Heart and lung transplantation are the primary life-saving treatment option for patients diagnosed with either end-stage heart or lung diseases, respectively. The first successful heart transplantation was performed at Groote Schuur Hospital, Cape Town, South Africa in 1967 and first successful lung transplantation in Toronto General Hospital, Toronto, Canada in 1983. With advances in surgical techniques, intensive care, control of infection diseases, and the discovery of calcineurin inhibitors, heart and lung transplantations have become a plausible treatment for many end-stage heart and lung diseases. Due to the organ shortage, marginal donors are increasingly used. Primary graft dysfunction is the leading cause of death within the first 30 days after transplantation. Thereafter, chronic allograft dysfunction with infection and malignancy account for the majority of deaths. According to the International Society of Heart and Lung Transplantation, the average life expectancy is 11.9 years after heart transplantation and 7.3 years after lung transplantation.
Donor brain-death with the subsequent catecholamine and cytokine storm may induce hemodynamic and microvascular dysfunction in the donor organs. At the time of organ procurement, donated organs are disconnected from blood circulation and preserved in ice-cold solution before transplantation. Re-establishment of blood circulation is vital, but may paradoxically result in primary graft dysfunction. We hypothesize that these early events may initiate microvascular dysfunction and pro-inflammatory and pro-fibrotic processes and may lead to primary graft dysfunction, acute rejection, and chronic allograft dysfunction. Clinically, chronic allograft dysfunction usually manifests as cardiac fibrosis or cardiac allograft vasculopathy, or as obliterative bronchiolitis or restrictive allograft syndrome, and results in poor quality of life and untimely death.
Donor microvascular blood endothelial cells form the first line barrier between the recipient circulating inflammatory cells and the allograft. On top of regulating tissue perfusion, they are extremely important in immunological recognition and inflammatory cell recruitment, and contribute to transplant fibrosis by undergoing endothelial-mesenchymal cell transition. Their counterparts in the lymphatic system, lymphatic endothelial cells, are critical in immune surveillance and resolution of inflammation by regulating the drainage of extravasated fluid and inflammatory cells from the allograft. In microvascular dysfunction, junctional complex proteins dissociate thus rendering these junctions leaky.
Hypoxia-inducible factor is the master regulator of gene transcription during low oxygen tension and forms the molecular link between shortage of oxygen and cellular adaptation mechanisms in response to hypoxia. The transcriptional activity of HIF is enhanced by stabilization of the HIF1a proteins under hypoxic conditions. There is extensive interplay between hypoxia and inflammation, and the pro-inflammatory transcription factor NF-kB is a critical activator of HIF1a. We have used animal models with small molecule inhibitors, monoclonal antibodies, gene transfer, and cell-specific conditional knockout mice and found that HIF1a and several of its downstream growth factors such as VEGFA, VEGFB, VEGFC, PDGFs, ANG1, ANG2, and ET1 may have important clinical implications in the prevention of pro-inflammatory and pro-fibrotic processes after heart transplantation.