex vivo isolated rabbit lungs were perfused with albumin buffer, and human granulocytes (PMN) were admixed to the recirculating perfusate. In presence of anti-5b antibody plus 5b-positive PMN plus rabbit plasma as complement-source, severe lung edema occurred after a latent period of 3 to 6 hours. Pulmonary artery pressure was only transiently and moderately increased, and the leakage reaction could be traced back to a several-fold increase in lung vascular permeability. In contrast, no vascular leakage was noted in lungs perfused in the absence of anti-5b antibody, PMN, or rabbit plasma. Moreover, no permeability increase occurred on use of 5b-negative PMN. This reproduction of TRALI in an ex vivo lung model corroborates the role of leukoagglutinating antibodies in initiating PMN-dependent respiratory distress and suggests a contribution of concomitant complement activation.

Transfusion‐related acute lung injury caused by human leucocyte antigen class II antibody

“…During the second infusion, the antibody could provoke further activation of the primed monocytes and release of soluble mediators, for example cytokines, which would then activate and recruit granulocytes. Subsequently, the granulocytes could become trapped in the vascular endothelium of the lung, causing damage to endothelial cells with the subsequent influx of fluid into the interstitium (as suggested by Seeger et al, 1990). The abnormally high granulocyte concentration at the time of monocyte recovery, together with the increase in body temperature, indicates immunological activation processes.…”

Endothelial pathomechanisms in acute lung injury

“…Cell culture and animal studies using models of TRALI have detected the release of inflammatory mediators and cytokines by neutrophils, which are incriminated in the pathogenesis of the syndrome (Grimminger et al, 1991;Wyman et al, 2002). Activation of neutrophils by anti-HLA antibodies induces endothelial adhesion molecule expression and cell death in cultured EC (Nishimura et al, 2007;Silliman et al, 2007), and permeability increases in perfused intact microvessels (Seeger et al, 1990); the mechanism of neutrophil activation however is not well understood. Since many patients receiving transfusions with antibodies to their white blood cells do not develop TRALI, it has been postulated that prior neutrophil activation and adhesion to lung EC in the setting of sepsis or other inflammatory condition is necessary for TRALI development (Silliman, 2006).…”

The Role of Complement in Transfusion-Related Acute Lung Injury

“…Furthermore, in a study by Sachs et al using an ex vivo rat model of anti-CD177-mediated TRALI, complement was not found to be required for TRALI induction (TRALI induction was more dependent on the density of the cognate antigen), as TRALI occurred in a complement-free environment [48]. In an earlier ex vivo TRALI study by Seeger and colleagues using rabbit lungs, rabbit plasma was suggested to have served as a source of complement and induced TRALI together with anti-5b (anti-HNA-3a) antibodies and PMNs [49]. In this study, however, there was no direct investigation regarding the contribution of complement.…”