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Hypoxia increases reepithelialization via an αvβ6‐dependent pathway
Author(s) -
Ridgway Paul F.,
Ziprin Paul,
Peck David H.,
Darzi Ara W.
Publication year - 2005
Publication title -
wound repair and regeneration
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.847
H-Index - 109
eISSN - 1524-475X
pISSN - 1067-1927
DOI - 10.1111/j.1067-1927.2005.130206.x
Subject(s) - fibronectin , wound healing , gelatinase , hypoxia (environmental) , cell migration , integrin , matrix metalloproteinase , chemistry , flow cytometry , zymography , microbiology and biotechnology , extracellular matrix , andrology , immunology , biology , cell , medicine , biochemistry , organic chemistry , oxygen
Reepithelialization is an essential step in successful cutaneous wound healing. Human keratinocytes, integral in this process, have been shown to have increased motility in the hypoxic healing edge of wounds correlating with the clinical success of semiocclusive hypoxic dressings, although the underlying mechanisms remain poorly understood. Subconfluent human keratinocyte cell monolayers were exposed to 1% hypoxia for up to 24 hours or control conditions. Re‐oxygenation studies were performed up to 72 hours. Cellular αv subunit and αvβ6 integrin expression was measured by flow cytometry. Migration scratch assays on fibronectin following hypoxic exposure were performed over 24 hours. Relative matrix metallo‐proteinase (MMP)‐2, 9 activity was determined by gelatin zymography with TIMP‐1 levels assayed by enzyme‐linked immunoassay. Sustained increases in αv and αvβ6 expression were shown up to 48 hours in re‐oxygenation studies ( P < 0.001). Standardized scratch assays confirmed increased migration in the hypoxic group ( P < 0.05). This effect was attenuated by the addition of a specific inhibitor of the αvβ6 integrin. MMP‐2 and ‐9 activity was up‐regulated following hypoxic exposure ( P < 0.001; P < 0.05, respectively), whereas increased MMP expression was significantly retarded by addition of an αvβ6 inhibitor ( P < 0.05). Migration on fibronectin was attenuated by a specific gelatinase inhibitor. We conclude that integrin αvβ6‐dependent MMP‐2 and ‐9 up‐regulation is an important feature of increased migration in hypoxic human keratinocytes.