title: Inhibition of the chemokine receptor CXCR2 prevents kidney graft function deterioration due to ischemia/reperfusion.
abstract: 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.
  
  
  CONCLUSIONS
  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.affiliation: Transplant Research Center Chiara Cucchi de Alessandri e Gilberto Crespi Mario Negri Institute for Pharmacological Research, Villa Camozzi, Ranica, Bergamo, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cugini
authors.forename: Nadia
authors.initials: N
authors.lastname: Azzollini
authors.forename: Elena
authors.initials: E
authors.lastname: Gagliardini
authors.forename: Paola
authors.initials: P
authors.lastname: Cassis
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bertini
authors.forename: Francesco
authors.initials: F
authors.lastname: Colotta
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.forename: Ariela
authors.initials: A
authors.lastname: Benigni
mesh_terms: D000818:Animals; D001483:Base Sequence; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000235:genetics; D006098:Granulocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D007668:Kidney / Q000187:drug effects / Q000293:injuries* / Q000503:physiopathology*; D016030:Kidney Transplantation / Q000009:adverse effects / Q000473:pathology / Q000502:physiology*; D007700:Kinetics; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
chemical_list: D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C513297:Cxcl1 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D012333:RNA, Messenger; D023063:Receptors, Interleukin-8B; D013449:Sulfonamides; C490707:reparixin