α-Lipoic Acid Modulates Extracellular Matrix and Angiogenesis Gene Expression in Non-Healing Wounds Treated with Hyperbaric Oxygen Therapy

Wound healing is a complex process that proceeds through a number of welldefined and orchestrated stages: inflammation, proliferation, matrix deposition, and remodeling (1,2). Enzymatic remodeling of the extracellular matrix (ECM) is considered essential for proper wound healing (3). Various types of proteinases are implicated in ECM degradation, with the major enzymes represented by matrix metalloproteinases (MMPs). MMPs are members of the Zn-dependent endopeptidase family (4), with very low steady-state activity, and their expression is transcriptionally controlled by inflammatory cytokines, growth factors, hormones, and cell-cell and cellmatrix interactions (5). Self-resolving inflammation is a normal and necessary prerequisite to fibroblast activation and net matrix synthesis, and this process must be regulated tightly, both temporally and spatially. Imbalances in wound proteases and their inhibitors, because of sustained production of inflammatory mediators and influx of inflammatory cells, prevent matrix synthesis and remodeling, essential for progression to a healed wound (6,7). Chronic wounds arise from recurrent or chronic injuries (that is, intermittent ischemia) and/or low-level bacterial contamination. Once established, positive autocrine feedback loops and ongoing insult maintain the chronic wound state, preventing progression of the healing process. Hyperbaric oxygen (HBO) therapy has been used successfully for the treatment of non-healing wounds (8,9). The healing effect is due to the local increase in the oxygen gradient, resulting in enhanced angiogenesis, growth factor stimulation (10), and increased local resistance to infection (11). Recently, it has been observed that α-lipoic acid (LA) administration in association with HBO efficiently contributes to accelerated regression of chronic ulcers, acting both as an antioxidant and as a modulator of inflammation (12). Here, we evaluated the effect of LA on the expression of genes involved in ECM remodeling and angiogenesis in patients affected by chronic wounds treated with HBO. We show that LA supplementation in combination with HBO therapy down-