Date: Tuesday, May 5, 2015
Session Time: 5:30pm-6:30pm
Presentation Time: 5:30pm-6:30pm
Location: Exhibit Hall E
Background and Aim: Heme oxygenase-1 (HO-1), an anti-oxidant enzyme, is essential in tissue resistance against innate immunity driven ischemia-reperfusion injury (IRI). Our group was the first to document that HO-1 overexpression is central to re-establish homeostasis in liver IRI. As the function of HO-1 in individual cell types remains to be elucidated, here we focused on the role of myeloid cell specific HO-1 in hepatoprotection. Methods and Results: We developed myeloid cell-specific HO-1 deficient (Mø-HO-1 KO) mice by breeding HO-1 floxed KO mice with myeloid-specific Cre transgenic mice under the control of the LysM promoter. Livers in Mø-HO-1 KO and WT controls (C57/BL6) were subjected to partial (70%) warm ischemia (90min). Sera and liver tissue samples were harvested and analyzed at 6h of reperfusion (n=6/gr). Conditional ablation of myeloid HO-1 expression exacerbated IR-hepatocellular damage, as compared with controls, and evidenced by circulating liver enzyme levels (sALT: 25521 ± 4468 vs. 10363 ± 4299 IU/L, p<0.05; sAST: 16378 ± 3239 vs. 10764 ± 3238 IU/L, p<0.05); and Suzuki's score of histological liver IRI (7.1 ± 1.9 vs. 4.0 ± 0.8, p<0.05). The numbers of neutrophils sequestered in the ischemic liver lobes were higher (118 ± 28/HPF vs. 48 ± 15/HPF, p<0.05), and MPO neutrophil activity was enhanced (5.1 ± 2.3 U/g vs. 2.8 ± 1.7 U/g, p<0.05) in the Mø-HO-1 KO group. Similarly, HO-1 deficiency increased the frequency of liver-infiltrating macrophages (47 ± 5/HPF vs. 32 ± 5/HPF, p<0.05). Western blotting analysis of IR-stressed hepatic tissue has revealed repressed expression levels for phospho-Akt, phospho-Stat3, Bcl-2 and Bcl-xL, with simultaneously increased TLR4, cleaved caspase-3 and caspase-8 proteins in the Mø-HO-1 KO group. By qRT-PCR analysis, we showed the mRNA levels coding for hepatic IRI proinflammatory signature, i.e., IL-6, IL-1β, IFNγ, TNFα, MCP-1, IP-10, MIP-2 and CXCL-1 were higher (p<0.05), while the mRNA levels of cytoprotective IL-10 and TGF-β were reciprocally diminished (p<0.05) in the Mø-HO-1 KO group. Conclusion: These results uncover a novel direct function for myeloid cell HO-1 in the regulation of innate immunity driven hepatocellular damage, and establish macrophage-specific HO-1 signaling as a critical cytoprotective mechanism in IR-stressed livers.
To cite this abstract in AMA style:Nakamura K, Zhang M, Ke B, Busuttil R, Araujo J, Kupiec-Weglinski J. Myeloid Cell-Specific Heme Oxygenase-1 Is Crucial for Hepatoprotection in Liver Ischemia-Reperfusion Injury [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/myeloid-cell-specific-heme-oxygenase-1-is-crucial-for-hepatoprotection-in-liver-ischemia-reperfusion-injury/. Accessed March 23, 2019.
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