Intramuscular gene transfer of interleukin-10 reduces neutrophil recruitment and ameliorates lung graft ischemia-reperfusion injury.
Interleukin-10 (IL-10) has potent anti-inflammatory properties but its direct effects on neutrophil trafficking in lung transplant ischemia-reperfusion (I/R) injury are unknown. This study was performed to determine if recipient intramuscular IL-10 gene transfer reduces neutrophil infiltration in lung isografts and ameliorates I/R injury. Twenty-four hours before transplantation, recipient rodents received intramuscular injection with 1 x 10(10) plaque-forming units (pfu) adenovirus encoding human IL-10 (hIL-10), 1 x 10(10) pfu adenovirus control encoding p-galactosidase, or saline. Gene expression in muscle and plasma was confirmed. Lung grafts were harvested, stored at 4 degrees C for 18h, and assessed 24 h after transplantation. Peak muscle and plasma expression of hIL-10 was achieved 24h after gene transfer and returned to baseline by 7 days (p < 0.05 vs. controls). Gene transfer of hIL-10 reduced neutrophil sequestration and emigration in lung grafts as measured by morphometry and myeloperoxidase activity (p < 0.03 vs. controls). Furthermore, hIL-10 improved graft oxygenation and reduced lung edema (p <0.01 vs. controls). Intramuscular gene transfer of hIL-10 releases hIL-10 protein into plasma and reduces neutrophil sequestration and emigration in lung isografts. This is associated with a reduction in I/R injury with improved isograft oxygenation and reduced tissue edema. Intramuscular gene transfer may be a useful strategy to reduce clinical l/R injury.
Kozower
Benjamin D
BD
Division of Cardiothoracic Surgery, Washington University School of Medicine, Barnes Jewish Hospital, St Louis, MO, USA.
Kanaan
Samer A
SA
Tagawa
Tsutomu
T
Suda
Takashi
T
Grapperhaus
Kathleen
K
Daddi
Niccolo
N
Crouch
Erika C
EC
Doerschuk
Claire M
CM
Patterson
G Alexander
GA
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D018014:Gene Transfer Techniques; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D009132:Muscles / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D015427:Reperfusion Injury / Q000628:therapy*
D016753:Interleukin-10; D009195:Peroxidase