Dose-dependent improvements in outcome with adenoviral expression of interleukin-10 in a murine model of multisystem organ failure.
Targeted expression of interleukin-10 (IL-10) has been proposed as a means to suppress acute and chronic inflammation. We explored the capacity of targeted adenoviral expression of human or viral IL-10 to improve outcome in a zymosan-induced model of acute lung injury and multisystem organ failure. Intratracheal administration of adenovirus expressing either human or viral IL-10 prior to zymosan administration significantly improved survival at a dose of 10(7) particles (P<0.01), whereas the same recombinant vectors were ineffective at 10(8) particles and increased mortality at 10(9) particles. Improved survival after administration of 10(7) particles of adenovirus expressing viral or human IL-10 was associated with local tissue expression of IL-10 (100-300 pg/g wet wt). In contrast, mortality after administration of 10(9) particles was associated with markedly elevated IL-10 expression, both in the lung (10000-70000 pg/g wet wt) and systemically (1000-3000 pg/ml plasma), with evidence of an exaggerated systemic inflammatory response (plasma IL-6 and TNFalpha). Targeted gene expression of IL-10 can be used to treat acute inflammatory processes, but increased doses resulting in its systemic release are not associated with improvements in outcome, and may actually exacerbate acute inflammatory processes.
McAuliffe
P F
PF
Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA.
Murday
M E
ME
Efron
P A
PA
Scumpia
P O
PO
Ungaro
R
R
Abouhamze
Amer
A
Tannahill
C L
CL
Hutchins
B
B
LaFace
D
D
Moldawer
L L
LL
D000208:Acute Disease; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001424:Bacterial Infections / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D015870:Gene Expression; D018390:Gene Targeting; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods*; D016753:Interleukin-10 / Q000235:genetics* / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood; D008168:Lung / Q000276:immunology; D008171:Lung Diseases / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009102:Multiple Organ Failure / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D011135:Polysaccharides, Bacterial; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics; D015996:Survival Rate; D014161:Transduction, Genetic / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D015054:Zymosan
D015850:Interleukin-6; D011135:Polysaccharides, Bacterial; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015054:Zymosan