Comparative analysis of the pathological events involved in immune and non-immune TRALI models.

BACKGROUND AND OBJECTIVES: Transfusion-related acute lung injury (TRALI) is characterized by leukocyte transmigration and alveolar capillary leakage shortly after transfusion. TRALI pathogenesis has not been fully elucidated. In some cases, the infusion of alloantibodies (immune model), whereas in others the combination of neutrophil priming by proinflammatory molecules with the subsequent infusion of biological response modifiers (BRMs) in the hemocomponent (non-immune model) have been implicated. Our aim was to compare the pathological events involved in TRALI induced by antibodies or BRMs using murine models. MATERIALS AND METHODS: In the immune model, human HNA-2(+) neutrophils were incubated in vitro with a monoclonal antibody (anti-CD177, clone 7D8) directed against the HNA-2 antigen and injected i.v. in NOD/SCID mice. In the non-immune model, BALB/c mice were treated with low doses of lipopolysaccharide (LPS) followed by platelet-activating factor (PAF) infusion 2 h later. Forty minutes after PAF administration, or 6 h after neutrophil injection, lungs were isolated and histological analysis, determination of a variety of cytokines and chemokines including keratinocyte-derived chemokine (KC), MIP-2, the interleukins IL-1ß, IL-6, IL-8 as well as TNFα, cell influx and alveolar capillary leakage were performed. RESULTS: In both models, characteristic histological findings of TRALI and an increase in KC and MIP-2 levels were detected. In contrast to the immune model, in the non-immune model, there was a dramatic increase in IL-1ß and TNFα. However, capillary leakage was only detected if PAF was administrated. CONCLUSIONS: Regardless of the triggering event(s), KC, MIP-2 and integrins participate in TRALI pathogenesis, whereas PAF is essential for capillary leakage when two events are involved.

(+)α-Tocopheryl succinate inhibits the mitochondrial respiratory chain complex I and is as effective as arsenic trioxide or ATRA against acute promyelocytic leukemia in vivo.

The vitamin E derivative (+)α-tocopheryl succinate (α-TOS) exerts pro-apoptotic effects in a wide range of tumors and is well tolerated by normal tissues. Previous studies point to a mitochondrial involvement in the action mechanism; however, the early steps have not been fully elucidated. In a model of acute promyelocytic leukemia (APL) derived from hCG-PML-RARα transgenic mice, we demonstrated that α-TOS is as effective as arsenic trioxide or all-trans retinoic acid, the current gold standards of therapy. We also demonstrated that α-TOS induces an early dissipation of the mitochondrial membrane potential in APL cells and studies with isolated mitochondria revealed that this action may result from the inhibition of mitochondrial respiratory chain complex I. Moreover, α-TOS promoted accumulation of reactive oxygen species hours before mitochondrial cytochrome c release and caspases activation. Therefore, an in vivo antileukemic action and a novel mitochondrial target were revealed for α-TOS, as well as mitochondrial respiratory complex I was highlighted as potential target for anticancer therapy.