Overexpression of Hypoxia-Inducible Factor-1α in Primary Graft Dysfunction Developing in an Orthotopic Lung Transplantation Rat Model

Background Primary graft dysfunction (PGD) is the major cause of early morbidity and mortality after transplantation. A high rate of PGD is a frequent complication in orthotopic lung transplantation (OLT) models, which are currently used to investigate acute and chronic rejection pathways. Hypoxia-inducible factor (HIF)-1α is a heterodimeric αβ transcription factor that mediates tissue response to hypoxia. In other solid organ transplantations, a significant correlation between HIF-1α expression and PGD was detected. To our knowledge no data are available on HIF-1α expression in PGD developing in lung transplantation. The aims of this study were to investigate HIF-1α expression (using immunohistochemistry) and correlate it to the main histological parameters related to ischemia-reperfusion (IR) injury, including terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) -positive apoptotic cells). Methods OLT was performed in 32 inbred rat strains and 11 of them died in the early postoperative period (from day 0–3) for IR injury. The histological and molecular evaluations were done in all lung tissues. Unimplanted donor rat lungs were used as controls. HIF-1α expression was correlated with all morphological parameters. Results Lung samples of animals with IR injury showed high scores of HIF-1α expression, edema, blood extravasation, granulocyte margination, apoptotic index, and necrosis in 91% of cases. Tissue overexpression of HIF-1α was detected in all lung samples with high scores of histological parameters and with high apoptotic indexes. Conclusion Our data demonstrate that HIF-1α was overexpressed in more severe rat lung IR injury. The use of HIF-1α inhibitors could provide a translatable route into manipulating this complex system in vivo.