Complement-mediated pulmonary xenograft injury: studies in swine-to-primate orthotopic single lung transplant models.
BACKGROUND
The pathogenesis of acute pulmonary xenograft injury has not yet been determined. The present study evaluates the role of complement in mediating pulmonary xenograft dysfunction by using cobra venom factor (CVF) to deplete recipient complement and transgenic swine, which express human regulators of complement activation (human decay-accelerating factor [hDAF] and hCD59).


METHODS
Fifteen orthotopic lung transplants were performed as follows: group I, swine-to-swine (n=5); group II, unmodified swine-to-baboon (n=3); group III, unmodified swine-to-(CVF treated) baboon (n=3); and group IV, hCD59/hDAF swine-to-baboon (n=4). Left pulmonary artery flow and pulmonary vascular resistance were measured at 30-min intervals. Serial lung biopsies were examined by light microscopy and immunofluorescence. The activation of complement was quantified by measurement of baboon plasma CH50 and C4 functional activity.


RESULTS
Group II xenotransplants ceased functioning within 30 min of reperfusion. Histopathologic ab normalities included erythrocyte/platelet aggregates and hemorrhagic pulmonary edema. Groups I and IV showed excellent function throughout. hDAF/hCD59 lungs (group IV) showed trace venular fibrin plugs and moderate loss of alveolar architecture. Pretreatment with CVF (group III) was ineffective in preventing xenograft injury.


CONCLUSIONS
These results characterize the fundamental features of discordant pulmonary xenotransplantation. Correction of the known defects in the regulation of heterologous complement activation was partially effective in preventing pulmonary xenograft dysfunction, suggesting that complement mediates, in part, some of the features of acute lung injury after discordant lung xenotransplantation.
Yeatman
M
M
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Daggett
C W
CW
Parker
W
W
Byrne
G W
GW
Logan
J S
JS
Platt
J L
JL
Davis
R D
RD
D000818:Animals; D030801:Animals, Genetically Modified; D015703:Antigens, CD / Q000096:biosynthesis / Q000502:physiology; D018958:CD55 Antigens / Q000235:genetics / Q000502:physiology; D018957:CD59 Antigens / Q000096:biosynthesis / Q000502:physiology; D003169:Complement Inactivator Proteins / Q000494:pharmacology*; D003165:Complement System Proteins / Q000187:drug effects / Q000502:physiology*; D004546:Elapid Venoms / Q000494:pharmacology*; D006085:Graft Survival; D006439:Hemodynamics; D006801:Humans; D016040:Lung Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D010215:Papio; D011652:Pulmonary Circulation; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D014184:Transplantation, Homologous / Q000276:immunology / Q000473:pathology / Q000502:physiology
D015703:Antigens, CD; D018958:CD55 Antigens; D018957:CD59 Antigens; D003169:Complement Inactivator Proteins; D004546:Elapid Venoms; C016310:cobra venom factor; D003165:Complement System Proteins