Attenuation of Flightless I, an actin-remodelling protein, improves burn injury repair via modulation of transforming growth factor (TGF)-beta1 and TGF-beta3.
BACKGROUND
The pathophysiological mechanisms involved in burn injury repair are still not fully understood but include processes involving cellular proliferation, migration and adhesion. The actin cytoskeleton is intricately involved in these key wound repair processes. Flightless I (Flii), an actin-remodelling protein and transcriptional regulator, is an important regulator of wound healing.


OBJECTIVE
To investigate the function of Flii gene expression in burn injury repair.


METHODS
Partial-thickness scald wounds were created on Flii heterozygous (Flii(+/-)), wild-type (WT) and Flii transgenic (Flii(Tg/+)) mice. Burns were assessed using histology and immunohistochemistry, real-time quantitative polymerase chain reaction and biochemical analysis.


RESULTS
Flii expression, while upregulated in burn injuries, was significantly lower in the wounds of Flii(+/-) vs. WT vs. Flii(Tg/+) mice and healing was improved in Flii(+/-) mice with their burns healing faster than WT and Flii(Tg/+). Pro-scarring transforming growth factor (TGF)-beta1 protein and gene expression were reduced in Flii(+/-) burns while antiscarring TGF-beta3 was significantly elevated. Anti-alpha-smooth muscle actin (alpha-SMA) was decreased in Flii(+/-) burns suggesting a decrease in contractile myofibroblasts in the developing scars. Although Flii is primarily a nuclear and cytoplasmic protein it is also released by wounded cells. Intradermal injection of Flii-neutralizing antibodies (FliAbs) to WT burn wounds significantly improved their healing, indicating a potential novel approach for treating burns. Decreased TGF-beta1 and elevated TGF-beta3 expression were observed in FliAb-treated burns, which may contribute to their observed improvement in healing.


CONCLUSIONS
Strategies aimed at reducing Flii expression, for example using neutralizing antibodies, may lead to improved burn outcomes.
Adams
D H
DH
Women's and Children's Health Research Institute, 72 King William Road, North Adelaide, SA, Australia.
Ruzehaji
N
N
Strudwick
X L
XL
Greenwood
J E
JE
Campbell
H D
HD
Arkell
R
R
Cowin
A J
AJ
D000818:Animals; D002056:Burns / Q000503:physiopathology*; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008840:Microfilament Proteins; D021381:Protein Transport / Q000502:physiology; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D053782:Transforming Growth Factor beta3 / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology*
D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C000609263:FlII protein, mouse; D008840:Microfilament Proteins; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3