Impact of human interleukin-10 on vector-induced inflammation and early graft function in rat lung transplantation.
This study was undertaken to examine the time course of human interleukin (hIL)-10 gene expression after transtracheal administration of adenoviral (Ad)hIL-10 and its effect on the early adenoviral proinflammatory cytokine response and on post-transplant lung function. Using a rat lung transplant model, we observed that lungs retrieved 12 h after the administration of AdhIL-10 were associated with significant improvement in post-transplant lung function. Shorter periods of transfection were associated with significantly elevated levels of tumor necrosis factor-alpha and macrophage inflammatory protein-2 in lung tissue, leading to an increased degree of injury. The release of proinflammatory cytokines secondary to the adenoviral vector was reduced by high-dose methylprednisolone (30 mg/kg) administered 3 h before transfection. Reduction in the early adenoviral inflammatory response was associated with significant improvement in post-transplant lung function when lungs were retrieved 6 or 12 h after transtracheal administration of AdhIL-10. Transtracheal administration of adenoviral-mediated hIL-10 to donor lungs is associated with a significant early inflammatory response that may enhance ischemia-reperfusion injury if insufficient hIL-10 is expressed in lung tissue before retrieval. The period between delivery of AdhIL-10 and lung retrieval can be reduced if the early inflammatory response is suppressed with methylprednisolone.
de Perrot
Marc
M
Thoracic Surgery Research Laboratory, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Ontario, Canada.
Fischer
Stefan
S
Liu
Mingyao
M
Imai
Yumiko
Y
Martins
Saulo
S
Sakiyama
Shoji
S
Tabata
Toshi
T
Bai
Xiao-Hui
XH
Waddell
Thomas K
TK
Davidson
Beverly L
BL
Keshavjee
Shaf
S
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; D015316:Genetic Therapy; D005822:Genetic Vectors; D005938:Glucocorticoids / Q000378:metabolism; D006085:Graft Survival; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D016040:Lung Transplantation; D008297:Male; D008775:Methylprednisolone / Q000378:metabolism; D015846:Monokines / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D054426:Chemokine CXCL2; D019743:Chemokines, CXC; C513296:Cxcl2 protein, rat; D005938:Glucocorticoids; D036341:Intercellular Signaling Peptides and Proteins; D015846:Monokines; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D010100:Oxygen; D008775:Methylprednisolone