• 2018-07
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  • br Methods br Results br


    Discussion TA-TMA is a severe complication for patients after HSCT. The pathogenesis of TA-TMA is unclear. Complement activation and endothelial cell injury may be involved in the pathogenesis of TA-TMA. Our previous investigations had demonstrated that plasma levels of C5b-9 and C3b were significantly increased in patients with TA-TMA [6]. An early rise in the C5b-9 level indicates poor prognosis of TA-TMA [25]. In these patients, complement factor autoantibodies and gene variations or mutations were found to be associated with TA-TMA 1, 8, which is similar to the complement-mediated aHUS. A mutation or autoantibody leads to overactivation of the alternative pathway and predisposes to the development of aHUS [26]. Case reports 27, 28 and clinical trials [7] proved that complement inhibition was a promising therapy in aHUS, a disease caused by complement dysregulation. Accordingly, Jodele et al. [8] found that 61% of TA-TMA patients achieved complete resolution of TMA from the complement blocker eculizumab. Therefore, complement activation and endothelial cell injury may be related to the pathogenesis of TA-TMA. It is still unclear, however, how the complement system was activated. In our study we found that plasma levels of HO-1 were significantly decreased in patients with TA-TMA. HO-1 is normally expressed at low levels in most tissues but is highly inducible by a variety of stimuli. Therefore, HO-1 may be involved in the process of cytoprotection. This process was activated upon cellular stresses such as inflammation, ischemia, hypoxia, hyperoxia, hyperthermia, and radiation [29]. In fact, infection, radiation, and hypertension are potential mechanisms underlying endothelial damage in TA-TMA [30]. In addition, neutrophil extracellular traps may serve as a mechanistic link between endothelial injury and complement activation in TA-TMA [31]. It is suggested that elevated serum levels of HO-1 are predictive of adverse events after acute myocardial infarction in patients with coronary artery disease [18]. HO-1 plays a key role in maintaining antioxidant/oxidant INCB-024360 and the prevention of vascular injury [32]. TA-TMA is a disease with histologic evidence of microangiopathy and endothelial injury. Here we proposed that HO-1 deficiency is associated with the vascular injury. This notion was supported by reduced HO-1 mRNA levels in HUVECs treated with TA-TMA plasma (Figure4). A meta-analysis indicated that the HO-1(GT)n repeat-length polymorphism is associated with decreased risk of coronary heart disease or restenosis after percutaneous coronary intervention [33]. This polymorphism was located in the HO-1 promoter region [34]. The nucleotide partial sequence of the 5’-flanking region and exon of human HO-1 is shown in Figure5. Previous studies suggested a long (GT)n sequence in the HO-1 promoter leads to a lower antioxidative activity of this protein 35, 36. To date, several HO-1 single nucleotide polymorphisms have been identified: class S (<27 (GT)n repeats), class M (27 to 32 (GT)n repeats), and class L (>32 (GT)n repeats) [36]. Interestingly, in our study sequencing of the HO-1 promoter revealed the presence of class L (GT)n repeat length in 3 of 5 TA-TMA patients. Regarding the limited number of TA-TMA patients, it is still too early to conclude that the HO-1 (GT)n repeat-length polymorphism is associated with the pathogenesis of TA-TMA. On the other hand, HO-1 also works in regulating the complement pathway. HO-1 was identified as a regulator of DAF, and the protection by HO-1 in complement-dependent glomerular injury involves DAF upregulation [21]. In this light, TA-TMA may be a disease caused by aberrant complement activation. We showed that HO-1 mediates TA-TMA via regulating the DAF-dependent pathway. In addition, in the group of HUVECs incubated with plasma of TA-TMA patients, DAF expression was significantly decreased. Mason et al. [37] showed that DAF expression on endothelial cells is regulated by cytokines, suggesting that induction of DAF may be important for maintenance of vascular integrity during inflammation. In our investigation we found that HO-1–inhibited HUVECs are susceptible to complement-mediated injury via the DAF pathway. We further demonstrated that DAF expression was suppressed after HO-1 inhibition by ZnPP. However, ZnPP only moderately enhanced complement deposition on HUVECs. On the other hand, Kinderlerer et al. [20] showed that in addition to DAF induction, HO-1 may inactivate alternative pathways to enhancing protection against complement activation.