Selective deficiency of HIF-1alpha in myeloid cells influences secondary intention wound healing in mouse skin.
BACKGROUND
Hypoxia-inducible factor-1 (HIF-1) influences myeloid cell function. In this study we examined the role of myeloid cell HIF-1alpha on wound healing in vivo using a cell-specific knockout (KO) mouse model.


METHODS
HIF-1alpha KO mice and wild-type (WT) controls received 8 mm full thickness dorsal dermal wounds. Wound dimensions were measured until full closure. Tissue was obtained from 3-day-old wounds for (immuno-)histochemical analysis. Production of interleukin-1beta (IL-1beta) and nitric oxide (NO) in response to lipopolysaccharide (LPS) and/or desferrioxamine (DFX) was examined in vitro.


RESULTS
Early wound closure occurred significantly faster in HIF-1alpha KO mice than in WT mice. Wounds of KO mice contained similar numbers of neutrophils and macrophages, but more activated keratinocytes, consistent with accelerated re-epithelialization. Interestingly, while LPS and LPS+DFX elicited a similar IL-1beta response in macrophages from the 2 mouse types, NO production was blunted in HIF-1alpha KO macrophages.


CONCLUSIONS
Absence of HIF-1alpha in myeloid cells accelerates the early phase of secondary intention wound healing in vivo. This may be associated with a deficient ability of myeloid cells to initiate an appropriate NO production response. Pharmacologic modulators of HIF-1alpha should be explored in situations with abnormal wound healing.
Owings
Richard A
RA
Department of Pathology, University of Arkanas for Medical Sciences, Little Rock, AR, USA.
Boerma
Marjan
M
Wang
Junru
J
Berbee
Maaike
M
Laderoute
Keith R
KR
Soderberg
Lee S F
LS
Vural
Emre
E
Jensen
Martin Hauer
MH
D000818:Animals; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D004338:Drug Combinations; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D012867:Skin / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
D004338:Drug Combinations; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D003676:Deferoxamine