Promotion of airway anastomotic microvascular regeneration and alleviation of airway ischemia by deferoxamine nanoparticles.
Xinguo Jiang, Andrey V Malkovskiy, Wen Tian, Yon K Sung, Wenchao Sun, Joe L Hsu, Sathish Manickam, Dhananjay Wagh, Lydia-Marie Joubert, Gregg L Semenza, Jayakumar Rajadas, Mark R Nicolls
Author Information
Xinguo Jiang: Division of Pulmonary/Critical Care, Department of Medicine, VA Palo Alto Health Care System/Stanford University School of Medicine, Stanford, CA, USA.
Andrey V Malkovskiy: Stanford BioADD Laboratory, Stanford, CA, USA.
Wen Tian: Division of Pulmonary/Critical Care, Department of Medicine, VA Palo Alto Health Care System/Stanford University School of Medicine, Stanford, CA, USA.
Yon K Sung: Division of Pulmonary/Critical Care, Department of Medicine, VA Palo Alto Health Care System/Stanford University School of Medicine, Stanford, CA, USA.
Wenchao Sun: Stanford BioADD Laboratory, Stanford, CA, USA.
Joe L Hsu: Division of Pulmonary/Critical Care, Department of Medicine, VA Palo Alto Health Care System/Stanford University School of Medicine, Stanford, CA, USA.
Sathish Manickam: Stanford BioADD Laboratory, Stanford, CA, USA.
Dhananjay Wagh: Stanford BioADD Laboratory, Stanford, CA, USA.
Lydia-Marie Joubert: Stanford Cell Sciences Imaging Facility, Stanford, CA, USA.
Gregg L Semenza: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Jayakumar Rajadas: Stanford BioADD Laboratory, Stanford, CA, USA.
Mark R Nicolls: Division of Pulmonary/Critical Care, Department of Medicine, VA Palo Alto Health Care System/Stanford University School of Medicine, Stanford, CA, USA.
Airway tissue ischemia and hypoxia in human lung transplantation is a consequence of the sacrifice of the bronchial circulation during the surgical procedure and is a major risk factor for the development of airway anastomotic complications. Augmented expression of hypoxia-inducible factor (HIF)-1α promotes microvascular repair and alleviates allograft ischemia and hypoxia. Deferoxamine mesylate (DFO) is an FDA-approved iron chelator which has been shown to upregulate cellular HIF-1α. Here, we developed a nanoparticle formulation of DFO that can be topically applied to airway transplants at the time of surgery. In a mouse orthotopic tracheal transplant (OTT) model, the DFO nanoparticle was highly effective in enhancing airway microvascular perfusion following transplantation through the production of the angiogenic factors, placental growth factor (PLGF) and stromal cell-derived factor (SDF)-1. The endothelial cells in DFO treated airways displayed higher levels of p-eNOS and Ki67, less apoptosis, and decreased production of perivascular reactive oxygen species (ROS) compared to vehicle-treated airways. In summary, a DFO formulation topically-applied at the time of surgery successfully augmented airway anastomotic microvascular regeneration and the repair of alloimmune-injured microvasculature. This approach may be an effective topical transplant-conditioning therapy for preventing airway complications following clinical lung transplantation.
