Document Detail


Inhibition of the chemokine receptor CXCR2 prevents kidney graft function deterioration due to ischemia/reperfusion.
MedLine Citation:
PMID:  15840022     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Ischemia/reperfusion (I/R) injury after organ transplantation is a major cause of delayed graft function. Following I/R, locally produced CXC chemokines attract and activate granulocytes, which in turn promote graft damage. METHODS: We examined the involvement of granulocyte recruitment via the CXCR2 pathway in a rat model of 4 hours cold ischemia followed by kidney transplantation. Serum creatinine and intragraft granulocyte infiltration were monitored in the early phase posttransplant. A CXCR2 inhibitor, repertaxin, was given to recipients before transplantation (at -24 hours or -8 hours or -2 hours), immediately before reperfusion and 2 hours later. RESULTS: An increase of granulocyte chemoattractant CINC-1/interleukin-8 (IL-8) mRNA expression after I/R both in syngeneic and allogeneic transplantation was associated with a marked infiltration of granulocytes in renal tissue. In syngeneic transplantation, Lewis rats given 15 mg/kg repertaxin 24 hours before surgery had granulocyte graft infiltration and serum creatinine levels significantly reduced in respect to vehicle-treated animals. Intermediate effects were observed with 5 mg/kg, whereas the dose of 30 mg/kg had toxic effects. We found that reducing the pretreatment time to 8 hours before surgery was still effective. Prevention of granulocyte infiltration and serum creatinine increase was also obtained in allogeneic transplantation, when Brown Norway recipients of Lewis kidneys were given 15 mg/kg repertaxin starting 8 hours before surgery. CONCLUSION: Repertaxin treatment of the recipient animal was effective in preventing granulocyte infiltration and renal function impairment both in syngeneic and in allogeneic settings. The possibility to modulate I/R injury in this rat model opens new perspectives for preventing posttransplant delayed graft function in humans.
Authors:
Daniela Cugini; Nadia Azzollini; Elena Gagliardini; Paola Cassis; Riccardo Bertini; Francesco Colotta; Marina Noris; Giuseppe Remuzzi; Ariela Benigni
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Kidney international     Volume:  67     ISSN:  0085-2538     ISO Abbreviation:  Kidney Int.     Publication Date:  2005 May 
Date Detail:
Created Date:  2005-04-20     Completed Date:  2005-08-22     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0323470     Medline TA:  Kidney Int     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1753-61     Citation Subset:  IM    
Affiliation:
Transplant Research Center Chiara Cucchi de Alessandri e Gilberto Crespi Mario Negri Institute for Pharmacological Research, Villa Camozzi, Ranica, Bergamo, Italy.
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MeSH Terms
Descriptor/Qualifier:
Animals
Base Sequence
Chemokine CXCL1
Chemokines, CXC / genetics
Granulocytes / drug effects,  pathology,  physiology
Humans
Intercellular Signaling Peptides and Proteins / genetics
Interleukin-8 / genetics
Kidney / drug effects,  injuries*,  physiopathology*
Kidney Transplantation / adverse effects,  pathology,  physiology*
Kinetics
Male
RNA, Messenger / genetics,  metabolism
Rats
Rats, Inbred BN
Rats, Inbred Lew
Receptors, Interleukin-8B / antagonists & inhibitors*
Reperfusion Injury / drug therapy*,  genetics,  physiopathology*
Sulfonamides / administration & dosage,  pharmacology
Transplantation, Homologous
Transplantation, Isogeneic
Chemical
Reg. No./Substance:
0/2-(4-isobutylphenyl)propionylmethanesulfonamide; 0/Chemokine CXCL1; 0/Chemokines, CXC; 0/Cxcl1 protein, rat; 0/Intercellular Signaling Peptides and Proteins; 0/Interleukin-8; 0/RNA, Messenger; 0/Receptors, Interleukin-8B; 0/Sulfonamides

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