Inhibition of TNF-^|^alpha; by Cyclophosphamide Reduces Myocardial Injury After Ischemia-Reperfusion

Abstract

Purpose: The purpose of this study was to determine whether cyclophosphamide (CP) can decrease myocardial and systemic TNF-αexpression and thus protects myocardial I/R injury. Methods: Open chest rats were subjected to 30 min of ischemia followed by 3h, 12h or 24h of reperfusion. Rats were divided into sham group, I/R group and CP group, and each group included 3 timepoint subgroups (3h, 12h and 24h). Plasma TNF-αwas measured by cytometric bead array (CBA) and immunohistochemistry was used to detect TNF-α in myocardium. Results: Compared with I/R group, rats treated with CP showed a significant difference with decreased plasma TNF-α (13.31 ± 2.62 vs 14.13 ± 5.95 pg/mL at 3 h reperfusion, 10.1 ± 2.73 vs 12.54 ± 5.00 pg/mL at 12 h reperfusion, 10.38 ± 5.59 vs 13.00 ± 3.59 pg/mL at 24 h reperfusion, p <0.05 respectively). Immunostaining was less intense with CP injection at each reperfusion time. The score of the intensity of myocardial TNF-αstaining was down regulated. Conclusions: TNF-α is expressed in the myocardium and plasma after myocardial I/R injury. CP might be a feasible strategy for anti-TNF-α to protect myocardial I/R injury.Keywords: cyclophosphamide, TNF-α, ischemia/reperfusion appeared to be associated with a reduced risk of cardiovascular disease. 1) We recently also disclosed that cyclophosphamide (CP) could improve myocardial function in rats after ischemia reperfusion injury. These findings could help to gain some insight into therapeutic potential of CP in myocardial I/R injury.2) However, the mechanism remains unclear. As we have known TNF-αis released during myocardial I/R from storage sites in tissue mast cells within the myocardium 3) and possibly also from cardiomyocyte itself 4) and the plasma inflammatory cells.5) Presently, we used open-chest ischemia-reperfusion rat model with minimal surgical trauma to further demonstrate whether down-regulation with TNF-α-related inflammatory pathways by CP could reduce myocardial injury after I/R.

RETRACTED: Cleavage of cyclic AMP-responsive element-binding protein H aggravates myocardial hypoxia reperfusion injury in a hepatocyte–myocardial cell co-culture system

“…23,24 The relationship between myocardial I/R injury and the systemic inflammatory response was also shown by an elevation in plasma CRP and TNF-a levels after myocardial I/R injury. 5 Recent research suggests that CRP levels are not only an important indicator of the risk of myocardial infarction, but they also directly promote inflammation 25 related to myocardial I/R injury. This increases the myocardial infarct area and it can be mitigated with use of immunosuppressants, such as cyclophosphamide, methotrexate, and sulfasalazine.…”

“…4 In contrast, some cytotoxic anti-inflammatory drugs, such as cyclophosphamide, can reduce systemic and local myocardial inflammatory responses. 5 additionally, the endoplasmic reticulum stress (ERS)-mediated acute phase response (APR) can induce inflammatory responses and aggravate myocardial injury. 6 However, to the best of our knowledge, there is no evidence regarding whether myocardial local inflammation is involved in development of the APR.…”

Effect of Cyclophosphamide Treatment on Central and Effector Memory T Cells in Mice

“…[1][2][3][4][5][6] Cyclophosphamide (CP) is an alkylating agent and is usually administrated orally or intravenously and much less frequently intramuscularly or intraperitoneally. [7][8][9][10][11][12][13][14] CP is hydrolyzed in the liver by cytochrome enzymes P450 to the active form 4-hydroxyclophosphamide, which can diffuse out into circulation and affects the target cells. In the cytosol of cell, through spontaneous b-elimination, acrolein and phosphoramide mustard evolve.…”

Effects of alpha, beta momorcharin fruit extract with the combination of Cyclophosphamide in the treatment of glioma cancer In-vivo

“…The fruit juice of M. charantia has been found to increase glucose up take by several tissues in vitro and moreover, it can increase the storage of glycogen by the liver [8][9][10]. Cyclophosphamide (CP) is an alkylating agent and is usually administrated orally or intravenously and much less frequently intramuscularly or intraperitoneally [11][12][13][14]. CP is hydrolyzed in the liver by cytochrome enzymes P450 to the active form 4-hydroxyclophosphamide, which can diffuse out into circulation and affects the target cells [14][15][16][17][18].…”