Effect of complement fragment 1 esterase inhibition on survival of human Decay-Accelerating factor pig lungs perfused with human blood

Carsten Schröder, Steffen Pfeiffer, Guosheng Wu, George L. Zorn, Li Ding, Catherine Allen, Richard A. Harrison, David J.G. White, Agnes M. Azimzadeh, Richard N. Pierson

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1365-1375
Number of pages11
JournalJournal of Heart and Lung Transplantation
Volume22
Issue number12
DOIs
StatePublished - Dec 2003

Fingerprint

Complement C1 Inactivator Proteins
Complement C1s
CD55 Antigens
Swine
Lung
Neutrophils
Complement C3a
Blood Platelets
Complement C3-C5 Convertases
Complement C5a
Complement Membrane Attack Complex
Complement Activation
Lung Injury
Heterografts
Vascular Resistance

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

Cite this

Effect of complement fragment 1 esterase inhibition on survival of human Decay-Accelerating factor pig lungs perfused with human blood. / Schröder, Carsten; Pfeiffer, Steffen; Wu, Guosheng; Zorn, George L.; Ding, Li; Allen, Catherine; Harrison, Richard A.; White, David J.G.; Azimzadeh, Agnes M.; Pierson, Richard N.

In: Journal of Heart and Lung Transplantation, Vol. 22, No. 12, 12.2003, p. 1365-1375.

Research output: Contribution to journalArticle

Schröder, C, Pfeiffer, S, Wu, G, Zorn, GL, Ding, L, Allen, C, Harrison, RA, White, DJG, Azimzadeh, AM & Pierson, RN 2003, 'Effect of complement fragment 1 esterase inhibition on survival of human Decay-Accelerating factor pig lungs perfused with human blood', Journal of Heart and Lung Transplantation, vol. 22, no. 12, pp. 1365-1375. https://doi.org/10.1016/S1053-2498(03)00026-3
Schröder, Carsten ; Pfeiffer, Steffen ; Wu, Guosheng ; Zorn, George L. ; Ding, Li ; Allen, Catherine ; Harrison, Richard A. ; White, David J.G. ; Azimzadeh, Agnes M. ; Pierson, Richard N. / Effect of complement fragment 1 esterase inhibition on survival of human Decay-Accelerating factor pig lungs perfused with human blood. In: Journal of Heart and Lung Transplantation. 2003 ; Vol. 22, No. 12. pp. 1365-1375.
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abstract = "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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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.

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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