Adenoviral gene transfer of an NF-kappaB super-repressor increases collagen deposition in rodent cutaneous wound healing.
BACKGROUND
The transcription factor nuclear factor-kappaB (NF-kappaB) plays an essential role in inflammation. To date, no studies have investigated the effect of inhibiting NF-kappaB-mediated inflammation on normal cutaneous wound healing. We tested this by locally administering an adenovirus recombinant that constitutively expresses a super-repressor isoform of inhibitory-kappaB (IkappaB) into rats undergoing a well-established model of dorsal wound healing.


METHODS
Seventy-two Sprague-Dawley rats underwent insertion of a sponge-pump construct into a dorsal subcutaneous pocket. One group of rats received pumps filled with the adenovirus expressing I-kappaB (rAd-Ikappab), a second group received pumps filled with adenovirus expressing green fluorescent protein (GFP) (rAd-gfp), and a third received pumps filled with normal saline (NS). Rats were killed in groups of 6 on days 1, 3, 5 and 7 postoperation. The wound fluid was analyzed for nitrite/nitrate (NOx) and tumor necrosis factor-alpha (TNF-alpha) concentrations. The wound fluid was assayed for hydroxyproline (OHP) content, an index of reparative collagen deposition.


RESULTS
Administration of rAd-Ikappab for 7 days resulted in higher collagen deposition (OHP) compared with the rAd-gfp and NS groups. NOx levels were significantly higher in the rAd-gfp group on day 1 and marginally so on day 5. TNF-alpha quantitation analysis found no significant difference among the 3 groups.


CONCLUSIONS
IkappaB expression through an adenoviral vector in the cutaneous wound may improve rodent healing, as shown by increased collagen deposition, through decreased inflammation. This mechanism appears to be TNF-alpha independent. Inhibition of NF-kappaB may reduce inflammation by reducing the local NOx concentrations.
Schreiber
Jeffrey
J
Department of Surgery, Sinai Hospital of Baltimore and the Johns Hopkins Medical Institutions, Baltimore, MD 21215, USA.
Efron
Philip A
PA
Park
Julie E
JE
Moldawer
Lyle L
LL
Barbul
Adrian
A
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003094:Collagen / Q000378:metabolism*; D003872:Dermatitis / Q000378:metabolism / Q000628:therapy*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics*; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014945:Wound Healing
D016328:NF-kappa B; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen