Overexpression of hypoxia-inducible factor (HIF)-1α in ischemia/reperfusion injury developed in a lung transplantation model

Ischemia/reperfusion (IR) injury is the major cause of early morbidity/mortality after transplantation. A better understanding of substrates of tissue damage is crucial for the identification of sensitive markers. Hypoxia-inducible factor (HIF)-1α is a transcription factor that mediates tissue response to hypoxia. To the best of our knowledge no data are available on HIF-1α expression in lung transplantation IR injury. The aim of the study was to correlate HIF-1α expression to the main histological parameters related to IR injury in an orthotopic lung transplantation (OLT) model. OLT was performed in 32 inbred rat strain (Lewis left lung rats transplanted into Fisher 344) and 11 of them died in the early post-operative period (from day 0 to 15) for IR injury. Morphological parameters indicative of IR injury and HIF-1α immunostaining were graded with a score 0-3. Apoptotic index was evaluated using TUNEL technique. Unimplanted donor rat lung samples were used as controls. Lung samples of animals with IR injury showed high scores of HIF-1α expression,edema,blood extravasation,granulocyte margination (all median scores: 3), apoptotic index (median: 20.5) and necrosis in 82% of cases. No HIF-1α expression was detected in 3 rats that died few hours after OLT, as well as in controls. Tissue overexpression of HIF-1α was detected in all lung samples with high scores of edema, blood extravasation, granulocyte margination and, overall, with high apoptotic index. Our data demonstrate that HIF-1α is overexpressed in more severe lung IR injury of our OLT model. The use of HIF-1α inhibitors could provide a translatable route into manipulating this complex system in vivo.