Background and Aim: With increased numbers of diabetic transplant patients, both pre- and post-transplantation, our understanding of how hyperglycemia regulates immunity is imperative. We studied acute liver IRI in a murine type I diabetes model.
Methods: Streptozotocin-induced diabetic and control mice were used in liver partial warm IR experiments. Injuries and immune responses were evaluated at 0, 6, and 24 h of reperfusion. Bone marrow-derived macrophages (BMMs) and primary hepatocytes were cultured in low (5mM) glucose condition. Hyperglycemia was simulated by culturing these cells in high glucose media (30mM) for 24h prior to inflammatory stimulation.
Results: Type I diabetic mice suffered significantly more severe liver IRI at both 6 and 24h post reperfusion, as documented by higher sALT levels (Figure 1) and more hepatocellular necrosis.
Liver immune responses against IR were selectively enhanced in diabetic mice: intrahepatic TNFΑ, IL1Β, IL6 and IL12, but not IL10, gene inductions were elevated. In addition, the anti-inflammatory Akt signaling pathway was inhibited in diabetic mice. In vitro, hyperglycemia augmented BMM pro-inflammatory immune activation by TLR ligands: TNFΑ, I1Β and IL6, but not IL10, productions were significantly increased (ELISA). Interestingly, hyperglycemia did not affect hepatocyte cell death pathways: cytotoxicities induced by TNF-a or H2O2 were similar under high and low glucose conditions. Hyperglycemia activated Rho kinase, as both ROCK protein and MYPT1 phosphorylation levels were increased in BMMs under the high glucose condition. ROCK inhibitor H1152 partially abrogated the pro-inflammatory effect of hyperglycemia, as it reduced TNFa production only in high, but not low, glucose conditioned BMMs.
Conclusion: Hyperglycemia increases severity of IRI by augmenting pro-inflammatory immune response. The activation of Rho and inhibition of Akt may constitutes a key regulatory mechanism of hyperglycemia on tissue inflammation.
To cite this abstract in AMA style:Yue S, Rao J, Zhu J, Bussutil R, Kupiec-Weglinski J, Zhai Y. Hyperglycemia Augments Inflammatory Immune Responses in Liver Ischemia Reperfusion Injury (IRI) Via the RhoA/Akt Pathway [abstract]. Am J Transplant. 2013; 13 (suppl 5). http://atcmeetingabstracts.com/abstract/hyperglycemia-augments-inflammatory-immune-responses-in-liver-ischemia-reperfusion-injury-iri-via-the-rhoaakt-pathway/. Accessed November 19, 2017.
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