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  • br The role of TNFs and


    The role of TNFs and AD The TNF superfamily includes 19 members that can bind 29 different receptors [56, 57]; the 19 members are Lta, TNF-α, lymphotoxin-β (LTβ), OX40L, TNF associated activation protein (TRAP, also named CD40L or gp39), factor associated suicide ligand (FasL), CD70, CD153, 4-1BB-L, TNF related apoptosis inducing ligand (TRAIL), receptor activator of nuclear factor-κ B Ligand (RANKL), tumor necrosis factor like weak apoptosis induction factor (TWEAK), TWE-PRIL, APRIL, B cell-activating factor of the TNF family (BAFF), LIGHT, TLIA, and GITRL [57]. All members play a role in inflammation via activation of the nuclear factor-kappa B (NF-κB) pathway, and some of them also regulate morphogenesis and proliferation [56]. There have been numerous studies on TNF-α and AD, while articles describing other members and AD were not found. In an earlier study, Wen D et al. reported that plasma TNF-α levels were observed in human AD patients [58]. Circulating TNF-α levels were also reported to be elevated in a dog AD model that was mediated by aortic surgery [37]. In another study, Cheuk BL et al. detected dynamic changes in plasma TNF-α levels of AD patients, and the results showed that the levels were significantly higher after AD and decreased after 4 h but were still higher than the control group [17]. Xu CE et al. reported that high-dose ulinastatin shortened the time of intubation and length of time in the intensive care unit for AD patients; these effects may be caused by a reduction in plasma TNF-α levels [59]. Glucocorticoids were also reported to reduce the occurrence of AD, inhibiting the section of TNF-α [60]. The TNF-α levels were also shown to change dependent on the time of occurrence and presence of type A AD [[61], [62], [63]]. Du XM et al. reported that the CC mutant genotype was closely related to TNF-α Lisinopril dihydrate in TAD patients and may be an independent predictive factor for TAD in the Chinese Han population [64]. Marfan syndrome is an important cause of AD, and TNF-α expression was unexpectedly raised in the aortic tissue of Marfan syndrome patients [65, 66]. In addition to other groups, we also found that circulating TNF-α was elevated in acute AD patients [[67], [68], [69]] and that no difference was observed between Stanford A and Stanford B groups [30]. In a recent study, the authors demonstrated that TNF may affect the apoptosis of SMCs and be involved in the progression of AD [70].
    The role of CSFs and AD Broadly speaking, all of the cytokines that stimulate hematopoiesis can be collectively called colony stimulating factors (CSFs) [71]. The CSFs contained six subgroups consisting of multi-colony stimulating factor (multi-CSF), Granulocyte-colony stimulating factor (G-CSF), Macrophage-colony stimulating factor (M-CSF), Granulocyte and Macrophage-colony stimulating factor (GM-CSF), Stem cell factor (SCF) and Erythropoietin (EPO). Among them, multi-CSF and GM-CSF were shown to be involved in AD. Multi-CSF is also named IL-3, and we have described its relationship to AD in a previous section. Weissen-Plenz G et al. found that a dramatic loss of structural integrity and excessive matrix deterioration were associated with massively increased levels of granulocyte GM-CSF in a 46-year-old patient suffering from AD [72]. In addition, Son BK et al. reported that GM-CSF was important for the occurrence of AD and that the transcription factor Krüppel-like factor 6 protected against the onset of AD via down-regulation of the expression of GM-CSF in a mouse model [73]. In a follow-up study, Ijaz T et al. found that the above effect was closely related to the excessive activation of Janus kinase (JAK)-signal transducers and activation of the transcription 3 (STAT3) signaling pathway [74]. Although changes in EPO levels and the effects of EPO on AD have not been reported, EPO has had a 25-year history of being used to treat clinical red blood cell deficiency and anemia in AD patients, from 1993 until now [[75], [76], [77], [78], [79]].