Sandra L. Kavalukas

Nutrition and wound healing: an update.

Summary: Nutrition has always been noted to be one of the major influences on the successful outcome of wound healing. The exuberant cellular and biochemical events that constitute the wound-healing cascade require energy, amino acids, oxygen, metals, trace minerals, and vitamins for successful completion. Many nutritional deficiencies impact on wound healing by impeding fibroblast proliferation, collagen synthesis, and epithelialization. There are also nutrients that can enhance wound-healing responses. It is imperative for physicians to obtain a complete nutritional history and consider nutritional intervention as a means of affecting the course of healing. This review examines many of the advances that have occurred in understanding nutrition/wound interactions.

Role of High Mobility Group Box 1 (HMGB1) in Wound Healing

BACKGROUND HMGB1, a non-histone chromosomal protein, can bind to the receptor for advanced glycation end products (RAGE) and act as an inflammatory mediator. We examined the role of HMGB1 in incisional wound healing and its possible mechanism of action through receptor for advanced glycation end products (RAGE). METHODS Male Sprague-Dawley rats undergoing full-thickness incisional wounding with subcutaneous implantation of PVA sponges were given daily injections of ethyl pyruvate (EP) (40 mg/kg, i.p.), a potent inhibitor of HMGB1 release. At 7 d post-wounding, wound breaking strength, sponge collagen content, and wound fluid HMGB1 levels were assessed. In vitro rat dermal or wound-derived fibroblasts were cultured with recombinant HMGB1 or advanced glycation end product (AGE). Some cultures were co-treated with a RAGE-blocking antibody. Fibroblast proliferation and collagen synthesis were assayed. RESULTS In vivo treatment with EP significantly decreased wound HMGB1 levels (P < 0.05), which was paralleled by increased wound breaking strength (P < 0.05) and wound collagen content (P < 0.05). In vitro treatment with HMGB1 (100 ng/mL) had no effect on fibroblast proliferation but significantly reduced collagen synthesis (P < 0.05). This effect was abrogated by co-treatment with anti-RAGE antibody. Fibroblasts treated with AGE had lower collagen synthesis (P < 0.01), which was restored by anti-RAGE antibody treatment. CONCLUSION HMGB1 impairs fibroblast collagen synthesis. Reducing wound HMGB1 levels lead to increased tensile strength and collagen synthesis. The data suggest that HMGB1 affects collagen synthesis through activation of RAGE.

Intra-abdominal Healing: Gastrointestinal Tract and Adhesions

The abdominal cavity represents one of the most active areas of surgical activity. Surgical procedures involving the gastrointestinal (GI) tract are among the most common procedures performed today. Healing of the GI tract after removal of a segment of bowel and healing of the peritoneal surfaces with subsequent adhesion formation remain vexing clinical problems. Interventions to modify both the responses are myriad, yet a full understanding of the pathophysiology of these responses remains elusive. Different aspects of GI and peritoneal healing, with associated factors, are discussed in this article.

Peptide Inhibitors of MK2 Show Promise for Inhibition of Abdominal Adhesions

BACKGROUND Abdominal adhesions are a common side effect of surgical procedures with complications including infertility, chronic pain, and bowel obstruction, which may lead to the need for surgical lyses of the adhesions. Mitogen-activated protein kinase-activated protein kinase 2 (MK2) has been implicated in several diseases, involving inflammation and fibrosis. Thus, the development of a cell-penetrating peptide (CPP) that modulates MK2 activity may confer therapeutic benefit after abdominal surgery in general and more specifically after bowel anastomosis. METHODS This study evaluated the function of a CPP inhibitor of MK2 in human mesothelial cells and in a rat bowel anastomosis model. To determine IC50 and basic specificity, kinase inhibition was performed using a radiometric assay. Enzyme-linked immunoassay (ELISA) was used to evaluate interleukin-6 (IL-6) expression in response to IL-1β and tumor necrosis factor-α (TNF-α) stimulation in vitro to validate MK2 kinase inhibition. Following bowel anastomosis (10 rats for each control and treatment at 4 and 10 d), the rats were evaluated for weight loss, normal healing (colonic burst strength and hydroxyproline content at the anastomosis), and number and density of adhesions. RESULTS The IC50 of the MK2 inhibitor peptide (22 μM) was similar to that of the nonspecific small molecule rottlerin (IC50 = 5 μM). The MK2 inhibitor peptide was effective at suppressing IL-1β and TNF-α stimulated IL-6 expression in mesothelial cells. In vivo, the MK2 inhibitor peptide was effective at suppressing both the density and number of adhesions formed as a result of bowel an anastamosis. Importantly, the peptide had no negative effect on normal healing. CONCLUSIONS In conclusion, the peptide inhibitor of MK2, MMI-0100, has the potential to significantly reduce inflammation through suppression of inflammatory cytokine expression and showed promise as a therapeutic for abdominal adhesions.

SDF-1α Mediates Wound-Promoted Tumor Growth in a Syngeneic Orthotopic Mouse Model of Breast Cancer

Increased growth of residual tumors in the proximity of acute surgical wounds has been reported; however, the mechanisms of wound-promoted tumor growth remain unknown. Here, we used a syngeneic, orthotopic mouse model of breast cancer to study mechanisms of wound-promoted tumor growth. Our results demonstrate that exposure of metastatic mouse breast cancer cells (4T1) to SDF-1α, which is increased in wound fluid, results in increased tumor growth. Both, wounding and exposure of 4T1 cells to SDF-1α not only increased tumor growth, but also tumor cell proliferation rate and stromal collagen deposition. Conversely, systemic inhibition of SDF-1α signaling with the small molecule AMD 3100 abolished the effect of wounding, and decreased cell proliferation, collagen deposition, and neoangiogenesis to the levels observed in control animals. Furthermore, using different mouse strains we could demonstrate that the effect of wounding on tumor growth and SDF-1α levels is host dependent and varies between mouse strains. Our results show that wound-promoted tumor growth is mediated by elevated SDF-1α levels and indicate that the effect of acute wounds on tumor growth depends on the predetermined wound response of the host background and its predetermined wound response.