In vivo regulation of von Willebrand factor synthesis - von Willebrand factor production in endothelial cells after lung transplantation between normal pigs and von Willebrand factor-deficient pigs

To evaluate the regulation of plasma von Willebrand factor (vWF) and its in situ production by endothelial cells (ECs), 12 swine leukocyte antigen (SL A)-compatible left lung transplantations were performed. Normal lungs were transplanted into 10 pigs homozygous for von Willebrand disease and into 2 normal pigs, Additionally, 1 normal pig underwent pneumonectomy, and 1 SLA- incompatible lung transplantation between normal pigs was performed. None o f the transplanted animals received immunosuppressive therapy. Plasma vWF l evel was evaluated by ELISA and multimeric pattern. EC vWF content was asse ssed by immunohistochemistry. Global hemostasis was assessed by standardize d ear bleeding time. Six of 12 SLA-compatible lung transplantations and the incompatible transplantation were successful and were used for the study. The functions and the viability of ECs, reflected by their ability to produ ce VWF and normal multimeric plasma VWF pattern, were preserved in SLA-comp atible and -incompatible lung transplantations. vWF production was preserve d in ECs that initially synthesized it. EC constitutive and storage pathway s are modulated differently according to transplantation compatibility and severity of rejection. In SLA-compatible lung transplantations without hist ological evidence of rejection, the production of VWF was preserved, wherea s constitutive vWF secretion appeared to be altered in cases with minor his tological signs of rejection. In pigs with von Willebrand disease that were transplanted with normal lungs without sign of rejection, plasma VWF was s ignificantly increased in an amount expected from the estimated production of a normal lung. In the transplanted normal lung, there was no vWF overexp ression by the ECs and no recruitment of ECs that initially did not express VWF. In SLA-incompatible transplantation, ECs were morphologically normal with increased and blurred vWF labeling, whereas plasma VWF levels remained normal, reflecting that EC activation is associated with an increased vWF production with probable diversion to storage pathway. This model depicts t he changes of EC regulation of vWF secretion in pig lung transplants. Howev er, this model cannot be directly extrapolated to human organ transplantati on because animals did not receive any immunosuppressive therapy, which may be toxic to ECs.