#11
MURINE TRALI: 1-HIT vs. 2-HIT MODEL.
R. Strait MD 1, B. Susskind PhD 2 and F. Finkelman MD 3. 1 Emergency Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA ; 2 Transplantation Immunology, Hoxworth Blood Center, Cincinnati, OH, USA and 3 Int Med-Immunology, U Cincinnati Medical School, Cincinnati, OH, USA .
Clinical studies suggest anti-HLA antibody in donor blood as a major cause of Transfusion Related Acute Lung Injury (TRALI), the #1 fatal complication of transfusion. We developed a murine TRALI model in which shock, dyspnea and pulmonary vascular leak are induced minutes after injecting male mice with anti-MHC class I monoclonal antibody (mAb). Pathogenic mechanisms in this 1-hit model are partially dependent on macrophages, granulocytes, leukotrienes and platelet activating factor, but not platelets, C3, C5a receptor, Fc
R, STAT4, histamine and serotonin. In contrast, female mice are refractory to 1-hit TRALI induction, but intratracheal inoculation with LPS, then challenge with specific mAbs, produced TRALI in female mice (2-hit model). Similarly, sublethal doses of the vasoactive mediators PAF and LTC4, as well as anti-leukocyte mAbs that stimulate their production, fail to cause dyspnea in the1-hit model, but did in the 2-hit model. These observations suggest that anti-MHC antibodies, other anti-leukocyte antibodies, and vasoactive mediators in transfused blood can independently induce TRALI by increasing pulmonary vascular permeability, and that patients with pre-existing lung disease are particularly at risk. These animal models suggest ways to treat and protect against TRALI.