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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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