Hyperacute rejection of mouse lung by human blood: characterization of the model and the role of complement.
BACKGROUND
The pathophysiology of hyperacute lung rejection (HALR) is not fully understood. A mouse model of HALR by human blood would be valuable to efficiently dissect the molecular mechanisms underlying this complex process, but it has not been described.


METHODS
We developed a xenogenic mouse lung-perfusion model. Perfusion with heparinized autologous blood (n=3) was compared with human blood unmodified (n=7) or pretreated with C1 inhibitor (n=5) or soluble complement receptor type 1 (n=6) at unchanged flow conditions.


RESULTS
Perfusion with autologous blood was associated with stable physiologic parameters and no overt evidence of lung injury for up to 2 hr. Pulmonary artery perfusion pressure increased rapidly after introduction of unmodified human blood, plasma anti-Gal(alpha)1,3Gal antibodies declined (90% immunoglobulin [Ig]M, 80% IgG), and lungs reliably met survival endpoints within 11 min (median 10 min, confidence interval [CI]: 9-11). Human Ig and neutrophils were rapidly sequestered in the lung. Survival was significantly prolonged in the soluble complement receptor type 1 group (36 min, CI: 26-46) (P<0.01) and in the C1 inhibitor group (23 min, CI: 21-25) (P<0.05), and pulmonary vascular resistance elevation and complement activation were significantly attenuated but not prevented.


CONCLUSIONS
Hyperacute rejection of mouse lung by human blood occurs with kinetics, physiology, and histology closely analogous to the pig-to-human model. In addition, as in that model, neither of two potent soluble-phase complement inhibitors prevented complement activation or HALR. We conclude that the mouse lung model is relevant to dissect the cellular and molecular mechanisms governing HALR.
D000208:Acute Disease; D000818:Animals; D000910:Antibodies, Heterophile / Q000276:immunology; D001769:Blood / Q000276:immunology*; D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; D003165:Complement System Proteins / Q000276:immunology*; D004187:Disaccharides / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007150:Immunohistochemistry; D016040:Lung Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D011652:Pulmonary Circulation / Q000502:physiology; D011951:Receptors, Complement / Q000276:immunology; D015843:Serpins / Q000276:immunology; D014022:Tissue Survival / Q000276:immunology*; D014655:Vascular Resistance / Q000502:physiology
D000910:Antibodies, Heterophile; D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; D004187:Disaccharides; D011951:Receptors, Complement; C469952:SERPING1 protein, human; D015843:Serpins; C055075:galactosyl-(1-3)galactose; C082885:soluble complement inhibitor 1; D003165:Complement System Proteins