Transfusion-associated effects of extra-cellular hemoglobin on development andseverity of ventilator-induced lung injury

我们的工作重点是呼吸机诱导的肺损伤(VILI)和输血的联合不良反应。最近，我们证实，输注储存的包装红细胞(SRBC)后，血浆中游离血红蛋白和血红素浓度的增加会加剧长期低血压引起的原发性损伤。通过这项建议，我们希望扩大我们的知识，并更详细地探索无细胞血红蛋白和输注SRBC可能加剧VILI的机制。由于输血、溶血和VILI在重症监护病房患者中都很常见，我们认为血浆中游离血红蛋白浓度的增加会加速VILI的发展并增加VILI的严重程度，而这两种情况都可以通过血红蛋白和血红素清除剂结合珠蛋白或血凝素的治疗来缓解。此外，我们还将评估输注SRBC对VILI发生和加重的影响，包括结合珠蛋白和血凝素的保护作用。VILI和输注SRBC均独立地诱导全身性促氧化和促炎效应。因此，我们将探索输注SRBC和不输注SRBC的VILI中肺和其他肺外炎症和细胞凋亡的病灶。这将有助于促进我们对ARDS器官串扰方面的理解。此外，我们的目的是评估血管内溶血对肺毛细血管血流灌注的影响。

Our work is focused on the combined adverse effects of ventilator-induced lung injury (VILI) and blood transfusions. Recently, we demonstrated that increased plasma concentrations of cell-free hemoglobin and heme after transfusion of stored packed red blood cells (SRBCs) potentiate a primary injury induced by prolonged hypotension. With this proposal, we would like to extend our knowledge and explore in more detail the mechanisms by which cell-free hemoglobin and transfusion of SRBCs might aggravate VILI. Since blood transfusions, hemolysis and VILI can all be found in intensive care unit patients quite frequently, we propose that increased plasma concentrations of cell-free hemoglobin accelerate the development and increase the severity of VILI while both can be attenuated by therapy with hemoglobin and heme scavengers haptoglobin or hemopexin. Furthermore, we shall evaluate the effects of transfusion of SRBCs on the development and aggravation of VILI including protective effects of haptoglobin and hemopexin. Both, VILI and transfusion of SRBCs independently induce systemic pro-oxidant and pro-inflammatory effects. Therefore, we shall explore pulmonary and additional extra-pulmonary foci of inflammation and apoptosis in VILI with and without transfusion of SRBCs. This will help advance our understanding on the aspects of organ cross talk in ARDS. In addition, we aim to evaluate the effects of intravascular hemolysis on pulmonary capillary perfusion.