Effect of complement fragment 1 esterase inhibition on survival of human decay-accelerating factor pig lungs perfused with human blood.
BACKGROUND
The role of complement in hyperacute lung xenograft rejection has not been fully elucidated. The present study evaluates the effect of complement (C) 1 esterase inhibition on hyperacute rejection of human decay-accelerating factor (hDAF)-positive pig lung by human blood.


METHODS
Using a modification of an established ex vivo model, right and left lungs from individual animals were surgically isolated and separately perfused. Pigs homozygous for hDAF were perfused with fresh human blood that was either untreated or treated with complement 1 esterase inhibitor (C1-Inh) at doses of 1 U/ml (n = 5), 5 U/ml (n = 3) or 10 U/ml plasma (n = 5).


RESULTS
Only C1-Inh at 10 U/ml prolonged survival time (230 +/- 48.3 minutes) as compared with controls (65.6 +/- 26.5 minutes, p < 0.05) and diminished complement activation (C3a and C5a, p < 0.05). Interestingly, a low concentration of C1-Inh increased the pulmonary vascular resistance (PVR; 1 U/ml: 0.54 +/- 0.3; 10 U/ml: 0.19 +/- 0.08). Sequestration of neutrophils (92 +/- 3%) and platelets (64 +/- 13%) was not prevented by any concentration of C1-Inh. Tissue deposition of C3b and C5b-9 were diminished by hDAF expression, and further blunted by treatment, with 10 U/ml C1-Inh.


CONCLUSIONS
Complement plays a critical role in early events of lung hyperacute rejection (HAR). However, even potent inhibition of C1 esterase and C3/C5 convertase, using serum C1-Inh in pig lungs homozygous for hDAF expression, does not prevent rapid lung injury. Our findings implicate innate immune pathways resistant to efficient complement regulation, and suggest a role for neutrophils and platelets in the lung's particular vulnerability.
Schröder
Carsten
C
Department of Cardiac and Thoracic Surgery, Vanderbilt University, 2986 Vanderbilt Clinic, Nashville, TN 37232-5734, USA.
Pfeiffer
Steffen
S
Wu
Guosheng
G
Zorn
George L
GL
Ding
Li
L
Allen
Catherine
C
Harrison
Richard A
RA
White
David J G
DJ
Azimzadeh
Agnes M
AM
Pierson
Richard N
RN
D000818:Animals; D030801:Animals, Genetically Modified; D018958:CD55 Antigens / Q000502:physiology*; D003174:Complement C1 Inactivator Proteins / Q000502:physiology*; D015926:Complement C3a / Q000378:metabolism; D015936:Complement C5a / Q000378:metabolism; D006084:Graft Rejection; D006085:Graft Survival / Q000502:physiology*; D006801:Humans; D008168:Lung / Q000276:immunology*; D023421:Models, Animal; D010477:Perfusion / Q000379:methods; D015539:Platelet Activation; D013552:Swine; D014183:Transplantation, Heterologous / Q000502:physiology
D018958:CD55 Antigens; D003174:Complement C1 Inactivator Proteins; D015926:Complement C3a; D015936:Complement C5a