Neutrophil adhesion inhibition prolongs survival of cardiac allografts with hyperacute rejection.
Hyperacute rejection results in rapid destruction of a cardiac allograft and is characterized by infiltration of neutrophils into the donor organ. We sought to ameliorate this response by using a potent inhibitor of neutrophil adhesion to vascular endothelium, NPC 15669 (N-[9H-(2,7-dimethylfluorenyl-9-methoxy) carbonyl]-L-leucine) and determine its effect on long-term graft survival and histology. This compound specifically prevents recruitment of neutrophils at inflammatory foci by inhibiting upregulation of the CD11b/CD18 adhesion molecule located on the neutrophil surface. Lewis rats were presensitized by three serial ACI rat skin grafts placed 10 days apart. ACI rat hearts were heterotopically transplanted into Lewis recipients 10 to 14 days after the final skin graft. Group I (n = 15) was treated with a 10 mg/kg intravenous bolus of NPC 15669 before reperfusion, followed by 3 mg/kg over 30 minutes. Group II (n = 13) was given saline vehicle intravenously. Two allografts in each group were harvested at 5, 15, 30, and 60 minutes, and the remainder were followed to cessation of graft function. Early 5- to 60-minute allograft histologic findings revealed focal interstitial hemorrhage, edema, and contraction-band necrosis associated with neutrophil infiltration in group II. Group I had significant reduction of all parameters at the earliest time points. Graft survival was significantly increased in group I, 89.2 +/- 20.3 hours (mean +/- SD) compared to 27 +/- 17 hours in group II (p < 0.0001). End-stage rejection was characterized by extensive neutrophil infiltrate and hemorrhage in group II; group I grafts had a predominantly mononuclear cell infiltrate with rare neutrophils.(ABSTRACT TRUNCATED AT 250 WORDS)
Zehr
K J
KJ
Division of Cardiac Surgery, Johns Hopkins Medical Institutions, Baltimore, MD 21287-4618.
Herskowitz
A
A
Lee
P C
PC
Poston
R S
RS
Gillinov
A M
AM
Baumgartner
W A
WA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004489:Edema, Cardiac / Q000473:pathology; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D006470:Hemorrhage / Q000473:pathology; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009336:Necrosis; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000502:physiology; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D016038:Skin Transplantation / Q000276:immunology; D013997:Time Factors; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
D000894:Anti-Inflammatory Agents, Non-Steroidal; C071244:N-(9H-(2,7-dimethylfluoren-9-ylmethoxy)carbonyl)leucine; D007930:Leucine