Fat metabolism in the healing wound

The need for proper nutrition to facilitate wound healing is a well-established paradigm in medicine.72-79 However, an understanding of the molecular, biochemical, and cellular processes that occur during wound healing is complicated by the fact that there are multiple types of both acute and chronic wounds. Acute wounds (e.g., surgical, trauma, or burns) require a different treatment regimen than chronic wounds (e.g., venous, pressure, or diabetic ulcers). Moreover, individuals with chronic wounds often have underlying disease or complicating factors that present additional challenges to healing (e.g., diabetes, obesity, frail geriatric patients). Although we have a good level of understanding about the effects of wounds on whole body energy metabolism, this data cannot be directly extrapolated to metabolism in the wound. The reason for this is that the wound functions within its own metabolic microenvironment. Tissue blood flow (perfusion) and oxygen tension may be lower than non-wound tissue, and the recruitment of inflammatory cells into the wound can influence local metabolism.80 Application of some newer technologies (e.g., in vivo nuclear magnetic resonance spectroscopy81 and genomic/proteomic profiling of wound fluids) should provide insights into localized, in vivo metabolism, in the future. In the meantime, an analysis and synthesis of the literature on this topic is probably best approached by considering the general nutritional requirements for wound healing and the potential role of fats to modulate the healing response.

The healing process for most wounds requires an increase in caloric intake over basal levels. This is especially true in severely injured, burned, or critical patients in whom the stress response has placed them in a hypermetabolic state.82,83 Induction of the stress response via the hypothalamus is initiated by proinflammatory cytokines and results in increased levels of the stress hormones (e.g., glucagon, cortisol, and catecholamines). These hormones then result in a protein-catabolic state as well as increased lipolysis. To meet the increased caloric demand, the accepted approach is to provide a diet high in protein and fat, as these are also needed for the synthesis of new tissues. Research has shown that injured or stressed patients utilize protein for only about 20% of the energy requirement, with glucose and fatty acids being the major energy suppliers.8485 Therefore, both dietary fat and fatty acids released from adipose tissue are readily utilized during wound healing and are potential modulators of the healing response.

Wound healing may be divided into an inflammatory phase, a proliferative (fibroblastic) phase, and a remodeling (maturation) phase.8687 In acute wounds, the inflammatory phase begins with vasoconstriction followed by vasodilation.88 This response is mediated, in part, by lipid-derived mediators, such as thromboxane A2 (vasoconstrictor) and prostacylin (vasodilator), which are products of cyclooxygenase enzyme metabolism of arachidonic acid. The vasoconstriction stems blood loss and allows clotting to occur, and the vasodilation begins the process of fluid and cellular infiltration necessary to initiate the healing process. Inflammation can be a two-edged sword, and the healing process can be delayed by either excessive inflammation, such as might occur in a septic wound, or the inability to mount an adequate inflammatory response (e.g., immunosuppressed patients). Depending upon the nature of the wound, the inflammatory phase during normal healing lasts from several days to weeks. Inflammation persisting beyond this initial period is considered to be chronic89 and may be due to foreign material in the wound or sepsis. In the next stage of healing (proliferative or fibroblastic phase), there is reepithelialization (for cutaneous wounds), neovascularization, and production of connective tissue fibers by fibroblasts. This stage may last up to 1 month, but again, this may be shorter or longer depending upon the nature of the wound. During the remodeling phase, which can last up to 1 year, there is progressive deposition of and remodeling of extracellular matrix material. This includes the turnover of collagen types, with type III reticular fiber collagen predominating early in the healing process, which is then replaced by type I collagen.

During all phases of wound healing, lipids, or mediators derived or regulated by lipids, are likely to influence metabolism in the wound. During the inflammatory phase, eicosanoids derived from rn-3 and rn-6 fatty acids via cyclooxygenase and lipoxygenase enzymes systems as well as cytokines play a central role as mediators of inflammation (see section on essential fatty acids). The eicosanoids derived from m-6 PuFA are the more potent mediators of pain and inflammation, and those from m-3 PuFA are less proinflammatory. The two-series prostanoids and four-series leukotrienes are derived from arachidonic acid. The three-series prostanoids and five-series leukotrienes are derived from eicosapentaenoic acid. In humans, rn-3 fatty acids also lead to decreased production of proinflammatory cytokines by peripheral blood monocytes.6 Oxidative stress likely influences the wound healing and local metabolism throughout the healing process. The vasoconstriction/vasodilation that occurs at the time of wound creation can produce ischemia-reperfusion injury in the tissues due to the generation of reactive oxygen species (ROS) (e.g., superoxide, hydrogen peroxide, hydroxyl and peroxyl radicals). Likewise, neutrophils that infiltrate the wound during the early stages of inflammation and monocyte/macrophages that appear later in the healing process are an abundant source of ROS. So how do

ROS relate to fat metabolism in the wound? The longer-chain PuFAs are known to be more susceptible to oxidation than LC-SFA or MuFA. This susceptibility to oxidation has often led investigators to hypothesize that these fats, although essential and beneficial for many disease states, could lead to increased lipid peroxidation in tissues. An examination of the literature will find that some in vivo studies do associate dietary PuFA with increased oxidative stress.90 However, there are also many studies that indicate that dietary PuFA, especially the rn-3 fatty acids, actually decrease oxidative stress.91-94 Additional research is necessary to determine if PuFA content of cellular phospholipids and WAT at the time of wounding, or whether PuFAs supplied in the diet (oral, parenteral, enteral) are a significant factor, beneficial or otherwise, in wound oxidative stress. Because oxidative stress is known to be one of the factors capable of inducing apoptosis in cells,95-97 it could influence the course of wound healing. This fact becomes especially pertinent when one considers the nonenzymatically derived products of PuFA. The effects of cyclooxygenase and lipoxygenase metabolites have been well characterized, but in recent years a new class of prostanoids derived from long-chain PuFA, called isoprostanes, was iden-tified.98-100 The isoprostanes are nonenzymatically derived from PuFA and are produced via lipid peroxidation in much greater quantities in vivo than prostaglandins generated by cyclooxygenase. The isoprostanes are associated with oxidative damage to tissues, and an additional product of the isoprostane pathway is the formation of isoketals. Isoketals may be formed from fatty acids esterified to phospholipids in the cell membrane. After formation, the isoketals rapidly adduct to membrane proteins, and they can alter membrane function.101,102 Oxidative stress could therefore influence wound metabolism by fostering the production of lipid-derived mediators, which could in turn lead to apoptosis of cells in the wound. One in vitro study found that proliferating fibroblasts at a wound margin were more susceptible to oxidative stress and induction of apoptosis. The authors suggested that their findings could be applicable to wounds that fail to heal.103 Chronic wounds are often characterized by hypoxia, and evidence for oxidative stress has been found in chronic venous ulcers. Elevated levels of allantoin:uric acid percentage ratio, a marker of oxidative stress, were found in the wound fluid from chronic leg ulcers compared to both plasma and acute surgical wound fluid. The elevated percentage ratio was correlated with wound fluid neutrophil elastase.104

The previously mentioned endocrine function of WAT may also play a role in wound metabolism during the early stages of wound healing. Leptin production increases during inflammation.47 Interestingly, leptin activity has been detected in the fluids of experimental wounds in pigs during the first few days following injury,105 and it was suggested by the authors that this hormone may function in an autocrine and paracrine manner during wound healing. The significance and role of leptin derived from fat stores located in the vicinity of acute and chronic wounds will require more research. However, leptin has been shown to have antiapoptotic activities for a number of cell types, to inhibit the hypothalamic-pituitary axis stress response,106 and to promote the secretion of proinflammatory cytokines.107 All of these leptin functions have a role in modulating the healing process.

Another previously mentioned regulator of lipid metabolism, PPARs, may also function in wound healing. PPARa and PPARp are both activated in cutaneous wounding.108-110 PPARa is activated in the early inflammation phase of the healing,108 and PPARP functions to protect keratinocytes from apoptosis and also may regulate keratinocyte migration via potentiation of transcription factor NF-kB activity and matrix-metalloprotease-9 (MMP-9) production.111

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