Keywords – Liver injury; Ischemia-Reperfusion; immunology; Hypoxia; T cells
Background - Natural immunity especially T cell immunity is recognized as an important mechanism of liver ischemia-reperfusion injury (IRI). Compared with conventional T cells, regulatory T cells (regT) response much earlier and more quickly. In our previous studies, we have proved HIF-2α plays an important role in the T cell inflammatory response in renal IRI.
Methods – We performed the warm IRI experiment to the Lck-Cre+HIF-2αloxp/loxp (HIF-2α TKO) mice, compared the ALT, AST levels and pathological changes with the control groups. FACS was used to show the difference on Natural kill T (NKT) cells and regT cells. Isolated T cells were stimulated by HA overnight with or without A2A adenosine receptor (A2AR) inhibitor ZM241385, proteins relating Ras-MAP kinase pathway were detected by Westernblot. A2AR agonist CGS21680 pretreated and HIF-2α overexpressed mice were used to confirm results in vivo.
Results - We found that HIF-2α TKO can exacerbate the hepatic IRI. Knockout and contral groups differed in the number of regT cells. Control groups pretreated with the A2AR agonist CGS21680 showed significant reduced injury; however, CGS21680 pretreatment failed to reduce IRI of mice in HIF-2α TKO groups. Ras-MAP kinase pathway can be activated by HA stimulation but were inhibited by the A2AR inhibitor.
Conclusions – RegT cells have an important role on liver IRI; HIF-2α is an important factor for the protective effect of CGS on hepatic IRI. The protective effect is through A2AR / Ras-MAP kinase pathway.
