Hyperacute lung rejection in the pig-to-human model. III. Platelet receptor inhibitors synergistically modulate complement activation and lung injury.
BACKGROUND
The influence of platelet von Willebrand factor (vWF)-glycoprotein (GP)Ib-V-IX and GPIIb-IIIa receptor interactions in the context of hyperacute rejection (HAR) of pulmonary xenografts has not previously been explored.


METHODS
Aurintricarboxylic acid (ATA, an inhibitor of platelet-GPIb interactions with vWF), SC52012A (SC, a synthetic GPIIb/IIIa inhibiting peptide), or both were added to heparinized whole human blood before perfusion of isolated piglet lungs. Results were compared with unmodified blood ("unmodified").


RESULTS
Perfusion of porcine lungs with unmodified human blood resulted in an immediate rise in pulmonary vascular resistance (PVR), fluid and platelet sequestration in the lung, and, without exception, cessation of function within 15 minutes with a mean survival of 8 minutes. Addition of ATA or SC before lung perfusion significantly decreased the rise in PVR, diminished histamine release, and prolonged survival to 31+/-11 and 31+/-22 minutes, respectively. When the therapies were combined, mean survival was 156+/-77 minutes (P<0.05 vs. either monotherapy). Complement activation was synergistically attenuated only when the drugs were used together.


CONCLUSIONS
Platelet protein receptor adhesive interactions play an important role in amplification of complement activation during hyperacute lung rejection. Inhibiting recruitment of platelets at the site of initial immunologic injury to endothelial cells may protect porcine organs against thrombosis and inflammation during the initial exposure to human blood.
Pfeiffer
Steffen
S
Zentrum für Herzchirurgie Erlangen-Nürnberg, Klinikum Nürnberg Süd, 90471 Nuremberg, Germany.
Zorn
George L
GL
Zhang
Jian-Ping
JP
Giorgio
Todd D
TD
Robson
Simon C
SC
Azimzadeh
Agnes M
AM
Pierson
Richard N
RN
D000208:Acute Disease; D000818:Animals; D001312:Aurintricarboxylic Acid / Q000494:pharmacology*; D001790:Blood Physiological Phenomena; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D003167:Complement Activation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D004357:Drug Synergism; D006084:Graft Rejection / Q000378:metabolism*; D006085:Graft Survival; D006400:Hematocrit; D006632:Histamine / Q000097:blood; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016040:Lung Transplantation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins; D013552:Swine; D013917:Thrombin / Q000096:biosynthesis; D013929:Thromboxane B2 / Q000378:metabolism; D014183:Transplantation, Heterologous
C095308:5-(4-amidinophenyl)pentanoyl-aspartyl-phenylalanine; D004151:Dipeptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; C032193:glycoprotein receptor GPIb-IX; D001312:Aurintricarboxylic Acid; D013929:Thromboxane B2; D006632:Histamine; D013917:Thrombin