Ischemic Preconditioning Affects Long-Term Cell Fate through DNA Damage–Related Molecular Signaling and Altered Proliferation

Abstract

Despite the potential of ischemic preconditioning for organ protection, long-term effects in terms of molecular processes and cell fates are ill defined. We determined consequences of hepatic ischemic preconditioning in rats, including cell transplantation assays. Ischemic preconditioning induced persistent alterations; for example, after 5 days liver histology was normal, but g-glutamyl transpeptidase expression was observed, with altered antioxidant enzyme content, lipid peroxidation, and oxidative DNA adducts. Nonetheless, ischemic preconditioning partially protected from toxic liver injury. Similarly, primary hepatocytes from donor livers preconditioned with ischemia exhibited undesirably altered antioxidant enzyme content and lipid peroxidation, but better withstood insults. However, donor hepatocytes from livers preconditioned with ischemia did not engraft better than hepatocytes from control livers. Moreover, proliferation of hepatocytes from donor livers preconditioned with ischemia decreased under liver repopulation conditions. Hepatocytes from donor livers preconditioned with ischemia showed oxidative DNA damage with expression of genes involved in MAPK signaling that impose G1/S and G2/M checkpoint restrictions, including p38 MAPKeregulated or ERK-1/ 2eregulated cell-cycle genes such as FOS, MAPK8, MYC, various cyclins, CDKN2A, CDKN2B, TP53, and RB1. Thus, although ischemic preconditioning allowed hepatocytes to better withstand secondary insults, accompanying DNA damage and molecular events simultaneously impaired their proliferation capacity over the long term. Mitigation of ischemic preconditioningeinduced DNA damage and deleterious molecular perturbations holds promise for advancing clinical applications. (Am J Pathol 2014, 184: 2779e2790; http://dx

Tumor Necrosis Factor Directs Allograft-Related Innate Responses and Its Neutralization Improves Hepatocyte Engraftment in Rats

“…38 The NF-kB signaling conjoins cell survival and apoptosis (eg, after ischemic preconditioning), although DNA damage in this setting may inhibit hepatic proliferation. 39 The prominence of Tnfa among persistently up-regulated cytokines, chemokines, and receptor genes following allografts with mycophenolate mofetil and tacrolimus treatment points to macrophages (KCs) and granulocytes (PMNs) as effector types, although this role in the latter is generally less recognized. The PMNs and KCs efficiently express TNF-a and chemokines and receptors, 6,15 including Ccl11, Ccl25, Cxcl2, Cxcl4, Cx3cl1 (ligands for Cccr3, Ccr9, Cxcr2, Cxcr4, and Cx3cr1, respectively), and Ccr1, which binds Ccl3, Ccl-4, and Ccl-5, as well as the IL-8 receptor agonist (or Cxcr1) with ligands of Cxcl1 and Cxcl2 sharing 90% sequence identity and Cxcl8 (also known asIL-8).…”

Replicative stress and alterations in cell cycle checkpoint controls following acetaminophen hepatotoxicity restrict liver regeneration

“…28 Previously, activation of p38 MAPK and other cell cycle regulators after oxidative hepatic DNA damage with ischaemia-reperfusion constituted a protective response, but at the cost of impaired LR capacity. 42 With overwhelming cell injury, ATM itself may undergo oxidative damage. 43 This may explain lower ATM protein levels in human ALF and should be significant since loss of ATM activity impaired DDR and restricted cycling.…”

Gene microarray analysis of expression profiles in liver ischemia and reperfusion

“…Firstly, for the lack of preconditioning data, we can't continue to mine biological function under the circumstance of precondition or other more relations. Kapoor et al ( 29 ) proposed that liver ischemic preconditioning activated MAPK signaling pathway, permitting hepatocytes to sustain secondary damage. Oyaizu et al ( 30 ) suggested that in rat pulmonary ischemia-reperfusion models, Src PTK activation was the major reason for reperfusion-induced lung injury but not gene expression alteration.…”