LAUSR

Transfusion-related acute lung injury (TRALI) is one of the leading causes of transfusionrelated fatalities and is characterized by the onset of acute respiratory distress within 6 hours upon blood transfusion. Specific therapies are unavailable. Pre-existing inflammation is a risk factor for TRALI and neutrophils (PMNs) are considered to be the major pathogenic cells. Osteopontin (OPN) is a multifunctional protein expressed at sites of inflammation and, for example, is involved in pulmonary disorders, can regulate cellular migration and can function as a PMN-chemoattractant. We investigated whether OPN is involved in TRALI-induction by promoting PMN-recruitment to the lungs. Using a previously established murine TRALI model, we found that in contrast to wildtype (WT) mice, OPN knock-out (KO) mice were resistant to antibody-mediated PMN-dependent TRALI induction. Administration of purified OPN to the OPN KO mice, however, restored the TRALI response and pulmonary PMNaccumulation. Alternatively, blockade of OPN in WT mice using an anti-OPN antibody prevented the onset of TRALI induction. Using pulmonary immunohistochemistry, OPN could be specifically detected in the lungs of mice that suffered from TRALI. The OPNmediated TRALI response seemed dependent on macrophages, likely the cellular source of OPN, and OPN-polymerization and independent from the OPN-receptor CD44, IL-6 and other PMN-chemoattractants including macrophage inflammatory protein (MIP)-2. These data indicate that OPN is critically required for induction of antibody-mediated murine TRALI through localization to the lungs and stimulation of pulmonary PMN-recruitment. This suggests that anti-OPN antibody-therapy may be a potential therapeutic strategy to explore in TRALI patients.