Identification of Immune Mechanisms Responsible for Initiation and Regulation of Transfusion-Related Acute Lung Injury (TRALI)

Transfusion related acute lung injury (TRALI) denotes lung injury after transfusion of blood products and is currently the leading cause of transfusion-related death.

The pathogenesis of TRALI is not well understood but appears to require a 2-hit mechanism where the first hit is the predisposing clinical condition of the recipient (eg sepsis which primes pulmonary neutrophils) and the second hit is transfusion of antibodies with potent neutrophil-activating activity.

To date, however, there is no effective treatment for TRALI and animal models are needed to better understand mechanisms of lung damage.

We developed a novel murine model of antibody-antibody mediated TRALI and we have identified several novel immune mechanisms of TRALI induction. Particularly,we have found that infectious first hits of TRALI induction dictate whether TRALI will proceed. We will build on this previous work to better identify how first hits and recipient immune factors affect TRALI.

We will investigate 5 hypotheses related to the overall aim: recipient innate immune responses against different infectious first hits dictate whether induction of TRALI will proceed.

We will take a comprehensive pre-clinical and translational approach to address the first hits that stimulate host factors and culminate in TRALI reactions.

The information gathered from this application will aid in the development of therapeutic modalities that can be translationally tested to reduce TRALI reactions and mortality.