Document Detail


Life-supporting function of genetically modified swine lungs in baboons.
MedLine Citation:
PMID:  17467457     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: During ex vivo perfusion with human blood, homozygous galactosyl transferase knockout swine lungs exhibit prolonged survival (approximately 2 hours) relative to wild-type (<15 minutes) and swine lungs expressing human decay accelerating factor (<1 hour). In this study, the in vivo behavior of galactosyl transferase knockout lungs was evaluated. METHODS: Three galactosyl transferase knockout swine left lungs were transplanted into baboons in a life-supporting model. One baboon lung allograft and two swine lung xenografts transgenic for human membrane cofactor protein (CD46) served as controls. RESULTS: Whereas two membrane cofactor protein lungs exhibited high pulmonary vascular resistance (>500 mm Hg x min/L) and failed to support life within 21 minutes, two of three galactosyl transferase knockout lungs supported life, for 90 and 215 minutes, and displayed low peripheral vascular resistance (48 +/- 12 mm Hg x min/L at 60 minutes), similar to the allogeneic control. Complement activation (delta C3a < 250 ng/mL through 60 minutes) and C5b-9 deposition were minimal in both galactosyl transferase knockout and membrane cofactor protein lungs. Neutrophils, monocytes, and platelets were rapidly sequestered in galactosyl transferase knockout and human membrane cofactor protein lung recipients, unlike the allogeneic control (<20%); and thrombin formation (delta plasma fraction 1+2 > 0.5 nmol/L) was seen in the galactosyl transferase knockout recipients. Platelet activation (beta-thromboglobulin rise > 200) and appearance of capillary congestion and vessel thrombosis confirmed coagulation activation associated with galactosyl transferase knockout lung failure. CONCLUSIONS: Galactosyl transferase knockout swine lungs are significantly protected in vivo from the physiologic consequences (increased pulmonary vascular resistance, capillary leak) associated with hyperacute lung rejection. As during ex vivo perfusion, dysregulated coagulation-thrombin elaboration, platelet activation, and intravascular thrombosis-mediates galactosyl transferase knockout lung xenograft injury.
Authors:
Bao-Ngoc H Nguyen; Agnes M Azimzadeh; Tianshu Zhang; Guosheng Wu; Henk-Jan Schuurman; Henk-Jan Shuurman; David H Sachs; David Ayares; James S Allan; Richard N Pierson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2007-04-02
Journal Detail:
Title:  The Journal of thoracic and cardiovascular surgery     Volume:  133     ISSN:  1097-685X     ISO Abbreviation:  J. Thorac. Cardiovasc. Surg.     Publication Date:  2007 May 
Date Detail:
Created Date:  2007-04-30     Completed Date:  2007-05-24     Revised Date:  2008-09-03    
Medline Journal Info:
Nlm Unique ID:  0376343     Medline TA:  J Thorac Cardiovasc Surg     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1354-63     Citation Subset:  AIM; IM    
Affiliation:
University of Maryland and Baltimore Veterans Administration Medical Center, Baltimore, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD46 / metabolism
Blood Cell Count
Complement Activation
Complement C3a / analysis
Galactosyltransferases / genetics
Graft Survival*
Immunologic Factors
Lung / pathology
Lung Transplantation*
Organisms, Genetically Modified
Papio anubis
Peptide Fragments / blood
Platelet Activation
Prothrombin
Pulmonary Circulation
Swine
Transplantation, Heterologous*
Vascular Resistance
beta-Thromboglobulin / analysis*
Grant Support
ID/Acronym/Agency:
F32 HL079818/HL/NHLBI NIH HHS; R01 HL67110/HL/NHLBI NIH HHS; U01 AI 066335/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD46; 0/Immunologic Factors; 0/Peptide Fragments; 0/beta-Thromboglobulin; 0/prothrombin fragment 1.2; 80295-42-7/Complement C3a; 9001-26-7/Prothrombin; EC 2.4.1.-/Galactosyltransferases
Comments/Corrections
Erratum In:
J Thorac Cardiovasc Surg. 2008 Jan;135(1):28A
Note: Shuurman, Henk-Jan [corrected to Schuurman Henk-Jan]
J Thorac Cardiovasc Surg. 2008 Aug;136(2):542

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