TY - JOUR
T1 - Effect of complement fragment 1 esterase inhibition on survival of human Decay-Accelerating factor pig lungs perfused with human blood
AU - Schröder, Carsten
AU - Pfeiffer, Steffen
AU - Wu, Guosheng
AU - Zorn, George L.
AU - Ding, Li
AU - Allen, Catherine
AU - Harrison, Richard A.
AU - White, David J.G.
AU - Azimzadeh, Agnes M.
AU - Pierson, Richard N.
N1 - Funding Information:
All experiments were conducted under protocols approved by the Vanderbilt Animal Care and Use Committee and in accordance with the guidelines from National Institutes of Health Publication No. 86-23, Guide for Care and Use of Laboratory Animals.
PY - 2003/12
Y1 - 2003/12
N2 - 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.
AB - 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.
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U2 - 10.1016/S1053-2498(03)00026-3
DO - 10.1016/S1053-2498(03)00026-3
M3 - Article
C2 - 14672751
AN - SCOPUS:10744231051
SN - 1053-2498
VL - 22
SP - 1365
EP - 1375
JO - Journal of Heart and Lung Transplantation
JF - Journal of Heart and Lung Transplantation
IS - 12
ER -