Future directions

Fats/lipids are an extremely diverse class of molecules that includes the fatty acids and all their metabolic derivatives, glycerophospholipids, glycolipids, neutral lipids, sphingolipids, and sterols. The recognition that this class of molecules functions not only as nutrients but also as signaling molecules has given rise to the new field of lipidomics, which seeks to profile this vast group. Many of the lipid derivatives are now known to be involved in regulating various stages of cell growth, and the implications extend far beyond wound healing and will likely have significant impact in cancer biology and autoimmune disease. There are several fields that will likely spur advances in wound healing in the next decade. An understanding of the healing process (inflammation, proliferation, and remodeling) in acute and chronic wounds will benefit from genomic, proteomic, and lipidomic profiling of wound tissue and wound fluids. This will undoubtedly lead to the identification of target molecules and pathways for pharmacological intervention to enhance healing, especially in chronic wounds. This profiling will also lead to a better understanding of how nutrients may be used as adjuvants to the healing process. In our laboratory, we have used gene expression profiling of fibroblasts grown in media containing varying ratios of œ-6 and œ-3 fatty acids, and we have found that PuFA are capable of altering gene expression for a number of growth factors, integrins, matrix metallo-proteases, and transcription factors (manuscript submitted and currently under review). Moreover, many of the genes affected by PuFA are responsive to different œ-6:œ-3 ratios. An example of one gene that displays an interesting expression pattern in response to different fatty acid ratios is Adamts1 (A disintegrin and metalloproteinase with thrombospondin motifs 1). Adamts1 is a matrix metallopro-tease that has antiangiogenic properties (e.g., blocks neovascular response induced by growth factors) and also has been shown to inhibit endothelial cell proliferation in vitro.152 In 3T3-Swiss fibroblasts incubated with an œ-3 as the primary fatty acid in the medium, the cells have a level of expression for this protein that is 60% of the level for the P-actin housekeeping gene. The level drops to 30% of P-actin expression at an œ-6:œ-3 ratio of 1:25, it increases back to 60% at an œ-6:œ-3 ratio of 1:10, and then drops back to 30% if the fatty acid source is primarily an œ-6 fatty acid. The process of collagen production and turnover is a necessary component of the healing process, and PuFA are capable of affecting in vitro collagen production by fibroblasts.153 There are situations when increasing the production of healthy collagen is desirable (e.g., healing torn ligaments or tendons) and other instances where collagen production needs to be minimized or controlled to prevent organ fibrosis.154 155 The fact that PuFA can alter the in vitro expression of production of extracellular matrix molecules offers the prospect that œ-6:œ-3 ratios could be used to enhance or suppress various biological processes necessary for healing, but more research is clearly necessary to determine if this is a viable approach.

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