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Wound Healing



Increases in callus formation and mechanical strength of healing fractures in old rats treated with parathyroid hormone.

Andreassen TT, Fledelius C, Ejersted C, Oxlund H. Department of Connective Tissue Biology, Institute of Anatomy, University of Aarhus, Denmark. tta@ana.au.dk

Acta Orthop Scand. 2001 Jun;72(3):304-7.

We studied the effects of intermittent administration of parathyroid hormone (PTH(1-34)) on callus formation and mechanical strength of tibial fractures in 27-month-old rats after 3 and 8 weeks of healing. 200 microg PTH(1-34)/kg was administered daily during both periods of healing, and control animals with fractures were given vehicle. At 3 weeks, PTH treatment increased maximum load and external callus volume by 160% and 208%; at 8 weeks, by 270% and 135%. It also enhanced callus bone mineral content (BMC) by 190% and 388% (3 and 8 weeks). From week 3 to week 8, callus BMC increased by 60% in the vehicle-injected animals, and by 169% in the PTH-treated animals. In the contralateral intact tibia, PTH treatment increased BMC by 18% and 21% (3 and 8 weeks). No differences in body weight were found between the vehicle-injected and the PTH-treated animals during the experiment. In conclusion, PTH treatment enhances fracture strength, callus volume and callus BMC after 3 and 8 weeks of healing.

The role of zinc in wound healing.

Andrews M, Gallagher-Allred C. Geriatric and Long Term Care Services, Ross Products Division, Abbott Laboratories, Columbus, OH, USA.

Adv Wound Care 1999 Apr;12(3):137-8

Zinc deficiency has been associated with delayed wound healing. Because zinc deficiency may be common in the United States, foods rich in zinc, as well as all other essential nutrients, should be promoted in the diet of patients who are malnourished or at risk for malnutrition.

Effects of supplemental pantothenic acid on wound healing: experimental study in rabbit.

Aprahamian M, Dentinger A, Stock-Damge C, Kouassi JC, Grenier JF.

Am J Clin Nutr 1985 Mar;41(3):578-89

The effect of pantothenic acid supplementation and deficiency on wound healing was investigated over a one month postoperative period in rabbits. The supplemented group was injected with pentothenate (20 mg/kg of body weight/24 h) for three weeks and compared to a placebo group (0.5 ml of distilled water). Deficient animals were fed with a pantothenate free diet also for three weeks. These three experimental groups were matched against a control group. The degree of wound healing was determined by the mean of postoperative breaking strength and wound fibroblast population changes. Pantothenic acid urinary excretion measured by gas chromatography served as control of pantothenate consumption. With regard to these three parameters no significant difference has been found between placebo and controls. The average urinary elimination in the pantothenic acid group was significantly higher as far as the pantothenate supplemented group was concerned, while the deficient group showed no significant decrease when compared to controls. Chronic pre- and postoperative pantothenic acid supplementation significantly increased aponeurosis strength after surgery; it improved slightly, but not significantly the strength of the skin. Furthermore, the fibroblast content of the scar became significantly greater during the fibroblast proliferation phase after pantothenic supplementation. These data suggest that pantothenic acid induces an accelerating effect of the normal healing process. The mechanism responsible for this improvement seems to be an increase in cellular multiplication during the first postoperative period. But the exact intimate mechanism of the beneficial effect of pantothenate remains unclear.

Topical estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response.

Ashcroft GS, Greenwell-Wild T, Horan MA, Wahl SM, Ferguson MW Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA. gashcroft@ydir.nidcr.nih.gov

Am J Pathol 1999 Oct;155(4):1137-46

The effects of intrinsic aging on the cutaneous wound healing process are profound, and the resulting acute and chronic wound morbidity imposes a substantial burden on health services. We have investigated the effects of topical estrogen on cutaneous wound healing in healthy elderly men and women, and related these effects to the inflammatory response and local elastase levels, an enzyme known to be up-regulated in impaired wound healing states. Eighteen health status-defined females (mean age, 74.4 years) and eighteen males (mean age, 70.7 years) were randomized in a double-blind study to either active estrogen patch or identical placebo patch attached for 24 hours to the upper inner arm, through which two 4-mm punch biopsies were made. The wounds were excised at either day 7 or day 80 post-wounding. Compared to placebo, estrogen treatment increased the extent of wound healing in both males and females with a decrease in wound size at day 7, increased collagen levels at both days 7 and 80, and increased day 7 fibronectin levels. In addition, estrogen enhanced the strength of day 80 wounds. Estrogen treatment was associated with a decrease in wound elastase levels secondary to reduced neutrophil numbers, and decreased fibronectin degradation. In vitro studies using isolated human neutrophils indicate that one mechanism underlying the altered inflammatory response involves both a direct inhibition of neutrophil chemotaxis by estrogen and an altered expression of neutrophil adhesion molecules. These data demonstrate that delays in wound healing in the elderly can be significantly diminished by topical estrogen in both male and female subjects.

Depletion of plasma vitamin C but not of vitamin E in response to cardiac operations.

Ballmer PE, Reinhart WH, Jordan P, Buhler E, Moser UK, Gey KF. Department of Medicine, Inselspital, University of Berne, Switzerland.

J Thorac Cardiovasc Surg 1994 Aug;108(2):311-20

The whole-body inflammatory response produced by cardiopulmonary bypass is an important cause of perioperative morbidity after cardiac operations. This inflammatory response produces reactive oxygen species and other cytotoxic substances, such as the cytokines. The generation of reactive oxygen species might deplete principal antioxidant micronutrients, that is, vitamins C and E and the carotenoids. Therefore, we have investigated the time course of the plasma concentrations of vitamins C and E and the carotenoids in 18 patients undergoing coronary bypass operations after randomization for previous vitamin E supplementation (300 mg dl-alpha-acetyl-tocopherol 3 times daily for 4 weeks) or placebo. Supplementation with alpha-tocopherol doubled the lipid-standardized plasma vitamin E concentration to 63.7 +/- 14.5 mumol/L when compared with that of the control subjects (31.2 +/- 9.0 mumol/L) before the operation. The plasma concentrations of vitamin C (36.0 +/- 19.0 mumol/L and 44.0 +/- 21.7 mumol/L, respectively) and of the carotenoids were not statistically different between the two groups at baseline. The absolute plasma concentrations of both vitamin E and the carotenoids decreased during and after cardiopulmonary bypass, but after correction for hemodilution the plasma concentrations of vitamin E and the carotenoids showed no decrease. The vitamin E concentrations in the erythrocytes did not change either. In contrast, the plasma concentration of vitamin C decreased in all subjects within 24 hours after the operation by roughly 70%. Correction for hemodilution still revealed a significant decrease in plasma vitamin C that persisted in most patients up to 2 weeks. In conclusion, the vitamin E and the carotenoid plasma concentrations are of no major concern during and after cardiac operations. In contrast, the serious depletion of vitamin C may deteriorate the defense against reactive oxygen species-induced injury during cardiac operations.

Biomechanical and histological aspects of fracture healing, stimulated with osteogenic protein-1.

Blokhuis TJ, den Boer FC, Bramer JA, Jenner JM, Bakker FC, Patka P, Haarman HJ. Department of Surgery/Traumatology, Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands. tj.blokhuis@azvu.nl

Biomaterials 2001 Apr;22(7):725-30

Fracture healing could be stimulated with osteoinductive bone morphogenetic proteins (bmp's), such as osteogenic protein-1 (OP-1), but little is known about its effectiveness in stimulation of fracture healing. In this study, biomechanical and histological aspects of fracture healing after an injection of OP-1 in the fracture gap were investigated. In 40 goats, a closed fracture was created in the left tibia. The fractures were stabilized with an external fixator and the animals were assigned to four different groups: no injection, injection of 1 mg OP-1, injection of 1 mg OP-1 with collagenous carrier material, and injection of carrier material alone. Twenty-one animals were sacrificed after 2 weeks and 19 after 4 weeks. Biomechanical testing was perfomed on both explanted tibiae. Four longitudinal samples of the fracture were sawn, processed for histology, and examined by two observers. Biomechanical evaluation showed a higher stiffness and strength at 2 weeks after injection of OP-1. Histological evaluation showed normal fracture healing patterns in all animals without adverse effects of the given injections. These data show that fracture healing can be accelerated with a single injection of OP-1, eventually resulting in normally healed bone.

Effects of exogenous zinc supplementation on intestinal epithelial repair in vitro.

Cario E, Jung S, Harder D'Heureuse J, Schulte C, Sturm A, Wiedenmann B, Goebell H, Dignass AU. University of Essen, Essen, Germany; Charite Medical School-Campus Virchow, Berlin, Germany.

Eur J Clin Invest 2000 May;30(5):419-28

BACKGROUND: Substitution of zinc modulates antioxidant capabilities within the intestinal mucosa and improves intestinal wound healing in zinc-deficient patients with inflammatory bowel diseases. The aim of this study was to characterize the modulating effects of zinc on intestinal epithelial cell function in vitro.

MATERIALS AND METHODS: The effects of zinc on intestinal epithelial cell morphology were assessed by phase contrast and transmission electron microscopy using the non-transformed small intestinal epithelial cell line IEC-6. Zinc-induced apoptosis was assessed by DNA fragmentation analysis, lactate dehydrogluase (LDH) release and flow cytometry with propidium iodine staining. Furthermore, the effects of zinc on IEC-6 cell proliferation were assessed using a colorimetric thiazolyl blue (MTT) assay and on IEC-6 cell restitution using an in vitro wounding model.

RESULTS: Physiological concentrations of zinc (25 microM) did not significantly alter the morphological appearance of IEC-6 cells. However, a 10-fold higher dose of zinc (250 microM) induced epithelial cell rounding, loss of adherence and apoptotic characteristics. While physiological zinc concentrations (< 100 microM) did not induce apoptosis, supraphysiological zinc concentrations (> 100 microM) caused apoptosis. Physiological concentrations of zinc (6.25-50 microM) had no significant effect on intestinal epithelial cell proliferation. In contrast, physiological concentrations of zinc (12.5-50 microM) significantly enhanced epithelial cell restitution through a transforming growth factor-beta (TGFbeta)-independent mechanism. Simultaneous addition of TGFbeta and zinc resulted in an additive stimulation of IEC-6 cell restitution.

CONCLUSION: Zinc may promote intestinal epithelial wound healing by enhancement of epithelial cell restitution, the initial step of epithelial wound healing. Zinc supplementation may improve epithelial repair; however, excessive amounts of zinc may cause tissue injury and impair epithelial wound healing.

Insulin-like growth factor-1 modulation of intestinal epithelial cell restitution.

Chen K, Nezu R, Wasa M, Sando K, Kamata S, Takagi Y, Okada A. Department of Biochemistry and Biophysics, University of Rochester Medical Center, New York, USA.

JPEN J Parenter Enteral Nutr 1999 Sep-Oct;23(5 Suppl):S89-92

After superficial intestinal injury, the mucosal integrity is reestablished by rapid migration of epithelial cells from the adjacent area in a process called restitution. Our previous study suggested that growth hormone improves intestinal healing in an experimental small bowel ulceration, mediated by insulin-like growth factor-1 (IGF-1). The aim of the present study was to assess the role of IGF-1 in mucosal epithelial restitution using an in vitro epithelial wound model. Wounds were established in confluent monolayers of the intestinal cell line, IEC-6. Migration was quantitated in the presence or absence of IGF-1 as the number of cells migrating across the wound edge. Proliferation was assessed by thymidine incorporation. IGF-1-enhanced epithelial cell migration by 2- to 2.5-fold after 12- and 24-hour treatment, respectively, the first step involved in gastrointestinal wound healing. Cell proliferation was significantly stimulated by IGF-1 as well. In addition, expression of transforming growth factor-beta (TGF-beta) mRNA was significantly enhanced in the wounded monolayers treated with IGF-1. IGF-1 receptor mRNA was found to be detectable throughout the gastrointestinal mucosa and in the intestinal epithelial cells. In conclusion, these findings suggest that IGF-1 plays an important role in reconstitution of intestinal epithelial integrity after mucosal injury.

Influence of Aloe vera on collagen characteristics in healing dermal wounds in rats.

Chithra P, Sajithlal GB, Chandrakasan G. Department of Biochemistry, Central Leather Research Institute, Adyar, Madras, India.

Mol Cell Biochem 1998 Apr;181(1-2):71-6

Wound healing is a fundamental response to tissue injury that results in restoration of tissue integrity. This end is achieved mainly by the synthesis of the connective tissue matrix. Collagen is the major protein of the extracellular matrix, and is the component which ultimately contributes to wound strength. In this work, we report the influence of Aloe vera on the collagen content and its characteristics in a healing wound. It was observed that Aloe vera increased the collagen content of the granulation tissue as well as its degree of crosslinking as seen by increased aldehyde content and decreased acid solubility. The type I/type III collagen ratio of treated groups were lower than that of the untreated controls, indicating enhanced levels of type III collagen. Wounds were treated either by topical application or oral administration of Aloe vera to rats and both treatments were found to result in similar effects.

Improvement of nitrogen retention by arginine and glycine supplementation and its relation to collagen synthesis in traumatized mature and aged rats.

Chyun JH, Griminger P.

J Nutr 1984 Sep;114(9):1697-704

The effect of arginine and glycine supplementation on reducing body protein losses and on enhancing wound healing after trauma was studied in two age groups. Mature (4 month) and aged (24 month) Fischer 344 male rats were fed a diet containing 25% casein and 0.4% methionine with or without supplementation with 2.4% arginine . HCl and 1.0% glycine for 7 days before and after laparotomy. Nitrogen (N) balance studies (N intake - urinary N) were carried out during the last three pretrauma days and seven posttrauma days. The supplemented rats retained significantly more N than the controls and the mature rats significantly more than the aged rats. Polyvinyl alcohol sponges, implanted during surgery and removed from the rats on day 3 or 7 after surgery, were analyzed for hydroxyproline content and for the ratios of type III/type I collagen synthesized. Sponges obtained from the supplemented and the mature rats had more hydroxyproline and higher ratios of type III/type I collagen than those from the control and the aged rats. The beneficial effect of arginine and glycine supplementation on improving N retention in traumatized rats appears to be due, at least in part, to increased collagen synthesis in wounds.

Enteral nutrition during multimodality therapy in upper gastrointestinal cancer patients.

Daly JM, Weintraub FN, Shou J, Rosato EF, Lucia M. Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, USA.

Ann Surg 1995 Apr;221(4):327-38

OBJECTIVE: The objective of this study was to evaluate long-term enteral nutrition support in postoperative cancer patients.

BACKGROUND: Multimodality therapy for surgical patients with upper gastrointestinal malignancies may improve survival, but often results in substantial malnutrition, immunosuppression, and morbidity. The benefits of combined inpatient and outpatient enteral feeding with standard diets or diets supplemented with arginine, RNA + omega-3 fatty acids are unclear.

METHODS: Sixty adult patients with esophageal (22), gastric (16), and pancreatic (22) lesions were stratified by disease site and percent usual weight and randomized to receive supplemental or standard diet via jejunostomy beginning on the first postoperative day (goal = 25 kcal/kg/day) until hospital discharge. Patients also were randomized to receive (n = 37) or not receive (n = 23) enteral jejunostomy feedings (1000 kcal/day overnight) for the 12- to 16-week recovery and radiation/chemotherapy periods. Plasma and peripheral white blood cells were obtained for fatty acid levels and PGE2 production measurements.

RESULTS: Mean plasma and cellular omega 3/omega 6 fatty acid levels (percent composition) increased significantly (p < 0.05) in the arginine + omega-3 fatty acid group by postoperative day 7 (0.30 vs. 0.13) and (0.29 vs. 0.14) and continued to increase over time. Mean PGE2 production decreased significantly (p < 0.05) from 2760 to 1600 ng/10(6) cells/mL at day 7 in the arginine + omega-3 fatty acid group, whereas no significant change over time was noted in the standard group. Infectious/wound complications occurred in 10% of the supplemented group compared with 43% of the standard group (p < 0.05); mean length of hospital stay was 16 vs. 22 (p < 0.05) days, respectively. Of the patients who received postoperative chemoradiation therapy, only 1 (6%) of the 18 patients randomized to receive tube feeding did not continue, whereas 8 (61%) of the 13 patients not randomized to tube feedings required crossover to jejunostomy nutritional support.

CONCLUSIONS: Supplemental enteral feeding significantly increased plasma and peripheral white blood cell omega 3/omega 6 ratios and significantly decreased PGE2 production and postoperative infectious/wound complications compared with standard enteral feeding. For outpatients receiving adjuvant therapy, those initially randomized to oral feedings alone required rehospitalization more frequently, and 61% crossed over to supplemental enteral feedings.

The use of adjuvant hyperbaric oxygen in treatment of the diabetic foot.

Davis JC.

Clin Podiatr Med Surg. 1987 Apr;4(2):429-37.

Hypoxia in the relatively ischemic diabetic foot impairs leukocyte bacterial killing and fibroblast-collagen support for capillary angiogenesis. Infection in even the relatively young, "warm-foot" diabetic with microangiopathy, neuropathy, and infection leads to hypoxia due to local high oxygen consumption. The 1100 to 1300 mm Hg arterial PO2 achievable with hyperbaric oxygen results in elevation of wound PO2. Periodic correction of wound hypoxia improves leukocyte bacterial killing and support for capillary angiogenesis. Hyperbaric oxygen is usually futile in the elderly diabetic with significant and generalized large-vessel occlusion.

Reversal of the detrimental effects of chronic protein malnutrition on long bone fracture healing.

Day SM, DeHeer DH. Grand Rapids Orthopaedic Surgery Residency Program, Grand Rapids, Michigan, USA.

J Orthop Trauma 2001 Jan;15(1):47-53

OBJECTIVE: To determine whether dietary intervention in the immediate postfracture period will reverse the detrimental influence of protein deprivation on fracture healing in the rat. DESIGN: Adult Sprague-Dawley rats were maintained on a diet containing either a normal or reduced protein concentration. After five weeks, both femora of each rat were pinned with an intramedullary 0.625-millimeter K-wire. A closed fracture of the right femur was created one week later, by use of a handheld device. Groups of rats were killed and the femora harvested at 14 days for histologic study and at twenty-eight and fifty-six days for mechanical testing.

INTERVENTION: Control rats (Group I) were maintained on a 20 percent protein diet. Malnourished (Group II) animals were maintained on a 6 percent protein diet during the six-week prefracture period and throughout the fifty-six-day postfracture period. Malnutrition was confirmed by measurement of serum concentrations of transferrin, immunoglobulin, and albumin. Renourished (Group III) animals were started on the 6 percent protein diet but were fed a 20 percent protein diet in the fifty-six-day postfracture period.

RESULTS: When compared with control, well-nourished rats, malnourished animals had callus composed primarily of fibrous-type tissue and had decreased periosteal and external callus as well as callus strength. The callus from renourished animals histologically resembled that from well-nourished animals with large amounts of periosteal and external callus. Based on mechanical testing results, callus from malnourished animals showed reduced strength and stiffness as compared with control renourished animals. In renourished animals, the cross-sectional area of the fracture callus, as well as callus stiffness and strength, were greater than those in malnourished and well-nourished animals.

CONCLUSION: Protein deprivation has a profound detrimental effect on fracture healing. The identification of a protein-reduced state and its reversal could result in improved fracture healing and presumably a better clinical outcome in malnourished patients.

Pharmacological nutrition after burn injury.

De-Souza DA, Greene LJ. Centro de Quimica de Proteinas, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, 14049-900, S.P., Brazil.

J Nutr 1998 May;128(5):797-803

Burn patients develop pathophysiological alterations, which include extensive nitrogen loss, malnutrition, markedly increased metabolic rate and immunologic deficiency. This predisposes burn patients to frequent infections, poor wound healing, increased length of hospitalization and increased mortality. The nutritional support requires high protein and high energy diets preferably administered enterally soon after injury. The effects of increased dietary components such as glutamine, arginine and (n-3) fatty acids and related compounds have been evaluated in burn victims. These components, when supplied in quantities two to seven times of those in normal diets of healthy persons, appear to have beneficial pharmacological effects on the pathophysiological alterations associated with burns. However, the efficacy of immune-enhancing diets remains to be convincingly shown.

Superoxide dismutase (SOD) for mustard gas burns.

Eldad A, Ben Meir P, Breiterman S, Chaouat M, Shafran A, Ben-Bassat H. The Burn Unit, The Department of Plastic Surgery, School of Pharmacology, The Hebrew University, Jerusalem, Israel.

Burns 1998 Mar;24(2):114-9

Mustard gas (MS) has been used in chemical warfare since World War I. The blistering skin lesions are slow to heal. Secondary inflammation might occur, as well as damage to organs distant from the original wound. Presently there is no specific antidote for burns and poisoning by MS. This study examined treatment modalities with free oxygen radical scavengers, copper-zinc, and manganese superoxide dismutase (SOD), for MS skin burns in an experimental guinea pig model. Each of the SOD compounds reduced dramatically burn lesion area when administered intraperitoneally/intralesionally (i.p./i.l.) before wound infliction. The protective action of the SODs was also evident in the significantly higher histopathological score of biopsies obtained on day 7 from local tissue, caused with the lower dose of MS. When the SOD compounds were administered i.p. 1 hour after burn infliction, and repeated daily for 7 days, no protective effect could be detected under the present experimental conditions.

Wound healing after photorefractive keratectomy.

Fagerholm P. St. Eriks Eye Hospital, Karolinska Institutet, Stockholm, Sweden.

J Cataract Refract Surg. 2000 Mar;26(3):432-47.

For more than 15 years, the excimer laser has been used as a surgical instrument on the cornea. Photorefractive keratectomy (PRK) followed radial keratotomy as researchers sought a more precise technique. In PRK, precision turned out to depend on surgical technique as well as the wound-healing process, with the 2 factors interdependent. The PRK technique has evolved toward a large diameter, flat ablation curvatures, and an even surface. The role of such factors as cytokines and interleukins has become more clear in the past 10 years. However, understanding the wound-healing process becomes more complicated with increasing know edge. Learning the contributing factors and performing trials with new drugs and antibodies to modulate wound healing have shown positive results on the experimental level. Patient selection based on the concentration of epidermal growth factor in tears may be another way to increase PRK s precision. The PRK technique has taught much about wound healing. For the technique to be competitive, increased precision, particularly in eyes with high myopia, is needed. Two other factors are imperative: controlling postoperative pain and decreasing visual rehabilitation time.

Burn injuries benefit from massage therapy.

Field T; Peck M; Krugman S; Tuchel T; Schanberg S; Kuhn C; Burman I Touch Research Institute, University of Miami School of Medicine, Florida 33101, USA.

J Burn Care Rehabil (UNITED STATES) May-Jun 1998 , 19 (3) p241-4

Twenty-eight adult patients with burns were randomly assigned before debridement to either a massage therapy group or a standard treatment control group. State anxiety and cortisol levels decreased, and behavior ratings of state, activity, vocalizations, and anxiety improved after the massage therapy sessions on the first and last days of treatment. Longer- term effects were also significantly better for the massage therapy group including decreases in depression and anger, and decreased pain on the McGill Pain Questionnaire, Present Pain Intensity scale, and Visual Analogue Scale. Although the underlying mechanisms are not known, these data suggest that debridement sessions were less painful after the massage therapy sessions due to a reduction in anxiety, and that the clinical course was probably enhanced as the result of a reduction in pain, anger, and depression.

Interleukin-6 treatment augments cutaneous wound healing in immunosuppressed mice.

Gallucci RM, Sugawara T, Yucesoy B, Berryann K, Simeonova PP, Matheson JM, Luster MI. Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, NIOSH/CDCP, 1095 Willowdale Road, Morgantown, WV 26505-2888, USA.

J Interferon Cytokine Res 2001 Aug;21(8):603-9

It has been postulated that the inflammatory response that occurs aftercutaneous wounding is a prerequisite for healing and that inflammatorycytokines, such as Interleukin-6 (IL-6) are involved in this process. We showed previously that IL-6-deficient mice display delayed wound healing, which could be reversed by administration of a murine IL-6 expression plasmid or recombinant murine IL-6 (rMuIL-6). In the present study, we observed that delayed cutaneous wound healing, which occurs as a result of glucocorticoid-induced immunosuppression, can also be reversed by rMuIL-6, as evidenced by epithelialization, granulation tissue formation, and wound closure. In vehicle control mice, rMuIL-6 did not augment healing but rather delayed the process. Immunochemical studies indicated that the expression of matrix metalloproteinase-10 (MMP-10) was increased in dexamethasone-treated mice and that rMuIL-6 treatment reduced its expression, indicating that IL-6 may influence dermal matrix formation and, specifically, collagen synthesis. These results demonstrate that IL-6 can restore abnormal wound repair that occurs in immunodeficiency and suggest its use as a potential therapy.

Effects of epidermal growth factor in artificial tear on vitamin C levels of corneal wounded eye tissues.

Gonul B, Kaplan B, Bilgihan K, Budak MT. Department of Physiology, Gazi University Faculty of Medicine, Ankara, Turkey. hbcgonul@turk.net

Eye 2001 Apr;15(Pt 2):213-6

PURPOSE: To investigate the effect of artificial tear (AT) solution and epidermal growth factor (EGF) treatment on the cornea and aqueous humour ascorbic acid (AA) levels of full-thickness corneal wounded eyes.

METHODS: The effect of EGF on the AA levels of aqueous humour and corneal wound tissue was determined in full-thickness corneal wounded rabbit eyes on the seventh post-operative day. There were three groups: untreated controls, AT-treated controls and an EGF treated experimental group (n = 6 in each group). Corneal wounded eyes were topically treated with 5 microl AT or 5 microl EGF in AT (1 mg/l EGF in AT preparation which contained 3.0% carbopol 940) twice daily for 6 days after operation. The wound strengths were also measured on the seventh post-operative day as a measure of wound healing. Statistical analysis was carried out using the Mann-Whitney U-test by Statview program.

RESULTS: The wound strengths of corneas, and AA levels of wound tissues and aqueous humour, increased significantly following AT and EGF treatment (p < 0.05).

CONCLUSION: In the corneal wounded eye, aqueous humour serves as a source of vitamin C and there may be a relation between EGF treatment in AT and AA levels of corneal wounded eye tissues.

Topical insulin in wound healing: a randomised, double-blind, placebo-controlled trial.

Greenway SE, Filler LE, Greenway FL. Department of Surgery, Harbor-UCLA Medical Center, Torrance, USA.

J Wound Care 1999 Nov;8(10):526-8

Two studies were carried out to assess the relative roles of insulin and zinc in the acceleration of wound healing. In the first study, six diabetic and five non-diabetic human volunteers had two uniform cuts created, one on each forearm. One forearm wound was treated with topical regular insulin (Iletin-II) and the other with normal saline four times a day until healed. Treatment was double-blind and forearms were assigned randomly. The wounds treated with insulin healed 2.4 0.8 days faster than the wounds treated with saline (P <0.001 by paired t-test). Zinc is used to crystallise insulin. When wounds are treated with insulin, they are therefore also being treated with zinc. If insulin accelerates wound healing, it is not clear if the increase in the rate of healing would be due to insulin (a known growth factor), the zinc it contains, or a combination of the two. The second study used a randomised, double-blind, placebo-controlled design to compare the efficacy of insulin with that of a solution containing the same amount of zinc in accelerating the healing of standardised wounds in rats and humans. Although these pilot investigations did not have the power to define the relative roles of insulin and zinc with accuracy, the results suggest that zinc does play a role in the wound healing process. It is concluded that topical insulin accelerates wound healing in humans. More importantly, however, this study describes a method of creating uniform wounds in humans acceptable to an institutional review board, thus solving one of the major impediments to the scientific evaluation of human wound healing.

Supplemental dietary arginine accelerates intestinal mucosal regeneration and enhances bacterial clearance following radiation enteritis in rats.

Gurbuz AT, Kunzelman J, Ratzer EE. Department of Surgery, Saint Joseph Hospital Medical Center, Denver, Colorado, USA. tayfun@netten.net

J Surg Res 1998 Feb 1;74(2):149-54 BACKGROUND: Arginine is a dibasic amino acid with significant metabolic and immunologic, effects especially in trauma and stress situations. Arginine supplementation has been shown to promote wound healing and improve immune system. We designed a study to evaluate the effects of supplemental dietary arginine on intestinal mucosal recovery and bacterial translocation and bacterial clearance after induction of radiation injury in rats.

METHODS: Twenty-one male Sprague-Dawley rats were subjected to a single dose of 1100 rads of abdominal X radiation. Rats were divided into three groups; the first group received diet enriched with 2% arginine, the second group with 4% arginine, and the third group with isonitrogenous 4% glycine. Rats were sacrificed 7 days after the radiation. Blood was drawn for arginine levels and mesenteric lymph nodes were harvested for quantitative aerobic and anaerobic cultures. Segments of ileum and jejunum were evaluated for villous height, number of villi per centimeter of intestine, and the number of mucous cells per villous.

RESULTS AND CONCLUSIONS: Arginine is absorbed reliably from the gut following oral administration. Dietary 4% arginine supplementation enhanced bacterial clearance from mesenteric lymph nodes compared to 2% arginine and 4% glycine supplemented diet following radiation enteritis in rats. Four percent arginine resulted in clear improvement in intestinal mucosal recovery when compared to 2% arginine and 4% glycine after abdominal irradiation in rats.

Omega-3 fatty acids enhance ligament fibroblast collagen formation in association with changes in Interleukin-6 production.

Hankenson KD, Watkins BA, Schoenlein IA, Allen KG, Turek JJ. Department of Basic Medical Sciences, Lipid Chemistry Laboratory, Purdue University, West Lafayette, Indiana 47907, USA.

Proc Soc Exp Biol Med 2000 Jan;223(1):88-95

Altering dietary ratios of n-3 and n-6 polyunsaturated fatty acids (PUFA) represents an effective nonpharmaceutical means to improve systemic inflammatory conditions. An effect of PUFA on cartilage and bone formation has been demonstrated, and the purpose of this study was to determine the potential of PUFA modulation to improve ligament healing. The effects of n-3 and n-6 PUFA on the in vitro healing response of medial collateral ligament (MCL) fibroblasts were investigated by studying the cellular coverage of an in vitro wound and the production of collagen, PGE2, IL-1, IL-6, and TNF. Cells were exposed to a bovine serum albumin (BSA) control or either eicosapentaenoic acid (EPA, 20:5n-3) or arachidonic acid (AA, 20:4n-6) in the form of soaps loaded onto BSA for 4 days and wounded on Day 5. AA and EPA improved the healing of an in vitro wound over 72 hr. EPA increased collagen synthesis and the overall percentage of collagen produced, but AA reduced collagen production and total protein. PGE2 production was increased in the AA-treated group and decreased in the EPA-treated group, but was not affected by wounding. IL-1 was not produced at the time point evaluated, but TNF and IL-6 were both produced, and their levels varied relative to the PUFA or wounding treatment. There was a significant linear correlation (r2 = 0.57, P = 0.0045) between IL-6 level and collagen production. These results demonstrate that n-3 PUFA (represented by EPA in this study) positively affect the healing characteristics of MCL cells and therefore may represent a possible noninvasive treatment to improve ligament healing. Additionally, these results show that MCL fibroblasts produce PGE2, IL-6, and TNF and that IL-6 production is related to MCL collagen synthesis.

Ascorbic acid in the prevention and treatment of cancer.

Head KA. Alternative Medicine Review. P.O. Box 25, Dover, ID 83825, USA. kathi@thorne.com

Altern Med Rev 1998 Jun;3(3):174-86

Proposed mechanisms of action for ascorbic acid (ascorbate, vitamin C) in the prevention and treatment of cancer include enhancement of the immune system, stimulation of collagen formation necessary for "walling off" tumors, inhibition of hyaluronidase which keeps the ground substance around the tumor intact and prevents metastasis, prevention of oncogenic viruses, correction of an ascorbate deficiency often seen in cancer patients, expedition of wound healing after cancer surgery, enhancement of the effect of certain chemotherapy drugs, reduction of the toxicity of other chemotherapeutic agents such as Adriamycin, prevention of free radical damage, and neutralization of carcinogenic substances. Scottish as well as Japanese studies have pointed to the potential benefit of high dose vitamin C for the treatment of "terminal" cancer. Mayo Clinic studies, however, have contradicted the Scottish and Japanese findings, resulting in accusations of methodological flaws from both sides. Numerous epidemiological studies have pointed to the importance of dietary and supplemental ascorbate in the prevention of various types of cancer including bladder, breast, cervical, colorectal, esophageal, lung, pancreatic, prostate, salivary gland, stomach, leukemia, and non-Hodgkin's lymphoma.

Effect of the combination of Aloe vera, nitroglycerin, and L-NAME on wound healing in the rat excisional model.

Heggers JP, Elzaim H, Garfield R, Goodheart R, Listengarten D, Zhao J, Phillips LG. University of Texas Medical Branch, Galveston, USA.

J Altern Complement Med 1997 Summer;3(2):149-53

PURPOSE: Many systemic and topical therapeutic agents such as growth hormone, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and insulin-like growth factor (IGF) have been used as vulnerary agents. However, the role of nitric oxide (NO) as a wound-healing stimulant has been received with mixed reviews. NO is a potent vasodilator that is thought to be an endothelium-dependent relaxing factor, and a regulator of blood pressure and regional blood flow. It affects vascular smooth muscle proliferation and inhibits platelet aggregation and leukocyte adhesion. Therefore we compared the effects of several topical substances that have similar or reverse properties.

METHODS: Using the excisional rat wound model, we evaluated the topical effects of Dermaide Aloe (D-Aloe, Dermaide Research Corp, Palos Heights, IL), nitroglycerin, Aquaphor (Beuersdorf, Inc., Norwalk, CT) alone, with D-Aloe with nitroglycerin, 2%, and L-NAME (NO inhibitor) with Aquaphor, and L-NAME with Aquaphor and D-Aloe for a 21-day period. All wounds were measured by planimetry at 1, 7, 10, 13, 16, 18, and 21 days.

RESULTS: At day 1, all wounds had an average wound size of 2.27 cm2 (SD 0.372) with no significant difference in wound size among the groups. Topically applied D-Aloe appeared to promote wound healing faster than the remaining other topicals (p <.05, Student-Newman-Keuls and Dunn's Method) over the study period. However, topicals combined with D-Aloe, the vehicle Aquaphor, and L-NAME improved the wound healing process when compared with nitroglycerin alone (p < .05).

CONCLUSIONS: D-Aloe appears to have a wound-healing advancement factor that can reverse the effects of petrolatum- and nitroglycerin-based products as observed in the remaining groups when compared with nitroglycerin alone. It appears that D-Aloe's effect of preventing dermal ischemia by reversing the effects of thromboxane synthetase (TxA2) may act synergistically with NO or could be an oxygen radical scavenger.

Topical hyperbaric therapy for problem skin wounds

Heng M.C.Y. Division of Dermatology, Veterans Administration Medical Ctr., UCLA School of Medicine, 16111 Plummer Street,Sepulveda, CA 91343 United States

Journal of Dermatologic Surgery and Oncology (United States) 1993, 19/8 (784-793) BACKGROUND. Hyperbaric oxygen remains the sole treatment capable of inducing growth of new blood vessels. However, systemic hyperbaric oxygen therapy risks central nervous system and pulmonary toxicity.

OBJECTIVE. To describe topical hyperbaric oxygen therapy for the treatment of recelcitrant open wounds.

METHODS. Topical and systemic hyperbaric oxygen treatments are described and contrasted from one another. Applications of topical hyperbaric oxygen therapy are described.

CONCLUSION. Topical hyperbaric oxygen therapy is useful only for open wounds. The advantages of topical hyperbaric oxygen therapy include low cost, the lack of systemic oxygen toxicity, and effectiveness, allowing this treatment to be prescribed for many patients early in the course of their disease rather than as a last resort.

Up-regulation of elastase in acute wounds of healthy aged humans and chronic venous leg ulcers are associated with matrix degradation.

Herrick S, Ashcroft G, Ireland G, Horan M, McCollum C, Ferguson M School of Biological Sciences, University of Manchester, United Kingdom.

Lab Invest 1997 Sep;77(3):281-8

Chronic wound healing states are often associated with aging, and despite the increased number of aged patients with nonhealing wounds, controversy still exists concerning the effects of age on wound repair. Our previous work showed that in both venous ulcers in humans and acute wounds in aged animals, fibronectin, an early component in granulation tissue, is deficient compared to normal skin and acute wounds in healthy young animals, respectively. In the present study, we have determined the protease responsible for fibronectin degradation by analyzing tissue taken from the margins of chronic venous ulcers and standardized acute cutaneous wounds collected from a large cohort of "Health status"-defined aged human subjects (screened as per the SENIEUR protocol). When tissue samples were subjected to fibronectin zymography, the main protease involved in the breakdown of fibronectin in both venous ulcers and acute wounds of elderly subjects was found to be a serine protease with a molecular weight of approximately 30 kd. This protease was identified as neutrophil elastase by immunoblotting. In tissue biopsies, elastase was localized to granulocytes by immunocytochemical techniques and shown to be present in greater quantities in venous ulcers and Day-7 and -14 healing acute wounds of healthy aged subjects relative to those of young subjects. The highest quantities were found in acute wounds of elderly women. Our results suggest that the process of aging in healthy human subjects is associated with an up-regulation of elastase during acute wound healing and that an abnormality in down-regulation of this protease could be partially responsible for the transition to chronic wound healing states in the aged.

Drotrecogin alfa (activated): the first FDA-approved treatment for severe sepsis.

Hosac, A.M.

BUMC Proc. 2002; 15: 224-7.

No abstract available.

Nutritional and metabolic effects and significance of mild orotic aciduria during dietary supplementation with arginine or its organic salts after trauma injury in rats.

Jeevanandam M, Begay CK, Holaday NJ, Petersen SR. Trauma Center, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.

Metabolism 1997 Jul;46(7):785-92

The effects of acute food deprivation and subsequent refeeding with isonitrogenous oral liquid diets supplemented with arginine (ARG), ARG alpha-ketoglutarate (AKG), or ARG alpha-ketoisocaproate (AKIC) were examined in a Sprague-Dawley rat trauma model (bilateral femur fracture). Both control and trauma rats were starved for 2 days and then pair-fed for 4 days with one of four liquid isonitrogenous diets: diet 1 was a basal casein-based diet, and diets 2, 3, and 4 were the basal diet in which 10% of the nitrogen was replaced by ARG, AKG, or AKIC nitrogen. Two days of starvation resulted in a 13% loss of body weight and also a 27% decrease in the excretion of orotic acid (OA) in control and trauma rats. Although the ARG content of diets 2, 3, and 4 was the same, ARG- and AKIC-supplemented rats excreted significantly (P < .05) more OA than AKG-fed rats. The low level of OA excretion in AKG-fed rats indicates greater use of ARG for metabolic purposes, including efficient urea cycle operation. The metabolic adaptation and nutritional efficacy, i.e., Increased nitrogen retention, larger weight gain, and altered amino acid (AA) metabolism, of AKIC rats seem to be better than in ARG- or AKG-fed rats.

Keratinocyte growth factor-2 accelerates wound healing in incisional wounds.

Jimenez PA, Rampy MA. Human Genome Sciences, Inc., Rockville, Maryland, 20850, USA. jimenez@hgsi.com

J Surg Res 1999 Feb;81(2):238-42

BACKGROUND: Keratinocyte growth factor-2 (KGF-2) also described as fibroblast growth factor-10 (FGF-10) is a newly identified member of the fibroblast growth factor family. KGF-2 is 96% identical to the recently identified rat FGF-10 and specifically stimulates growth of normal human epidermal keratinocytes. The present study was undertaken to examine the effects of topically applied KGF-2 in an incisional wound healing model. KGF-2 treatment resulted in an improvement in incisional wound healing as characterized by an increase in breaking strength, collagen content, and epidermal thickness.

METHODS: KGF-2 was topically applied to linear incisions made in the dorsal skin of Sprague-Dawley rats. Biomechanical testing was done using an Instron tensiometer for breaking and tensile strength determinations. Wound collagen content was determined using the Sircol collagen assay. Epidermal thickness measurements were conducted using Masson's trichrome-stained sections of the wound.

RESULTS: A single topical application of KGF-2 at the time of wounding resulted in an increase in wound breaking and tensile strength at Day 5 after wounding. Breaking strength of KGF-2-treated wounds was significantly higher compared with the buffer control (1 microgram, 222.1 +/- 13.5 g, P = 0.0007; 4 microgram, 248.7 +/- 15.4 g, P = 0.0001; 10 microgram, 247.2 +/- 21.9 g, P = 0.001; buffer, 141.0 +/- 9.7 g). Epidermal thickness and wound collagen content were significantly increased following treatment with KGF-2.

CONCLUSIONS: Based on our findings, KGF-2 is a potent stimulator of wound healing as demonstrated by increased mechanical strength accompanied by an increase in wound collagen content. KGF-2 could be an important cellular mediator responsible for the initiation and acceleration of wound healing and may enhance the healing of surgical wounds. Copyright 1999 Academic Press.

Effect of Ca-panthotenate on human granulocyte oxidative metabolism.

Kapp A, Zeck-Kapp G. Department of Dermatology, University of Freiburg.

Allerg Immunol (Leipz) 1991;37(3-4):145-50

Activated granulocytes play an important role in propagation of the inflammatory response by production of reactive oxygen species and release of their granule content. Hyperactivation of these cells is suggested to result in deterioration of wound healing and, probably, increase of cicatrization. Pantothenic acid and its stable salt form, Ca-Panthotenate, were shown to significantly improve surgical wound healing. Therefore, in the present study the modulating effect of Ca-pantothenic acid to subsequent stimulation with a variety of stimuli was investigated on isolated human PMN using functional assay systems: Lucigenin-dependent chemiluminescence (CL), release of myeloperoxidase (MPO). Ca-Panthotenate significantly inhibited the CL response of PMN upon stimulation with the chemotactic petide f-met-leu-phe, the tumor promotor PMA, and the granulocyte activating cytokines GM-CSF and TNF alpha at a concentration range of 5 to 50 mM, but not upon stimulation with opsonized zymosan. Moreover, Ca-Panthotenate significantly inhibited the release of myeloperoxidase from PMN upon stimulation with f-met-leu-phe at a concentration of 5 mM. In contrast, Ca-Panthotenate did not directly activate PMN in the assay systems tested. These in vitro results support the concept of an anti-inflammatory action of Ca-Panthotenate in vivo.

Proinflammatory cytokines differentially regulate hyaluronan synthase isoforms in fetal and adult fibroblasts.

Kennedy CI, Diegelmann RF, Haynes JH, Yager DR Department of Surgery, Medical College of Virginia Hospitals, Virginia Commonwealth University, Richmond, USA.

J Pediatr Surg 2000 Jun;35(6):874-9

BACKGROUND/PURPOSE: Fetal wound healing is a relatively scarless process that occurs in an hyaluronan-rich environment. Understanding the regulation of hyaluronan expression may provide insight into the process of fetal repair. Therefore, the purpose of this study was to compare the regulation of hyaluronan and hyaluronan synthase transcripts by the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in human adult and fetal fibroblasts.

METHODS: Hyaluronan deposited in the medium of untreated fibroblasts or fibroblasts treated with either IL-1beta or TNF-alpha was determined by an assay utilizing iodine I 125-hyaluronan binding protein. HAS transcript levels were compared in using a ribonuclease protection assay.

RESULTS: IL-1beta induced an increase in hyaluronan accumulation by both fetal and adult fibroblasts. In contrast, TNF-alpha induced higher levels of hyaluronan only in fetal fibroblasts. HAS-2 and HAS-3 transcript levels were constitutively expressed by both fetal and adult fibroblasts. Proinflammatory cytokines induced a differential increase in HAS-1 and HAS-3 transcript levels.

CONCLUSIONS: Differential regulation was observed in hyaluronan accumulation and for HAS transcript levels in fetal and adult dermal fibroblasts. The muted response of fetal fibroblasts to cytokines may be relevant to the minimal inflammation associated with fetal repair.

Arginine stimulates wound healing and immune function in elderly human beings.

Kirk SJ, Hurson M, Regan MC, Holt DR, Wasserkrug HL, Barbul A. Department of Surgery, Sinai Hospital of Baltimore, MD 21215.

Surgery 1993 Aug;114(2):155-9; discussion 160

BACKGROUND. Experimentally, arginine enhances immune function and promotes wound healing. In this randomized double-blind study we investigated the effect of oral arginine supplementation on wound healing and T-cell function in elderly human beings (more than 65 years of age).

METHODS. Thirty elderly, healthy, human volunteers (15 men and 15 women) received daily supplements of 30 gm arginine aspartate (17 gm free arginine). Fifteen volunteers (nine men and six women) received a placebo syrup. Fibroplastic wound responses were assessed by inserting a polytetrafluoroethylene catheter subcutaneously into the right deltoid region. Epithelialization was examined by creating a 2 x 2 cm split thickness wound on the lateral aspect of the upper thigh. Mitogenic response of peripheral blood lymphocytes to concanavalin A, phytohemagglutinin, pokeweed mitogen, and allogeneic stimuli was assayed at the beginning and end of supplementation. Polytetrafluoroethylene catheters were analyzed for alpha-amino nitrogen (assessment of total protein accumulation), hydroxyproline (index of reparative collagen synthesis), and DNA accumulation (index of cellular infiltration).

RESULTS. Arginine supplementation for 2 weeks significantly enhanced wound catheter hydroxyproline accumulation (26.49 +/- 2.39 nmol/cm vs 17.41 +/- 2.04 nmol/cm) and total protein content (43.47 +/- 3.85 micrograms/cm vs 21.95 +/- 2.5 micrograms/cm). Arginine did not influence the DNA content of the catheters or the rate of epithelialization of the skin defect. Peripheral blood lymphocyte responses to mitogenic and allogenic stimulation were greater in the arginine supplemented group. Serum insulin-like growth factor-1 levels were significantly elevated in the arginine group.

CONCLUSIONS. The data suggest that arginine supplementation may improve wound healing and immune responses in the elderly.

[The modern approach to wound treatment]. [Article in Serbo-Croatian (Roman)]

Komarcevic A. Institut za zdravstvenu zastitu dece i omladine Klinika za decju hirurgiju, Medicinski fakultet, Novi Sad. komarac@Eunet.yu

Med Pregl 2000 Jul-Aug;53(7-8):363-8

INTRODUCTION: Wound healing is a complex process involving interactions among a variety of different cell types. The normal wound repair process consists of three phases--inflammation, proliferation, and remodeling that occur in a predictable series of cellular and biochemical events. Wounds are classified according to various criteria: etiology, lasting, morphological characteristics, communications with solid or hollow organs, the degree of contamination. In the last few years many authors use the Color Code Concept, which classifies wounds as red, yellow and black wounds. This paper presents conventional methods of local wound treatment (mechanical cleansing, disinfection with antiseptic solutions, wound debridement--surgical, biological and autolytic; wound closure, topical antibiotic treatment, dressing), as well as general measures (sedation, antitetanous and antibiotic protection, preoperative evaluation and correction of malnutrition, vasoconstriction, hyperglycemia and steroid use, appropriate surgical technique, and postoperative prevention of vasoconstriction through pain relief, warming and adequate volume resuscitation). THE ROLE OF PHYSIOLOGICAL FACTORS AND ANTIMICROBIAL AGENTS IN WOUND HEALING: Growth factors play a role in cell division, migration, differentiation, protein expression, enzyme production and have a potential ability to heal wounds by stimulating angiogenesis and cellular proliferation, affecting the production and the degradation of the extracellular matrix, and by being chemotactic for inflammatory cells and fibroblasts. There are seven major families of growth factors: epidermal growth factor (EGF), transforming growth factor-beta (TGF-beta), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), interleukins (ILs), and colony-stimulating factor (CSF). Acute wounds contain many growth factors that play a crucial role in the initial phases of wound healing. The events of early wound healing reflect a finely balanced environment leading to uncomplicated and rapid wound healing. Chronic wounds, for many reasons, have lost this fine balance. Multiple studies have evaluated the effect that exogenously applied growth factors have on the healing of chronic wounds. In the study conducted by Knighton and colleagues, topical application of mixture of various growth factors (PDGF, TGF-beta, PDAF, PF4, PDEGF) demonstrated increased wound healing over controls. Brown and associates demonstrated a decrease in skin graft donor site healing time of 1 day using topically applied EGF. Herndon and ass. used systemic growth hormone in burned children and reduction in healing time made a significant clinical difference by allowing earlier wound coverage and decreasing the duration of hospitalization. The TGF family of growth factors is believed to be primarily responsible for excessive scar formation, especially the beta 1 and beta 2 isoforms. TGF-beta 3 isoform has recently been described and may have an inhibitory function on scar formation by being a natural antagonist to the TGF-beta 1 and TGF-beta 2 isoforms. Cytokines, especially interferon-alpha (INF-alpha), INF-alpha, and INF-alpha 2b, may also reduce scar formation. These cytokines decrease the proliferation rate of fibroblasts and reduce the rate of collagen and fibronectin synthesis by reducing the production of mRNA. Expression of nitric oxide synthase (NOS) and heat shock proteins (HSP) have an important role in wound healing, as well as trace elements (zinc, copper, manganese). Applications of some drugs (antioxidants--asiaticoside, vitamin E and ascorbic acid; calcium D-pantothenate, exogenous fibronectin; antileprosy drugs--oil of hydnocarpus; alcoholic extract of yeast) accelerate wound healing. Thymic peptide thymosin beta 4 (T beta 4R) topically applicated, increases collagen deposition and angiogenesis and stimulates keratinocyte migration. Thymosin alpha 1 (T alpha 1R), peptide isolated from the thymus, is a potent chemoattractant which accelerates angiogenesis and wound healing. On the contrary, steroid drugs, hemorrhage and denervation of wounds have negative effect on the healing process.

Fetal wound repair results in scar formation in Interleukin-10-deficient mice in a syngeneic murine model of scarless fetal wound repair.

Liechty KW, Kim HB, Adzick NS, Crombleholme TM. Children's Institute for Surgical Science at The Children's Hospital of Philadelphia, The University of Pennsylvania School of Medicine, 19104, USA.

J Pediatr Surg 2000 Jun;35(6):866-72; discussion 872-3

BACKGROUND: Fetal dermal wound healing is characterized by minimal inflammation, restoration of normal dermal architecture, and scarless repair. The authors have shown that proinflammatory cytokines Interleukin-6 (IL-6) and Interleukin-8 (IL-8) are diminished during fetal wound repair. Interleukin-10 (IL-10) is an antiinflammatory cytokine that decreases production of IL-6 and IL-8. The authors hypothesized that diminished IL-6 and IL-8 and minimal inflammation may be caused by IL-10.

METHODS: To test this hypothesis, the authors developed a new syngeneic murine model of fetal wound repair in which 15-day-gestation skin from either normal C57BL/6 or transgenic C57BL/6 IL-10 knockout mice was grafted to the back of the same strain adult mice. The grafts were incisionally wounded after 5 days, harvested at 1 week, and analyzed for inflammatory response and scar formation.

RESULTS: Wounds in normal fetal skin grafts showed minimal inflammation and normal dermal reticular collagen pattern at the site of the wound, consistent with scarless repair. In contrast, wounds in IL-10 knockout fetal skin grafts showed significant inflammation and scar formation.

CONCLUSIONS: Fetal skin grafts on adult syngeneic mice heal without inflammation or scar formation. The absence of IL-10 in fetal skin results in scar formation.Intrinsic lack of IL-10 may result in continued amplification of the inflammatory cytokine cascade, continued stimulation of fibroblasts, and abnormal collagen deposition. IL-10 is necessary for scarless wound repair to occur.

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