Reversal of impaired wound repair in iNOS-deficient mice by topical adenoviral-mediated iNOS gene transfer.
Most evidence indicates that nitric oxide plays a role in normal wound repair; however, involvement of inducible nitric oxide synthase (iNOS) has not been established. Experiments were carried out to determine the requirement for iNOS in closing excisional wounds. Wound closure was delayed by 31% in iNOS knockout mice compared with wild-type animals. An identical delay in wound closure was observed in wild-type mice given a continuous infusion of the partially selective iNOS inhibitor N6-(iminoethyl)-L-lysine. Delayed wound healing in iNOS-deficient mice was completely reversed by a single application of an adenoviral vector containing human iNOS cDNA (AdiNOS) at the time of wounding. Reverse transcription PCR identified iNOS mRNA expression in wild-type mice peaking 4-6 d after wounding, and confirmed expression of human iNOS in the adenoviral vector containing human iNOS cDNA-treated animals. These results establish the key role of iNOS in wound closure, and suggest a gene therapy strategy to improve wound healing in iNOS-deficient states such as diabetes, and during steroid treatment.
Yamasaki
K
K
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Edington
H D
HD
McClosky
C
C
Tzeng
E
E
Lizonova
A
A
Kovesdi
I
I
Steed
D L
DL
Billiar
T R
TR
D016475:3T3 Cells; D000199:Actins / Q000235:genetics / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014945:Wound Healing
D000199:Actins; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D012333:RNA, Messenger; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D008239:Lysine