Hyperacute rejection of mouse lung by human blood: Characterization of the model and the role of complement

Carsten Schröder, Guosheng S. Wu, Edward Price, Joyce E. Johnson, Richard N. Pierson, Agnes M. Azimzadeh

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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-Galα1,3Gal 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.

Original languageEnglish (US)
Pages (from-to)755-760
Number of pages6
JournalTransplantation
Volume76
Issue number5
DOIs
StatePublished - Sep 15 2003

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Lung
Perfusion
Complement Receptors
Complement Activation
Complement Inactivating Agents
Confidence Intervals
Survival
Lung Injury
Vascular Resistance
Pulmonary Artery
Immunoglobulin M
Immunoglobulins
Histology
Neutrophils
Swine
Immunoglobulin G
Pressure
Antibodies

ASJC Scopus subject areas

  • Transplantation

Cite this

Schröder, C., Wu, G. S., Price, E., Johnson, J. E., Pierson, R. N., & Azimzadeh, A. M. (2003). Hyperacute rejection of mouse lung by human blood: Characterization of the model and the role of complement. Transplantation, 76(5), 755-760. https://doi.org/10.1097/01.TP.0000069836.91593.09

Hyperacute rejection of mouse lung by human blood : Characterization of the model and the role of complement. / Schröder, Carsten; Wu, Guosheng S.; Price, Edward; Johnson, Joyce E.; Pierson, Richard N.; Azimzadeh, Agnes M.

In: Transplantation, Vol. 76, No. 5, 15.09.2003, p. 755-760.

Research output: Contribution to journalArticle

Schröder, C, Wu, GS, Price, E, Johnson, JE, Pierson, RN & Azimzadeh, AM 2003, 'Hyperacute rejection of mouse lung by human blood: Characterization of the model and the role of complement', Transplantation, vol. 76, no. 5, pp. 755-760. https://doi.org/10.1097/01.TP.0000069836.91593.09
Schröder, Carsten ; Wu, Guosheng S. ; Price, Edward ; Johnson, Joyce E. ; Pierson, Richard N. ; Azimzadeh, Agnes M. / Hyperacute rejection of mouse lung by human blood : Characterization of the model and the role of complement. In: Transplantation. 2003 ; Vol. 76, No. 5. pp. 755-760.
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AU - Schröder, Carsten

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AU - Johnson, Joyce E.

AU - Pierson, Richard N.

AU - Azimzadeh, Agnes M.

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N2 - 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-Galα1,3Gal 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.

AB - 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-Galα1,3Gal 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.

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