Xenogeneic Lung Transplantation Models

Abstract

Study of lung xenografts has proven useful to understand the remaining barriers to successful transplantation of other organ xenografts. In this chapter, the history and current status of lung xenotransplantation will be briefly reviewed and two different experimental models, the ex vivo porcine-to-human lung perfusion and the in vivo xenogeneic lung transplantation, will be presented. We will focus on the technical details of these lung xenograft models in sufficient detail, list the needed materials and mention analysis techniques to allow others to adopt them with minimal learning curve.

Thromboxane and histamine mediate PVR elevation during xenogeneic pig lung perfusion with human blood

“…Induction of anesthesia and surgical organ dissection were performed as previously described . Prior to flushing the lungs, 1‐benzylimidazole (1‐BIA, 5 mg/kg BW; Sigma‐Aldrich), and synthetic prostaglandin I 2 (0.06 mg/kg, Remodulin (treprostinil), United Therapeutics) were administered intravenously and allowed to circulate for several minutes.…”

“…The right and left lungs were separately perfused via the pulmonary artery using side‐by‐side circuits fashioned from silicon tubing and polyurethane connectors as previously described . Pulmonary artery flow was measured and recorded with a flowmeter (Transonic Systems Inc., Model TTFM 73‐0146).…”

Interleukin‐8 mediates neutrophil‐endothelial interactions in pig‐to‐human xenogeneic models

“…Anaesthesia protocol and the harvest of the lung xenograft were performed as previously described . In brief, prior to flushing the lungs, heparin (500 U/kg, MWI, Boise, ID, USA), 1‐benzylimidazole (BIA,5 mg/kg BW; a thromboxane synthase inhibitor; Sigma–Aldrich, St. Louis, MO, USA) and synthetic prostaglandin I 2 (Remodulin, 0.06 mg/kg, United Therapeutics, Silver Spring, MD, USA) were administered intravenously and allowed to circulate for several minutes.…”

“…In brief, prior to flushing the lungs, heparin (500 U/kg, MWI, Boise, ID, USA), 1‐benzylimidazole (BIA,5 mg/kg BW; a thromboxane synthase inhibitor; Sigma–Aldrich, St. Louis, MO, USA) and synthetic prostaglandin I 2 (Remodulin, 0.06 mg/kg, United Therapeutics, Silver Spring, MD, USA) were administered intravenously and allowed to circulate for several minutes. After procurement, the right and left lungs were surgically divided and perfused separately via the pulmonary artery using side‐by‐side circuits fashioned from silicon tubing and polyurethane connectors as previously described . GalTKO.hCD46 (n = 5) and GalTKO.hCD46.hCD55 (n = 5) transgenic pig lungs were perfused with heparinized (3 U/mL perfusate) fresh human blood in an ex vivo circuit as previously described .…”

“…2,21,23 Surgical aspects of the auto-(n = 1), allo-(n = 2) (non-xeno controls) and xeno-lung (n = 19) in vivo transplantation procedures in baboons have been reported in detail. 23 Xeno-lung in vivo transplantation utilized pig lungs that are genetically modified, either for 3-genes (GalTKO.hCD46.hTBM, n = 2; GalTKO.hCD46.hEPCR, n = 5) or for four added genes (including hCD55, hTBM, hTFPI, hEPCR, HO-1, hCD47, and hCD39 in various combinations n = 6, seen in Table 1), all on the GalTKO.hCD46 background. Methylprednisolone (Solumedrol, starting at 10 mg/kg and then tapered down to 0.5 mg/ kg; MWI, Boise, ID, USA), C1 esterase inhibitor (500 IU, CSL Behring, King of Prussia, PA, USA) and αGPIb (1 mg/kg BW, University of Leuven, Leuven, Belgium) were given to all in vivo lung recipients.…”