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  • br Acknowledgments Work in SI s

    2022-01-14


    Acknowledgments Work in SI’s laboratory is supported by grant IM 20/4-1 from the Deutsche Forschungsgemeinschaft, Bonn (Germany) and grant EKFS 2012_A309 from the Else Kröner Fresenius Stiftung, Bad Homburg (Germany). FW’s group is supported by the Dr Vaillant Foundation and the Dutch Burns Foundation (P16.03).
    Introduction Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication in patients after hematopoietic stem cell SC75741 transplantation (HSCT). Previous investigations suggest that multiple factors resulting in endothelial cell injury lead to the occurrence of TA-TMA. Specifically, the abnormity of the complement system contributes to the development of TA-TMA. TA-TMA shares a similar clinical manifestation with thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS), which is characteristic with microangiopathic hemolytic anemia, platelet consumption, fibrin deposition in the microcirculation, and, ultimately, end-organ injury [1]. However, the diagnostic criteria of TA-TMA are far from accurate. Although several diagnostic criteria have been proposed, no criterion has been rigorously evaluated clinically because of a lack of pathologic diagnosis. Moreover, the pathogenesis of TA-TMA is still unclear. Conventional treatment management is less efficient [2]. Plasma infusions or therapeutic SC75741 exchange is considered to have limited efficacy, with relatively low response rates (20% to 50%) in comparison with idiopathic TTP (75%) generally reported [3]. Studies showed that activation of the complement system may be the key to TA-TMA 4, 5. Our previous investigations demonstrated that plasma levels of complement component C5b-9 and C3b were significantly increased in the patients with TA-TMA [6]. In addition, eculizumab, a synthetic anti-C5 monoclonal antibody, inhibits complement-mediated thrombotic microangiopathy in aHUS [7]. Jodele et al. [8] found that 61% of patients achieved complete resolution of TA-TMA with the complement blocker eculizumab. Future studies are important to understand TA-TMA further and may figure out the role of complement activation in TA-TMA, enhance diagnostic strategy, and determine therapeutic approaches and strategies [9]. It is still unclear, however, how the complements are activated. Heme oxygenase-1 (HO-1) is a stress-inducible cytosolic cytoprotective protein that degrades heme into carbon monoxide (CO), ferrous iron, and biliverdin [10]. In oxidative stress response, it protects endothelial cells from apoptosis 11, 12. HO-1 attenuates cellular injury by its antioxidative, antiapoptotic, and anti-inflammatory effects 13, 14. The dysfunction of HO-1 has been implied in a variety of pathologic conditions, including hypoxic lung disease [15], vascular injury [16], and cardiac transplant rejection [17], especially in acute myocardial infarction [18]. In addition, it also regulates the complement pathway by activating complement regulatory proteins [19]. HO-1 increases the level of the complement inhibitor decay-accelerating factor (DAF), a membrane-bound complement regulatory protein that inhibits the synthesis of complement 3 (C3) and C5 convertases. HO-1 may also exert potent cytoprotective and anti-inflammatory effects by minimizing the deposition of C3 and the membrane-attack complex 20, 21. N-acetylcysteine (NAC) has been suggested as a potential treatment for patients with TTP. Li et al. [22] reported a case of a TTP patient relieved with NAC, providing the first clinical evidence for the efficacy of NAC in treating TTP. Furthermore, Cai et al. [23] reported that NAC contributes to a significant increase in the expression of HO-1 mRNA in liver injured by carbon tetrachloride (CCl4). In our study we explored whether TA-TMA patients might benefit from NAC via targeting HO-1. We hypothesized a strong correlation between lack of HO-1 and TA-TMA. Therefore, HO-1, as a physiologic regulator of DAF, minimizes complement component C5b-9. HO-1 may play a protective role in the pathogenesis of TA-TMA.